Guidance On Medicinal Product Registration in Singapore 2009 - Complete With Appendices

GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE

Effective 1 January 2009
Please visit HSAs website at http://www.hsa.gov.sg for the latest
update
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 2 of 64

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TABLE OF CONTENTS

GENERAL OVERVIEW
1 Foreword........................................................................................................................... 7

MEDICINAL PRODUCT REGISTRATION
2 Application Types..............................................................................................................8
3 Dossier Types ................................................................................................................... 9
4 Dossier Format................................................................................................................ 11

REGISTRATION PROCESS
5 Pre-Submission Preparations ......................................................................................... 12
6 Application submission.................................................................................................... 13
6.1 PRISM Application.............................................................................................. 13
6.2 Dossier Requirements ........................................................................................ 31
6.2.1 NDA submissions.................................................................................. 31
6.2.2 GDA Submissions................................................................................. 34
6.3 Submission Requirements.................................................................................. 36
6.3.1 Hardcopy And Softcopy Requirements................................................. 37
6.4 Documentary Requirements............................................................................... 38
6.4.1 Language.............................................................................................. 38
6.4.2 Administrative Documents .................................................................... 40
6.4.3 CTD Overview and Summaries ............................................................ 44
6.4.4 Quality Documents................................................................................ 45
6.4.5 Non-clinical Documents ........................................................................ 48
6.4.6 Clinical Documents ............................................................................... 49
7 Application Screening ..................................................................................................... 49
8 Application Evaluation..................................................................................................... 50
9 Regulatory Decision........................................................................................................ 50

POST-APPROVAL PROCESS
10 Post-Approval Changes .................................................................................................. 52
10.1 Dossier Format ................................................................................................... 53
10.2 Variation Application Process............................................................................. 53
10.3 Major Variation Applications ............................................................................... 54
10.3.1 MAV-1 Applications............................................................................... 55
10.3.2 MAV-2 Applications............................................................................... 59
10.4 Minor Variation Applications ............................................................................... 60

OTHER INFORMATION
11 Data Protection and Data Exclusivity.............................................................................. 62
12 Patent Linkage................................................................................................................ 62
13 Responsibilities of the Applicant ..................................................................................... 63
14 Fees ................................................................................................................................ 64


LIST OF APPENDICES

APPENDIX 1 Target Processing Timelines

APPENDIX 2 Application Checklist (ICH CTD)

APPENDIX 3 Application Checklist (ACTD)

APPENDIX 4 Guideline on Submission for Non-Prescription Medicinal Products

APPENDIX 5 Flowchart for Translation of Non-English Documents

APPENDIX 6 Points to Consider for Singapore Labelling

APPENDIX 7 Patent Declaration Form

APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs

APPENDIX 9 Singapore Quality Overall Summary for Biologics

APPENDIX 10 Guideline on the Registration of Human Plasma-derived Medicinal
Products

APPENDIX 11 Guideline on the Registration of Human Medicinal Products Containing
Materials of Animal Origin

APPENDIX 12 Product Interchangeability and Biowaiver Request for Chemical
Generic Drug Applications

APPENDIX 12A Quick Reference for Acceptability of Bioequivalence Study

APPENDIX 13 MIV Filing and Submission Inquiry Form

APPENDIX 14 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for
Chemical Drugs

APPENDIX 14A Checklist for Minor Variation Applications (MIV-1) for Chemical Drugs

APPENDIX 14B Checklist for Minor Variation Applications (MIV-2) for Chemical Drugs

APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics

APPENDIX 15A Checklist for Minor Variation Applications (MIV-1) for Biologics

APPENDIX 15B Checklist for Minor Variation Applications (MIV-2) for Biologics


ABBREVIATIONS AND ACRONYMS

ACRA Accounting and Corporate Regulatory Authority
ACTD ASEAN Common Technical Document
ACTR ASEAN Common Technical Requirements
ADEC Australian Drug Evaluation Committee
ASEAN Association of Southeast Asian Nations
ATC Anatomical Therapeutic Chemical
BA Bioavailability
BAN British Approved Name
BE Bioequivalence
BP British Pharmacopoeia
BSE Bovine Spongiform Encephalopathy
BWP Blood Working Party
CAS Chemical Abstracts Service
CEP Certificate of Suitability (Ph Eur monograph)
CHMP Committee for Medicinal Products for Human Use (formerly Committee
for Proprietary Medicinal Products) (EU)
CJD Creutzfeldt-Jakob Disease
CMC Chemistry, Manufacturing and Controls
CMI Consumer Medicine Information
CMS Concerned Member State
COO Country of Origin (Finished product manufacturer)
CPP Certificate of Pharmaceutical Product
CPMP Committee for Proprietary Medicinal Products
CTD Common Technical Document
CVMP Committee for Medicinal Products for Veterinary Use
CWD Chronic Wasting Disease
DMF Drug Master File
EDQM European Directorate for the Quality of Medicines
EMEA European Medicines Agency (formally the European Agency for the
Evaluation of Medicinal Products) (EU)
F2 Similarity factor
FDA Food and Drug Administration (US)
FTA Free Trade Agreement
GDA Generic Drug Application
GSL General Sale List medicine
GMP Good Manufacturing Practice
HBV Hepatitis B Virus
HCV Hepatitis C Virus
HIV Human Immunodeficiency Virus
HPLC High Performance Liquid Chromatography
HPRG Health Products Regulation Group
HSA Health Sciences Authority (Singapore)
ICH International Conference on Harmonisation (of Technical
Requirements for Registration of Pharmaceuticals for Human use)
INN International Non-proprietary Names
JP Japanese Pharmacopoeia
MAV Major Variation
MHRA Medicines and Healthcare Products Regulatory Agency (UK)
MIV Minor Variation
MQA Manufacturing and Quality Audit
NAT Nucleic Acid Test
NDA New Drug Application
NfG Note for Guidance
OIE Office International des Episooties

OTC Over-The-Counter
P Pharmacy only medicine
PD Pharmacodynamics
PDF Portable document format
Ph Eur European Pharmacopoeia
PI Package Insert (Singapore), Product Information
PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection
Co-operation Scheme
PIL Patient Information Leaflet
PK Pharmacokinetics
PMF Plasma Master File
POM Prescription Only Medicine
PRISM Pharmaceutical Regulatory and Information System
QOS Quality Overall Summary
RH Relative Humidity
RMS Reference Member State
RNA Ribonucleic Acid
RSD Relative Standard Deviation
SMF Site Master File
SmPC Summary of Product Characteristics
SOP Standard Operating Procedure
SQOS Singapore Quality Overall Summary
TGA Therapeutic Goods Administration (Australia)
TRIPS Trade-Related Aspects of Intellectual Property Rights
TSE Transmissible Spongiform Encephalopathy
UK United Kingdom
URL Uniform Resource Location
US United States
USA United States of America
USAN United States Adopted Name
USP United States Pharmacopeia
vCJD Variant Creutzfeldt-Jakob Disease
WHO World Health Organisation
WTO World Trade Organisation


GENERAL OVERVIEW

1 FOREWORD

This guidance document is intended to provide assistance in the submission of
applications relating to medicinal products in Singapore, including applications for a new
Product Licence for a medicinal product (i.e. drug registration) and applications to make
variations to an existing Product Licence.

This document should be read in conjunction with the current laws governing
pharmaceutical products in Singapore, which includes the following:

Medicines Act (Chapter 176)
Poisons Act (Chapter 234)
Misuse of Drugs Regulations subsidiary legislation under the Misuse of Drugs
Act (Chapter 185)
Sale of Drugs Act (Chapter 282)
Medicines (Advertisement and Sale) Act (Chapter 177)

If there is any contradiction between this document and any written law, the latter shall
take precedence.

As the licensing authority under the Medicines Act, the Chief Executive of the Health
Sciences Authority (HSA) and the officers in HSAs Health Products Regulation Group
(HPRG) have the authority to grant, renew, vary, suspend and revoke licences and
certificates under the Medicines Act. Applicants are strongly encouraged to familiarise
themselves with the contents of this guidance document before submitting their
applications.

1.1 Scope of this guidance document

This guidance document describes the procedures and requirements for submitting an
application to obtain a new Product Licence or to make variations to an existing
registered medicinal product.

Applicants are expected to comply with the procedures and requirements laid out in this
guidance. However, alternative approaches to the specified procedures and requirements
may be accepted, provided there is adequate scientific evidence and justification. Any
alternative approach should be discussed with HSA and agreed upon in advance in order
to avoid rejection of the application. Conversely, HSA may request for information or
specify conditions not described in this document but is deemed necessary to adequately
assess the safety, efficacy and quality of the product under evaluation.

Take note that, within this document, the term quality may be used to describe chemical,
pharmaceutical and biological data while the term non-clinical may be used to describe
preclinical, pharmacological and toxicological data.

Applicants are advised to check HSAs website
1
for the latest version of this guidance
document and other related medicinal product registration guidelines.

1
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

MEDICINAL PRODUCT REGISTRATION

Under the Medicines Act, a medicinal product refers to any substance or article (not
being an instrument, apparatus or appliance) which is manufactured, sold, supplied,
imported or exported for use wholly or mainly in the following ways:
use by being administered to one or more human beings for a medicinal purpose;
and/or,
use as an ingredient in the preparation of a substance or article which is to be
administered to one or more human beings for a medicinal purpose.

A medicinal purpose means any one or more of the following purposes:
treating or preventing disease;
diagnosing disease or ascertaining the existence, degree or extent of a
physiological condition;
contraception;
inducing anaesthesia; and/or,
otherwise preventing or interfering with the normal operation of a physiological
function, whether permanently or temporarily, and whether by way of terminating,
reducing or postponing, or increasing or accelerating, the operation of that
function or in any other way.

Unless otherwise exempted under the law, a Product Licence is required before a
medicinal product can be sold or supplied in Singapore (Medicines Act, section 5). Each
Product Licence is specific to a product:
of a particular name;
with a particular formulation;
in a particular dosage form (i.e. physical presentation) and strength; and
with a particular set of approved indications and directions for use.

Any changes to the above parameters may result in the need to submit an application to
vary the existing Product Licence or possibly obtain a new Product Licence altogether.

2 APPLICATION TYPES

In applying for a new Product Licence for a medicinal product in Singapore, there are two
types of applications: a new drug application (NDA) and a generic drug application
(GDA):

NDA New Drug Application for an innovator product
NDA-1

:
For the first strength of an innovator product containing a new
chemical
entity or a biological entity.
NDA-2
:
For the first strength of an innovator product
containing a new* combination of registered chemical/biological
entities;
containing registered chemical/biological entity(ies) in a new dosage
form;
containing registered chemical/biological entity(ies) for use by a
different route of administration and marketed under a different product
name; or,
containing registered chemical/biological entity(ies) for new
indication(s), dosage recommendation(s) and/or patient population(s)
and marketed under a different product name.

has not been registered for medicinal use in Singapore


NDA-3
:
For subsequent strength(s) of an innovator product that has been
registered or has been submitted as an NDA-1 or NDA-2. The product
name and pharmaceutical dosage form shall be the same as that for the
NDA-1 or NDA-2.

GDA Generic Drug Application for a product that is essentially similar to a currently
registered product in Singapore (not applicable to biologics).
GDA-1 : For the first strength of a generic product.
GDA-2 : For subsequent strength(s) of the generic product that has been
registered or has been submitted as a GDA-1. The product name and
pharmaceutical dosage form shall be the same as that for the GDA-1.

A schematic diagram to illustrate the various types of applications is seen in Figure 1
below:

Figure 1. Schematic diagram of application routes for drug registration.

3 DOSSIER TYPES

There are three types of evaluation dossiers for a new drug application. Figure 2 below is
a schematic diagram to illustrate the various types of evaluation dossiers:

Figure 2. Schematic diagram of evaluation dossiers for drug registration.

IS PRODUCT
REGISTERED?
Post-Approval
Process section
First strength of
product?
Essentially similar
to a currently
registered product?
NDA 1
Contains new
chemical/
biological entity?
NO
YES
YES
NO
NDA 2
NDA 3
GDA 1
GDA 2
NO
NO
YES
YES
Approved by at
least two of HSAs
reference
agencies?
NDA 1
Is product
registered with
any competent
agency?
NO
NDA 2
NDA 3
FULL DOSSIER
ABRIDGED
DOSSIER
YES
NO
YES
VERIFICATION
DOSSIER

3.1 Full Dossier

The full dossier evaluation route applies to a drug product that has not been approved by
any competent drug regulatory agency at the time of submission for registration to HSA.
This route applies to an innovator product containing a new chemical/biological entity,
new combination of chemical/biological entities or an innovative use of a registered
product.

3.2 Abridged Dossier

The abridged evaluation route applies to a drug product that has been evaluated and
approved by at least one competent drug regulatory agency.

3.3 Verification Dossier

The verification evaluation route applies to a medicinal product that has been evaluated
and approved by at least two of the following HSAs reference drug regulatory agencies:

Australia Therapeutic Goods Administration (TGA);
Health Canada (HC);
US Food and Drug Administration (FDA);
the European Medicines Agency (EMEA)*; or
UK Medicines and Healthcare Products Regulatory Agency (MHRA)
#
.

*
For products approved via the Centralised Procedure.
#

For products approved by UK MHRA through the national procedure or where the UK MHRA acted as the
Reference Member State (RMS) for the Decentralised and Mutual Recognition Procedures in Europe.

However, approval by these reference regulatory agencies does not obligate HSA to
approve the application.

A verification dossier must be submitted within 3 years from the date of approval by the
chosen primary reference agency. The primary reference agency is defined as the
reference agency for which the qualifying supporting documents, as outlined in this
guidance, will be submitted by the applicant.

The approved indication(s), dosing regimen(s), patient group(s), and/or direction(s) for
use must be similar across the reference regulatory agencies. If there are apparent
differences, the application will be re-routed to the abridged route. HSA reserves the right
to accept only the most stringent indication(s), dosing regimen(s), patient group(s) and/or
direction(s) of use amongst those approved by the reference regulatory agencies.

Furthermore, all aspects of the drug products quality must be identical as that currently
approved by the chosen primary reference regulatory agency that has evaluated and
approved the product. This includes, but is not limited to, the formulation, site(s) of
manufacture, release and shelf life specifications, primary packaging and the PI/PIL.

HSA will not accept a verification dossier if the application falls within one of the
categories listed below:
The product is a biologics;
The product and its intended use including indication(s), dosing regimen(s) and
patient group(s) have been rejected, the application withdrawn from, approved via
appeal process or pending deferral by a competent drug regulatory agency for
safety and/or efficacy reasons;

The product needs a more stringent assessment as a result of differences in local
disease patterns and/or medical practices (e.g. blood products, vaccines and
some anti-infectives).

For a product with a proposed indication that has been designated as an orphan drug by
at least one reference agency, or a product that has been approved by at least one
reference agency via accelerated/fast-track approval, approval under exceptional
circumstances, or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.

4 DOSSIER FORMAT

Applications shall be submitted to HSA using the Common Technical Document (CTD)
format. The CTD provides a common format for the preparation of a well-structured
submission dossier. It uses a modular framework described in ICH Topic M4
2
or the
ASEAN guidances on the Common Technical Document for Registration of
Pharmaceuticals for Human use: Organisation of the Dossier
3
. This guidance document
should be read in conjunction with the most recent version of the ICH CTD and the
ASEAN CTD (ACTD) guidance documents.

Thus, submission will be in one of the two formats, either the ICH CTD or the ACTD
format. According to the chosen format, in each application, the documents will be
grouped into five Modules (ICH CTD) or four Parts (ACTD); the main differences between
these two formats are the numbering and naming of the sections, as seen in Table 1
below:

Documents Location in
ICH CTD ACTD
Administrative Documents and
Product Information
Module 1 Part 1
Common Technical Document
Overview and Summaries
Module 2 Incorporated in Parts 2, 3 and 4
Quality documents

Module 3 Part 2
Non-clinical documents

Module 4 Part 3
Clinical documents Module 5 Part 4

Table 1. Format of the ICH CTD and ACTD.

The CTD format cannot be changed once the application is approved. Any subsequent
variation applications for the product would need to follow the same format.

2
http://www.ich.org/
3
NOTE: It is important to note that the implementation and use of the CTD
represents a work in progress. It is expected that future refinements to this
guidance document will continue to be necessary as a result of experience
gained.

REGISTRATION PROCESS

One part of a Product Life Cycle is the pre-marketing activities, namely registration of a
product prior to market entry. The registration process involves a series of steps as can
be seen in Figure 3 below:

Figure 3. Registration Process for a Medicinal Product

5 PRE-SUBMISSION PREPARATIONS

This first step in the registration process is one of the most important because it involves
compiling all of the necessary documents into a CTD format for submission to HSA.
However, if questions arise or clarification is needed during the preparations, the
applicant is encouraged to contact HSA via one of two methods:

1. Pre-Submission Inquiry via e-mail
2. Pre-Submission Consultation

PRE-SUBMISSION
PREPARATIONS
APPLICATION
SUBMISSION
APPLICATION
SCREENING
APPLICATION
EVALUATION
REGULATORY
DECISION
POST-APPROVAL
CHANGES
NON-ACCEPTANCE /
WITHDRAWAL
ACCEPTANCE

5.1 Pre-Submission Inquiry

The applicant may submit a Pre-Submission Inquiry via e-mail if any clarification is
needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Pre-
submission inquiry, in order for the e-mail to be sent to the relevant officer.

Once the inquiry has been received, an officer will look into the matter and a response will
be sent back to the applicant.

5.2 Pre-Submission Consultation

For larger or complex issues relating to an impending submission, applicants are advised
to consult with HSA in a pre-submission consultation. The request for a consultation
should be made in writing, with the purpose and agenda for the consult stated, via email
to HSA_MedProd_Registration@hsa.gov.sg.

For a full dossier submission, the applicant is required to notify HSA two months prior to
the intended submission date of the application dossier.

Advice given by HSA will be based on knowledge that is current at the time of the
consultation. However, such advice is not binding and does not have direct bearing on
the eventual outcome of the application concerned.

6 APPLICATION SUBMISSION

There are two parts in submitting an application for product registration: through on-line
PRISM and CTD dossier submission.

6.1 PRISM Application

HSA only accepts applications on-line via PRISM (Pharmaceutical Regulatory and
Information System). Applicants are advised to visit the prism@hsa
4
webpage for further
details on PRISM.

A separate product licence, and therefore a separate application form, would be required
for each pharmaceutical dosage form and strength of the medicinal product. Separate
application forms are also required for the following:
Powder for injections containing different amounts of drug substance per
container;
Concentrates for reconstitution labelled with the actual amount of drug substance
before reconstitution; and,
Pre-filled syringes.

Examples are listed in the table on the next page:

4
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism.html

Examples Labelled strength
before reconstitution
Application type
25mg/vial 1 Powder for
Injection 50mg/vial
Submit as 2 separate applications:
One as NDA-1/GDA-1 and the other as NDA-3/GDA-2
2mg/ml in a vial 2 Solution for
Injection 2mg/ml pre-filled syringe
10mg/5ml 3 Concentrate
20mg/10ml
4 Concentrate 2mg/ml: presented in
5ml vial and 10ml vial
Submit as a single application with two pack sizes
(i.e., 5ml and 10ml)
100 iu/ml 5 Pre-filled
syringe 400 iu/4 ml

6.1.1 PRISM section 1 Company Particulars

Each application for a Product Licence is company-specific. The company named in this
section must be based and registered in Singapore. The company must be authorised by
a responsible person in the company or organisation that owns the medicinal product
before it can apply for a Product Licence for a specific medicinal product in Singapore.

In this section, input the company telephone and fax numbers; the name, address and
Business Registration number will be automatically entered. If there is a direct telephone
and/or fax number, input it into this section to ensure no communication delays between
HSA and the applicant.

The company bears full responsibility for ensuring that all available and relevant
information is submitted in support of an application. For every successful application for
registration of a medicinal product granted approval, a Product Licence will be issued in
the name of the company, which will be the product licence holder.

6.1.2 PRISM section 2 Applicant Particulars

The person named in this section should be a permanent staff of the company and
residing in Singapore. If the applicant is an external party engaged by the applicant
company to submit the application on their behalf (i.e. consultant), an original letter of
authorisation from the applicant company must be submitted (see section 6.5.2
Administrative Documents Authorisation Letters).

In this section, input the particulars of the named person name, NRIC/FIN and
designation. For PRISM sections 2.4 and 2.5, the company address and contact details
(as in PRISM section 1) may be entered as an alternative, as seen in the example on the
next page:


Care should be taken to ensure that the contact details are entered correctly to ensure no
communication delays between HSA and the applicant. Applicants are advised to
immediately notify HSA if there is any change to this PRISM section, especially to the
contact details.

From this point on, any mention of the word applicant in this guidance document will
refer to the person named within this PRISM section.

6.1.3 PRISM section 3 Application Details

In this PRISM section, enter specific details of the application, such as the application
type, dossier type, format type and any reference product(s), if applicable. Below is an
example of PRISM section 3:

Company address
may be entered
Direct telephone and
fax numbers in
company may be
entered

Type of Application (section 3.1)

Input the type of application to be submitted to HSA.

If the type of application is entered incorrectly, and it needs to be changed
within the same application type (e.g. from NDA-2 to NDA-3), HSA will send an
Input Request to allow the amendment; or,
to a different application type (e.g. NDA-1 to GDA-1), then the original PRISM
application must be withdrawn first before re-submission under the correct
application type.

HSA reserves the right to re-categorise the application type when appropriate.

Type of Product (section 3.2)

Input either Chemical Drug for chemical drug products or Biological Drug for biologic
drug products. Please note that once the product type is set, it cannot be changed.

A biological medicinal product (a biologic) refers to products derived from biological
systems, which include:
Whole cells or organisms, e.g. whole virus/bacterium used as a vaccine;
Part of organisms, e.g. sub-unit vaccines, blood/serum-derived products;
Macromolecules extracted from or produced by organisms, e.g. proteins, nucleic
acids, proteoglycans, cytokines and growth factors; and,
Biotechnology products, e.g. recombinant hormones, enzymes, antibodies, DNA
vaccines;
but does not include:
Metabolites from micro-organisms, e.g. antibiotics; and,
Macromolecules produced by chemical synthesis, e.g. peptides/oligo-nucleotides
produced by chemical synthesisers.

Applicants are advised to contact HSA, via Pre-Submission Inquiry or consultation, as
stated in section 5.1 of this document, when in doubt on whether the drug product is
considered a chemical or biologic drug.

Reference Product (section 3.3)

This section refers only to GDA-1, GDA-2 or NDA-3 applications.

For all GDA applications, applicants need to specify the Singapore Reference Products
SIN number, which can be obtained by searching HSAs online database
5
. If a GDA-2
application is not submitted at the same time as a GDA-1 application, applicants are
required to specify both the Singapore Reference Products and the GDA-1 products SIN
numbers. If an NDA-3 application is not submitted at the same time as an NDA-1 or NDA-
2 application, then, the Singapore-registered NDA-1 or NDA-2 products SIN number
should be inputted.

Type of Dossier (section 3.5)

Only one option can be selected from the drop-down menu full, abridged or verification.

HSA reserves the right to re-categorise the dossier type when appropriate. The applicant
will be informed if re-categorisation is necessary.

5
http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load

Type of Format (section 3.6)

Indicate whether the dossier format is ICH CTD or ACTD. Once the format type has been
set in PRISM, it cannot be changed.

Applicants are expected to organise the documents into the respective CTD sections
before submitting the dossier to HSA. Explanatory notes on the documents required can
be found in section 6.5 Documentary Requirements of this guidance.

6.1.4 PRISM section 4 Product Information

Product Name (section 4.1)

The Product Name is the products trade name that is shown on the product labelling
i.e. inner label, outer carton, package insert (PI) and/or patient information leaflet (PIL).

Applicants should ensure that the medicinal product name:
does not suggest greater safety or efficacy than that supported by clinical data;
does not imply superiority over another similar product in Singapore;
does not imply the presence of substance(s) not present in the product; and
shall not be confused with another product.

If the proposed product name is not acceptable, the applicant will be informed of the
reasons at the screening stage, and will be asked to amend it.

For this PRISM section, the Product Name should be entered in the following format:

Product Name
Pharmaceutical
Dosage Form
Product Strength
Product Standard
(optional)

Applicants are advised to use the same format for the product labelling and PI/PIL.
However, in the PI, the International Non-proprietary Name (INN) or common name of the
active substance(s) may be used when referring to the active ingredient(s)s properties.

The product strength represents the amount of the active substance in the
pharmaceutical dosage form, which is stated as per unit dose or concentration.
Concentration can be stated as a unit of mass (e.g. mg/g), a unit of volume (e.g. mg/mL)
or as a percentage (e.g. %w/v or %w/w).

For specific pharmaceutical dosage forms, there are additional points to take note of as
seen in the table on the next page:

ABC Injection 5mg/ml USP
Medicinal Product Name

Product Format Example
Fixed-combination Strength of each active
ingredient separated by a /
Multi-Tab Tablet
100mg/25mg
Single-dose preparation,
total use
State the amount of active
ingredient per unit dose
Ingredient 300mg per vial
Multi-dose preparation State the concentration per mL, per puff, per drop,
per kg, per m
2
, etc.
Powder for reconstitution,
oral
State the concentration after
reconstitution
Antibiotic 200mg/5mL
Powder for reconstitution,
injection or infusion
State the amount of active
ingredient before reconstitution
or dilution
Ingredient 300mg per vial
Transdermal patches State the amount of active
ingredient released in 24 hours
Trans-Patch 24mg/24 hrs

Product Formula (section 4.2)

The Product Formula is a list of all of the active substance(s) and excipients (including
water) that are present in the final pharmaceutical dosage form.

The name for each ingredient should be listed by its INN. Proper or commercial names
for ingredients such as printing inks or colourants are permissible but internal
abbreviations, acronyms or codes for any ingredient are not acceptable. Ingredients
related to the pharmaceutical dosage form, such as tablet film coating or capsule shell,
should be indicated within parentheses before the ingredient name see the next page
for an example:


The grade for each ingredient should be specified e.g. BP, USP, Ph. Eur., JP or in-
house.

Quantities of each active substance and excipient must be expressed in international
units of measure, wherever appropriate. If an active substance is present in the form of a
salt, the quantity should be clearly stated in the following format:

XX phosphate (active substance salt) 32mg eqv XX.

Information on residual amounts of certain materials, such as antibiotics, thiomersal and
materials of biological origin (e.g. human serum albumin), added or present in the drug
product must be declared. Information to declare includes the following:
the materials name enter (Residual), followed by the materials name in the
Name of Substance field;
the materials grade, if applicable;
the materials limit in the product enter , followed by the limit in the Strength
field.

An example is shown in the screenshot on the next page:

Film coating ingredient
Printing ink
Enter the strength of
the active substance
base here.

Ingredients Derived From Human Blood/Animal Sources (section 4.3)

A screenshot of PRISM section 4.3 is seen below:

Ingredients Derived From Human Blood (4.3(a))

Human plasma-derived products used as an active substance, as an excipient or within
the manufacturing process, must be declared in this PRISM section.

If the answer is Yes, the following information must be inserted as per the format below:
the source product the ingredient is derived from i.e. the species and nature of
the product;
its role in the drug product i.e. as an active substance, excipient or within the
manufacturing process; and,
the country of the source product.

A screenshot of PRISM section 4.3(a) is given on the next page:

This strength will
actually be entered here

If constrained by PRISMs text limit, reference to a document uploaded into PRISM
section 7 is permissible e.g. Yes see file xyz.doc attached in PRISM.

Ingredients Derived From Animals (4.3(b))

Animal-derived materials used either as an excipient or within the manufacturing process
must be declared in this PRSIM section.

If the answer is Yes, the following information must be inserted as per the format below:
the source product and species the ingredient is derived from;
its role in the drug product (i.e. excipient or within the manufacturing process);
and,
the country of the source product.

If constrained by PRISMs text limit, reference to a document uploaded into PRISM
section 7 is permissible e.g. Yes see file xyz.doc attached in PRISM.

Pharmacotherapeutic Group (section 4.4)

Indicate the WHO Anatomical Therapeutic Chemical (ATC) code for each distinct
therapeutic indication proposed for a product, if available. Applicants may refer to the
WHO Collaborating Centre for Drug Statistics Methodology
6
for the ATC Code and more
information.

6
http://www.whocc.no/
NOTE: additional information is required when human plasma-derived products are used.
Refer to Appendix 10 for details on the data requirements for submission.
NOTE: refer to Appendix 11 for details on the data requirements for submission.

Dosage Form (section 4.5)


The dosage form is the pharmaceutical dosage form of the drug product, e.g. tablet,
injection and cream. The dosage form should be as specific as possible because each
form is considered distinct e.g. effervescent powder, powder for reconstitution,
modified-release tablet and gastro-resistant capsule. In certain cases, the dosage form
may also include information about the container closure system e.g. pre-filled syringe,
spray pump and pressurised container.

Route of Administration (section 4.6)

A screenshot of PRISM section 4.6 is given below:

Include all routes of administration proposed for the product.

Choose from the droplist
and Save before adding
another option

Packaging, Shelf Life and Storage Conditions (section 4.7)


Container Closure System (CCS) (section 4.7.1) refers to the container immediately
enclosing the dosage form. Information should be specific, including the type of
material(s) used, colour, size, etc. For example, 1mL Type I amber glass vial and
PVC/PVdC blister with Alu foil.

Quantity per CCS (section 4.7.2) refers to the quantity/amount of the dosage form per
container closure system. For example, 10 tablets/blister, 5ml/vial and 15g/tube may
be entered.

CCS per Pack Size (section 4.7.5) refers to the number of container closure systems in
each commercial pack of the product. For example, for a commercial box of 50 tablets
packed as 5 blister strips of 10 tablets in each strip, the pack size should be 5.

Shelf Life (section 4.7.3) refers to the proposed shelf life of the drug product, which
should be supported by stability data. If there is more than one component in a drug
product (e.g. powder for injection and diluent as a composite pack) and each component
has a different shelf life, the shorter shelf life is to be used as the shelf life of the
composite pack. HSA reserves the right to amend the proposed shelf life after review of
the stability data submitted in the dossier.

Storage Condition (section 4.7.4) refers to the proposed storage condition of the drug
product for example, store below 25C, do not freeze, keep away from light, etc which
should be supported by stability data. HSA reserves the right to amend the proposed
storage condition after review of the stability data submitted in the dossier.

An example is shown on the next page:


Furthermore, information on shelf life after the first opening of the product (e.g. eye drops)
and shelf life after reconstitution (e.g. lyophilised powder for reconstitution) should be
provided and supported by stability data. The information should be inserted in PRISM
sections 4.7.6 and 4.7.7, respectively:

Forensic Classification (section 4.8)

State the forensic classification proposed for the drug product in Singapore.

Medicinal products approved for registration in Singapore are classified under three
forensic classes:
Prescription Only Medicine (POM);
Pharmacy only medicine (P); or
General Sale List medicine (GSL).

POM control is required in the following situations:
a) The product poses a direct
7
or indirect
8
danger to human health, even when used
correctly, if used without medical supervision;
b) The product is frequently and widely used incorrectly, and as a result is likely to
present a direct or indirect danger to human health;
c) The product requires further investigation into its activity and/or side effects; or,
d) The product is normally prescribed by a doctor or dentist to be administered
parenterally.

7
Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or of
high frequency
8
Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart
disease

The following also needs to be taken into consideration when deciding whether a product
should be classified as a POM:
i. Whether the product contains a substance which is listed in either the Narcotic Drug
Convention or the Psychotropic Substances Convention;
ii. Whether the product is likely, if incorrectly used to present medicinal abuse, lead to
addiction or used for illegal purposes;
iii. Whether the product contains a substance which by reason of its novelty or properties
has the potential to fall within point (ii) above;
iv. Whether the product, by reason of its pharmaceutical characteristics, is reserved for
treatments which can only be instituted in a hospital;
v. Whether the product is used in the treatment of conditions which must be diagnosed
in a hospital or in an institution with special diagnostic facilities; or,
vi. Whether the product is intended for outpatients but may produce serious side effects,
which would require medical supervision throughout the treatment.

P control is required for products that possess characteristics which are not sufficiently
critical to warrant POM control but for which the following apply:
a) Consultation with a pharmacist is necessary to confirm the appropriate choice of
therapy;
b) The contraindications, drug interactions, precautions or warnings need reinforcement
by a pharmacist or are not easily recognised by the purchaser; or,
c) Special precaution is needed in the storage and handling of the product.

GSL control is sufficient in the following situations:
a) The product is reasonably safe and can be sold or supplied without the need for
supervision by a registered doctor, dentist or pharmacist;
b) The contraindications, drug interactions, precautions and warnings are easily
recognised by the consumer; and,
c) The hazard to health, the risk of misuse, the risk of misdiagnosis, or the need to take
special precaution in the storage and handling the product is small.

HSA reserves the right to approve the product under a different forensic classification, as
deemed appropriate.

Registration Status in Other Countries (section 4.9)

Applicants are required to provide information on the registration status of the application
in other countries at the time of submission. A screenshot of PRISM section 4.9 is given
on the next page:


For each country, the applicant must state the application status and status date. For the
country of origin and all reference agencies, the applicant must state the application
status, status date, application details and forensic classification. This is described in
Table 2 below.

Country Application Status Status Date Application Details
APPROVAL State the approval
date

REJECTION or
WITHDRAWAL
State the date of
rejection/withdrawal
State the reason(s)
For all countries
DEFERRAL
e.g. non-approvable,
approvable, conditional
approval, conditional
marketing
authorization, etc.
State the date of
deferment
State the reason(s)
APPROVAL State the approval
date
State the approved
indication(s) and dosing
regimen(s)
PENDING
EVALUATION
State the
submission date
State the expected regulatory
decision date, if applicable
For all reference
agencies and
country of origin
(if applicable)
PENDING
SUBMISSION
- State the expected submission
date

Table 2. Registration Status of Drug Product in Other Countries.

For products approved via an appeal process, following either a negative
opinion/rejection/non-approvable decision or an approvable/conditional approvable
decision, the applicant must provide reasons for the initial regulatory decision along with
the subsequent approval.

The screenshot on the next page is an example of an entry into PRISM section 4.9:


For applications submitted to the European Union agencies, applicants should identify the
type of application i.e. centralised, decentralised, mutual recognition or national. For
decentralised and mutual recognition applications, the reference member state should be
indicated.

For products approved by the UK MHRA, applicants are required to indicate whether
approval was granted through the national procedure or whether the MHRA acted as
Reference Member State (RMS) or as Concerned Member State (CMS) for the
Decentralised and Mutual Recognition Procedures in Europe.

The applicant is required to update HSA on the registration status of any pending
applications in other countries while pending evaluation by HSA. The applicant shall
inform HSA of any rejection, withdrawal or deferral of any application and provide details
of the reason(s) once it becomes known.

In the event that the PRISM text space does not allow input of full details of the
indication(s), dosing regimen(s), and/or reason(s), a brief description may be entered.
The full details should be attached in softcopy (PDF) in PRISM section 7 (Supporting
Attachments) and in hardcopy in section 1.16 of the CTD Module 1/Part 1. The document
should be in the format as seen in Table 3 on the next page:


Country Application
status
Status Date Approved application
indication/dosing regimen details*
Approved
forensic
classification

Country 1 Approved 12 Jan 2005 Adjuvant treatment of colorectal cancer
stage III (Dukes C) following complete
resection of primary tumour.
POM
Country 2 Approved 2 Feb 2006 Adjuvant treatment of colorectal cancer
following surgery
POM
Country 3 Withdrawn
by applicant
14 April 2002 Indication submitted Adjuvant
treatment of colorectal cancer.
Withdrawn due to insufficient long-term
efficacy data (only phase II data
submitted).
Re-submitted on 16 June 2005 with
completed phase III data for Adjuvant
treatment of colorectal cancer following
surgery.
POM
Country 4 Approved 21 Nov 2004 Adjuvant treatment of colorectal cancer
stage III (Dukes C) following complete
removal of primary tumour.

Notice of Compliance with Conditions
issued on 16 April 2003 based on
promising efficacy results with
condition to furnish confirmatory
efficacy data.
POM
Country 5 Pending Submitted:
15 Jun 2005
Adjuvant treatment of colorectal cancer
stage III (Dukes C) following surgery.
POM
* Applicable to information on reference agencies, Country of Origin, and all rejections/withdrawals/deferrals
Applicable to information on reference agencies and Country of Origin.

Table 3. Format for Submission of the Registration Status in Other Countries.

Product Owner Information (section 4.10)

Input the full name and address of the legally registered owner of the product formulation,
i.e. the drug product. An example is given below:


6.1.5 PRISM section 5 Manufacturer Particulars

Enter information on the various manufacturers involved in all aspects of producing the
final drug product. Information to be entered include:
Manufacturer type involved either in Active Substance or Finished Product
manufacture;
Manufacturers name;
Manufacturing operation involved in bulk production, packing, labelling or any
combination of the three; and,
Manufacturers address input both the manufacturing site and office (i.e.
headquarters) address.

For example,

Multiple entries of manufacturers are possible as manufacturers of active substance(s),
drug product and diluent used to reconstitute the product (if packed and sold together
with the drug product) must be declared. Primary/secondary packaging sites must also be
declared but for secondary packagers, enter (Secondary packager) after the name of the
manufacturer.

Note that all manufacturers names and addresses should be consistent throughout all of
the documents submitted in the application, such as GMP certificates, CPPs, Letters of
Authorisation, Module 3/Part II of the CTD and so forth.

6.1.6 PRISM section 6 Batch Release details

Enter the name, site/plant address and office address of the company responsible for
batch release of the drug product in the exporting country:

The screenshot on the next page is an example of an entry into PRISM section 6:


If there are multiple companies responsible for batch release, the applicant must declare
all of the sites.

6.1.7 PRISM section 7 Supporting Attachments

Before completion of the on-line application, applicants must attach all documents relating
to Module 1/Part I of the CTD into this PRISM section. For the remaining Modules/Parts,
applicants can opt to either attach the documents in full into this PRISM section or submit
soft copies of the documents in a CD.

A screenshot example is given on the next page:


Here are some additional points to note:
Use Portable Document Format (PDF) whenever possible;
Do not combine documents if the content is unrelated for example, do not
submit a GMP certificate with Letters of Authorisation as a single PDF;
Ensure that the documents are appropriately named for easier recognition to
facilitate screening more detail in the file name will enhance recognition of its
contents;
During scanning of documents, applicants are advised not to break seals of
authenticated documents as this will render them invalid.

6.2 DOSSIER REQUIREMENTS

The submission of the complete dossier should take place within 2 working days after the
PRISM application submission to prevent delays in processing of the application. The
date of submission will be defined as the date when HSA receives the complete
dataset for the application.

The dossier requirements for each application will differ, depending on the type of
application and type of dossier. It is advisable that the applicant familiarise him/her-self
with the requirements prior to submitting an application. The Application Checklist in
Appendix 2 or 3 of this guidance will serve as a guide to the necessary documents
required for submission.

6.2.1 NDA submissions

For an NDA, there are different dossier requirements for each of the three evaluation
routes. The dossier type and data requirements are as follows:

6.2.1.1 Full dossier

Full information on chemical/biological development, pharmaceutical/genetic
development, toxicological, pharmacological and clinical data needs to be submitted in
support of the application.

The technical documents required include:

complete Chemistry, Manufacturing and Controls (CMC) or quality documents for
both drug substance and drug product;
complete pharmaco-toxicological or non-clinical documents; and,
complete clinical documents; i.e. all study reports from phase I to phase III,
including tables and appendices.

6.2.1.2 Abridged dossier

For the abridged route, all aspects of the products quality and direction(s) for use
(including dosing regimen(s), indication(s) and patient group(s)) should be the same as
that approved by the competent drug regulatory agency that issued the proof of approval.

complete quality documents for both drug substance and drug product;
a non-clinical overview; and,
a clinical overview, summaries of clinical efficacy and clinical safety, synopses of
relevant studies, a tabular listing of the clinical development programme and study
reports of the pivotal studies (the tables and appendices to the pivotal study
reports may be submitted upon request by HSA).

If the abridged NDA is for a non-prescription medicine, the applicant may submit a written
request for a waiver of clinical data submission. Eligibility for waiver is subject to the
criteria defined in Appendix 4 Guideline on Submission Requirements for Non-
Prescription Medicines. However, HSA still reserves the right to request for the complete
clinical data set if it is deemed appropriate.

For NDAs submitted via the abridged route, the applicant may request for priority review
for life-saving drug if there are unmet medical needs. The following states the criteria
based on which a drug application for a new product will be considered for priority review:

The drug is intended for treatment of a serious life-threatening condition and
demonstrates the potential to address local unmet medical needs, as defined by:
the absence of a treatment option; or
the lack of safe and effective alternative treatment, and the drug would be a
significant improvement compared to available marketed products, as
demonstrated by
i. evidence of increased effectiveness in treatment, prevention, or diagnosis;
or
ii. elimination or substantial reduction of a treatment-limiting drug reaction.

Disease conditions that are of local public health concerns will be given primary
consideration for priority review. Currently these include:
cancer
infectious diseases: dengue, tuberculosis, hepatitis and malaria.

The request for priority review should be accompanied by justification on why the
application concerned warrants a priority review and how the product is expected to
benefit patients, as substantiated by the following evidence:
The seriousness of the disease condition, local and worldwide mortality rates,
anticipated morbidity and debilitation as a consequence of the disease;
Local epidemiology data and volume of requests through the exemption route on
a named-patient basis;
The unmet needs, current available treatment options and standard therapies, and
the inadequacy of current therapies;
The extent to which the product is expected to have a major impact on medical
practice, its major benefit, and how it addresses the unmet needs;

Clinical evidence supporting the claims of significant improvement compared to
available treatments.

HSA reserves the right to deny a request for priority review if it is deemed appropriate.

6.2.1.3 Verification dossier

For the verification route, one of the two reference drug regulatory agencies must be
declared as the primary reference agency. All aspects of the products quality and
direction(s) for use (including dosing regimen(s), indication(s) and patient group(s))
should be the same as that approved by the chosen primary reference agency.

complete quality documents for both drug substance and drug product, which
includes:
i. the initial dossier submitted to the primary reference agency;
ii. all Questions and Answers between the primary reference agency and
sponsor the Answers should include supporting documents used in
response to the Questions; and,
iii. all post-approval variations approved by the primary reference agency up to
the time of submission to HSA;
a non-clinical overview; and,

The complete assessment report and other relevant supporting documents from the
primary reference agency must be submitted along with the relevant application dossier
sections, as tabulated below:

Primary reference
agency
Documentary requirements
Australia TGA Clinical and quality assessment reports, including all
annexes, question and answer documents between the
sponsor and the Agency
Delegates overview
Pre-ADEC response
ADEC minutes
Assessment reports and/or documents pertaining to post-
approval variations, if applicable
Health Canada Clinical and quality assessment reports, including all
EMEA Summary of CHMP Opinion
European Assessment Reports (i.e., Rapporteur, Co-
Rapporteur as well as the Joint Clinical and Joint quality
assessment reports), including all annexes, question and
answer documents between the sponsor and the Agency

Primary reference
agency
Documentary requirements
UK MHRA Clinical and quality assessment reports, including all
US FDA Clinical and quality assessment reports (unredacted),
including all annexes, question and answer documents
between the sponsor and the Agency

The assessment reports must be unredacted or unedited. Reports obtained from the
public domain are deemed unacceptable.

The following additional documents are required at the time of submission to HSA:
Official approval letter or an equivalent document, from the relevant reference
regulatory agencies that certify the registration status of the drug product;
GMP certificate of the drug product manufacturer(s) from the primary reference
agency;
SmPC/Package Insert (PI)/Patient Information Leaflet (PIL) currently approved by
the reference regulatory agencies that issued the approval letters;
Official letter declaring that the application as submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have
not been rejected, withdrawn, approved via appeal process
9
, or pending deferral
10

by any competent regulatory agency, with reasons in each case if applicable; and
Official letter declaring that all aspects of the products quality intended for sale in
Singapore are identical as currently approved by the primary reference regulatory
agency. This includes, but is not limited to, the formulation, site(s) of manufacture,
release and shelf life specifications, primary packaging and the PI/PIL. For
example, if a product was approved by FDA and EMEA and the assessment
report was from EMEA, the Singapore proposed product and PI/PIL should be
identical to the currently approved EMEA product.

Data submitted to HSA must be the same as the data package submitted to the reference
regulatory agencies. Differences between the dossier submitted to HSA and data
reviewed by the reference regulatory agencies will not only delay the processing of the
application, but may also lead to re-routing of the dossier to the abridged evaluation route
if significant undisclosed differences have been discovered.

6.2.2 GDA Submissions

Generic drug applications require approval from at least one competent drug regulatory
agency.

A generic product is essentially similar to a currently registered product in Singapore
(known as the Singapore reference product) but excludes biologics. Essentially similar
11

is defined as having the same qualitative and quantitative composition in terms of active
substances, having the same pharmaceutical form and being bioequivalent. By extension,

9
Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
10
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.
11
Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.

the concept of essentially similar also applies to different conventional immediate
release oral dosage forms (i.e. tablets and capsules) which contain the same active
ingredient(s).

For generic products containing a different salt or ester form of the active substance
compared to the Singapore reference product, applicants are required to submit data to
demonstrate that the different salt/ester form does not affect the pharmacokinetic,
pharmacodynamic, efficacy or toxicity profile of the active substance in the reference
product.

GDAs generally are not required to include non-clinical (animal) and clinical (human) data
to establish a drug products safety and efficacy. Instead, the generic product must fulfil
the following criteria:
a) the generic drug product is the same pharmaceutical dosage form as the
Singapore reference product;
b) the route of administration of the generic drug product is the same as the
Singapore reference product;
c) the conditions of use for the generic drug product fall within the directions for use
[including indication(s), dosing regimen(s) and patient group(s)] for the Singapore
reference product; and,
d) the generic drug product is bioequivalent with the Singapore reference product.

With effect from 1
st
April 2004, in vivo bioequivalence (BE) data is required for
Prescription Only Medicines (POM) in oral solid dosage forms. Also, GDA-2 applications
will require bioequivalence data if the application is for a Prescription Only Medicine
(POM) in an oral solid dosage form, even if the first strength (GDA-1) application was
submitted to HSA before 1 April 2004. Applicants are advised to consult HSA for
guidance to determine whether the GDA-2 application requires in vivo bioequivalence
data.

Take note that the in vivo BE requirement may be extended to other medicinal product
categories in the future.

Singapore Reference Product

The Singapore reference product must be a currently registered product. It must also be
the same pharmaceutical dosage form and strength as the proposed generic drug (with
the exception of conventional, immediate release oral solid dosage form). Applicants are
advised to search HSAs online database
12
to identify the Singapore reference product.
Applicants submitting GDAs should also refer to Appendix 12 for further details on
product interchangeability and biowaiver request.

The applicant is encouraged to contact HSA to discuss the acceptability of a GDA if the
generic product does not have a registered Singapore reference product of the same
strength. In these instances, applicants shall provide a scientific justification for HSAs
consideration. However, a generic drug application for a higher strength than the
Singapore reference product will not be accepted.

Applicants are also advised to refer to section 11.1 and 11.2 for information on Data
Protection and Data Exclusivity and Patent Linkage, respectively, for additional
information.

12

6.3 SUBMISSION REQUIREMENTS

Table 4 outlines the CTD Modules/Parts required for NDAs and GDAs submitted as a full,
abridged or verification dossier:

Documents Location in Module/Part required for
ICH CTD ACTD Full
NDA
Abridged NDA Verification NDA GDA
Administrative
Documents and
Product Information
Module 1 Part 1 Yes Yes Yes Yes
Common Technical
Document Overview
and Summaries
Module 2 Incorporated
in Parts 2, 3
and 4
Yes Yes Yes Yes
Quality documents

Module 3 Part 2 Yes Yes Yes Yes
Non-clinical
documents
Module 4 Part 3 Yes ICH: No

ACTD: Overview
only
ICH: No

ACTD: Overview
only
No
Clinical documents Module 5 Part 4 Yes Study report(s) of
pivotal studies
and synopses of
all studies (phase
I-IV) relevant to
requested
indication, dosing
and/or patient
group
Study report (s)
of pivotal studies
and synopses of
all studies (phase
I-IV) relevant to
requested
indication, dosing
and/or patient
group
No
Non-clinical overview included in Module 2 of the ICH CTD.

Table 4. Dossier Submission Requirements for NDA and GDA.


6.3.1 HARDCOPY and SOFTCOPY REQUIREMENTS

Table 5 outlines the softcopy and hardcopy required for NDAs and GDAs submitted as a
full, abridged or verification dossier:

CTD Requirement
#
NDA
(F)
NDA
(A)
NDA
(V)
GDA ICH CTD
Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy
Module 1 PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 set
Module 2 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional
Module 3 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional
Module 4 PRISM/CD Optional N/A N/A N/A N/A N/A N/A
Module 5 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional N/A N/A

CTD Requirement
#
NDA
(F)
NDA
(A)
NDA
(V)
GDA ACTD
Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy
Part 1 PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 set
Part 2 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional
Part 3 PRISM/CD Optional
Overview
Only:
PRISM/CD
Overview
Only:
Optional
Overview
Only:
PRISM/CD
Overview
Only:
Optional
N/A N/A
Part 4 PRISM/CD Optional PRISM/CD Optional PRISM/CD Optional N/A N/A
#
F: full route; A: abridged route; V: verification route; N/A: not applicable

Table 5. Requirements for ICH CTD and ACTD dossiers.

In order to ensure that the dossier is complete, application checklists for both ICH CTD
and ACTD dossiers are provided in Appendix 2 and 3, respectively. Each checklist states
the required documents for each dossier type and application type tick boxes marked
with * indicate a mandatory document for the application. Refer to the specific Appendix
for more details.

An electronic copy of the complete CTD dossier is to be submitted with the application
i.e. Modules 1 to 5 of the ICH CTD or Parts 1 to 4 of the ACTD. Applicants are
responsible to ensure that the e-copies e.g. scanned documents of the dossier are
legible.

As mentioned earlier in section 6.1.7 of this document, all administrative documents
[Module 1 (ICH CTD) or Part 1 (ACTD)] are to be attached as soft copies into PRISM
section 7 (Supporting Attachments).

For the remaining Modules/Parts, applicants can opt to either attach the documents in full
into PRISM section 7 (Supporting Attachments) or submit soft copies (e.g. PDF format) of
the documents in a CD. However, applicants are advised not to combine PRISM
attachments with a CD submission i.e. all supporting documents must be attached in
PRISM or all supporting documents submitted in a CD.

When submitting a CD, applicants are encouraged to organise the dossier via the CTD
format, using folders and subfolders, and to include bookmarks to facilitate
screening/reading of the reports.

Applicants shall ensure that access to the CD is not restricted. If so, the applicant must
provide the password(s) to access the CD contents.


When applicable, upon acceptance, applicants will be notified to submit additional
copy(ies) of clinical documents (in CD).

Applicants should also note that hardcopy submission of all administrative documents in
CTD Module 1/Part 1, as indicated in Table 5, are also required for the application.
Applicants should ensure that the electronic copies are identical to the hardcopy
documents.

If an electronic copy of the complete CTD dossier is not possible, HSA will accept the
complete dossier in hardcopy.

For hardcopy submissions, each Module/Part should be bound into separate volumes
and numbered sequentially, starting from 1 for example Module 5, Vol. 1 of 3. Each
volume should also be labelled according to the section(s) it contains.

For example,

A document is a set of pages that is numbered sequentially and divided from other
documents by a tab. Page numbering should be at the document level and not at the
volume or module level; i.e. the entire submission should never be numbered
consecutively by page. In general, all documents should have page numbers. Since the
page numbering is at the document level, there should only be one set of page numbers
for each document.

Cross-referencing to documents is acceptable by referring to the CTD module, volume,
tab identifier and page number (for example, refer to Module 3, Vol. 6, P.4.3 Method
Validation, p 23).

Volumes packed in sturdy cardboard boxes should be clearly labelled with the contents
(e.g. Module 2, Volume 1 to 5), and the boxes should not weigh more than 20 kilograms.

6.4 DOCUMENTARY REQUIREMENTS

6.4.1 Language

Information and documents supporting an application, such as certificates and approval
letters, must be in English and authenticated. If documents are not originally in English,
applicants should refer to Appendix 5 for the flow chart for the translation of non-English
documents.

Authentication of foreign documents for use in Singapore is required when the
authenticity of the documents cannot be determined.

If the foreign document is an original and bears the seal and signature of a recognised
government agency, the document does not require notarisation. Any other type of
ABC
Tablet 250mg

Module 3
Vol. 3 of 4

3.2.P.7 to
3.2.P.8
Product Name, generic name of
the drug and the Applicant
Company
This volume contains information
on drug product container
closure system and stability

document, such as declarations, translations, photocopies, documents lacking an original
signature, etc., must be notarised by a notary public in the country where the document
was issued before the document can be authenticated. The notary public will sign the
document and affix their seal. Notarisation is generally not required for documents
executed in Singapore for use in Singapore.

As an example, for notarisation the information included on the document could be:
The name of the notary;
A statement that the notary is duly admitted to practice in the place of issue of the
certificate;
The names of the signatories and the capacity in which they have executed the
document, whether on their own behalf or in an official or representative capacity;
A statement authenticating the signatures of the parties and, where appropriate,
indicating that evidence has been produced to the notary proving the capacity in
which they have executed the document;
The place and date of issue of the notarial certificate; and
The signature and seal of the notary.

Authentication (also known as legalisation or consularisation) refers to the process
whereby the origins of a document are attested. Authentication of documents in support
of applications made to HSA can be done by:
The Ministry of Foreign Affairs of the country in which the document was issued;
or
The Singapore Embassy/Consulate in the country where the document was
issued.

Applicants are advised to consult the Singapore Embassy/Consulate in the country where
the document originated on local requirements for document legalisation, as these may
deviate from the process as outlined in the preceding paragraph.

By international agreement, an apostille can be issued for documents that are to be used
in another country that is party to the Hague convention. When an apostil stamp is
attached to a document, it is exempted from all forms of confirmation; i.e. no further
legalisation from a foreign embassy is normally required. Although Singapore at present
is not a party of the Hague Convention, an apostille is acceptable for the authentication of
documents to be submitted to HSA as part of the application dossier.

Certificates and documents issued in English by the national drug regulatory agency do
not require legalisation.

A certified true copy certifies that the photocopy presented is a true and accurate copy of
the original document. Acceptable certification of documents to support drug product
applications to HSA can be done by the Company Director or Company Secretary as
registered with ACRA or above, or by an independent authority such as a lawyer, notary
public, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the original
issuer of the document or Embassy/Consulate. A notarised copy is the same as a
certified true copy.

A certified true copy of approval letters (see section 6.5.2 Proof of Approval) requires
certification by the drug regulatory agency that issued the approval letter, notary public or
Singapore Embassy/Consulate in the country where the approval letter was issued.
Certification of approval letters is not required in the event the approval letter is available
on the drug regulatory agencys website. In this instance, applicants shall provide the
internet address (URL) for validation by HSA.


6.4.2 Administrative Documents

The administrative documents relate to Module 1 of the ICH CTD or Part 1 of the ACTD.
The following sections are to be submitted:

Comprehensive Table of Contents (1.1)

The comprehensive table of contents is a complete list of all documents provided in the
application dossier by Module/Part. The location of each document should be identified
by the Module/Part number. For hardcopy submissions, the location of each document
should be identified by the volume number and tab identifier (name of the document or
section heading according to the ACTD or ICH CTD format).

Introduction (1.2)

Applicants should give a concise and precise summary of the application and justify the
need for the application for example, whether the product presents an advantage to
patient groups in terms of improved quality, safety and efficacy compared to available
alternatives. Applicants should also justify the lack of certain documents within the
dossier and any deviation from the guidelines.

Application Form (1.3)

A printout of the PRISM application form is to be included in the dossier. Take note that a
separate application form is required for each pharmaceutical dosage form.

Labelling, Package Insert and Patient Information Leaflet (1.4)

Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL, as described in the table below:

Forensic Classification in Singapore
POM P GSL
Package Insert (PI), also known as
prescribing information, SmPC, or product
monograph
Required Optional Optional
Patient Information Leaflet (PIL), also known
as consumer medicine information (CMI)
Optional,
unless
warranted
Required Required

The artwork/drafts should be legible. Any handwritten information is not acceptable.
Separate drafts must be submitted for each different pack size of the drug product.

The product labels, PI and/or PIL must be in English. If non-English text is included in the
labelling, applicants must provide an official statement to declare that the non-English text
is complete, accurate and unbiased information and is consistent with the English text.
Applicants should also highlight any non-English country-specific labelling requirements
on the artwork/drafts if the labelling is shared with other countries.

Appendix 6 of this guidance contains specific details on product labelling requirements for
Singapore.


Approved SmPC/PI/PIL (1.5)

In this section, the applicant shall submit the following:
a) the approved SmPC, PI and/or PIL from the products Country of Origin;
b) the approved SmPC, PI and/or PIL from the drug regulatory agency that issued
the proof of approval, if different from the Country of Origin; and,
c) the approved SmPC, PI and/or PIL from each of HSAs reference drug regulatory
agencies, where applicable.

Assessment Report from Reference Agencies (1.6)

This section refers only to verification dossier submissions. Assessment reports and
supporting documents issued by the primary reference agency and inserted into this
section must be unredacted and unedited. Applicants should refer to section 6.2.1.3 for
specific details on the required documents.

Description of Batch Numbering System (1.7)

Detailed information on the system of assigning unique codes to different production
batches of the product should be provided to allow for batch identification.

Proof of Approval (1.8, 1.9)

Proof of approval is not required for full dossier submissions.

For abridged NDA and GDA submissions of an imported product, proof of approval by
any competent drug regulatory agency is required. Proof of approval must come in the
form of:
an official approval letter, or equivalent document (e.g. Certificate of
Pharmaceutical Product), which certifies the registration status of the drug
product; and
the GMP certificate(s) of the drug product manufacturer(s) from the relevant
authority; and
the SmPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.

If the SmPC is in a non-English language, applicants should refer section 6.4.1 of this
guidance document. In addition, a declaration is required stating that the translation
submitted conforms to the SmPC/PI/PIL currently approved by the drug regulatory
agency concerned.

Note that all aspects of the products quality and intended direction(s) for use in
Singapore should be the same as approved by the drug regulatory agency that issued the
approval letter. For verification dossiers, the products quality and intended direction(s) for
use in Singapore should be the same as approved by the primary reference regulatory
agency.

For verification dossier, the following documents are required at the time of submission to
HSA:
official approval letters, or equivalent document, from the relevant HSAs reference
regulatory agencies that certify the registration status of the drug product;
a GMP certificate of the drug product manufacturer(s) from the primary reference
agency; and,
the SmPC/PI/PIL currently approved by the reference regulatory agencies that issued
the approval letters.


Approval letters should be either an original copy or a certified true copy. Applicants
should refer to section 6.4.1 for more details.

HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), if
deemed appropriate.

If the product is not approved in the Country of Origin, the applicant is required to clarify
the products registration status in the Country of Origin. If the product is not marketed in
the Country of Origin/Manufacture or by the Product Owner, the reason for the non-
marketing status should be provided.

Business Registration Certificate

Documents for this section are no longer required.

Authorisation Letters (1.10)

All submitted authorisation letter(s) shall be hardcopy originals on the authorising
companys (i.e. Product Owners) letterhead, dated and signed by the designated
authorised person in the company.

If the Product Owner is not the local Applicant Firm, Manufacturer and/or Batch Releaser,
then the following authorisation letter(s) must be submitted:

a) from Product Owner to the Applicant Firm (1.10.1) this letter authorises the local
applicant firm to apply for and be the Product Licence Holder for a specific
medicinal product.

b) from Product Owner to Manufacturer (1.10.2) this letter authorises the specified
manufacturer to produce, pack and/or label the drug product intended for
Singapore. If there are multiple drug product manufacturers, the applicant may opt
to submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product. For
biologic drug products, an additional authorisation letter from the Product Owner
to the Drug Substance Manufacturer is required.

c) from Product Owner to Batch Releaser (1.10.3) this letter authorises the
specified company to test and batch release the drug product. If there are multiple
sites of batch release, the applicant may opt to submit one authorisation letter
which clearly states all of the batch releasers (names and addresses) and their
responsibilities.

Applicants are to ensure that all names and addresses in the authorisation letter(s) must
be consistent with the information provided in PRISM and the dossier. For Manufacturers
and Batch Releasers, the actual site address of the named company should be stated in
the letter(s) i.e. do not state the office address. Any discrepancy found will delay the
registration process.

All authorisation letters should also state specific product details, such as the product
name, dosage form and strength.

Applicants also have the option to combine authorisation letters (b) and (c) above into
one document, provided that all names, addresses and responsibilities are clearly stated.

NOTE: if an applicant company has engaged a consultant to submit applications,
an additional Letter of Authorisation must be submitted from the company that
authorises the named consultant to register product(s) on their behalf.

GMP Certification/Proof of GMP Compliance (1.11)

Documentary evidence must be provided to certify that the registered manufacturer(s)
complies with current applicable GMP standards. Applicants must submit either an
original or certified true copy of a GMP certificate issued by a competent regulatory
agency for all drug product manufacturing sites including, but not limited to, bulk product
manufacturer(s), primary packer(s) and secondary packer(s). Proof of GMP compliance
must not expire within 6 months from the time of submission to HSA.

With effect from 1
st
April 2004, all overseas drug product manufacturing sites previously
not registered with HSA who intend to register their Western medicinal products in
Singapore will be subjected to a GMP Conformity Assessment by HSA. Thus, when
applicable, applicants must also submit a GMP Conformity Assessment application form
13

with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer
14
.

It should be noted that diluents used for reconstituting the drug product and are packaged
together with the drug product will be considered as part of the final drug product. Thus,
manufacturer(s) of the supplied diluent(s) will follow the same requirements applicable to
the drug product e.g. proof of GMP compliance.

Applicants are also required to register GMP-compliant secondary packagers of medicinal
products. Secondary packaging facilities not previously registered with HSA are required
to obtain GMP clearance from HSAs MQA unit prior to registering the site with HSA.

Furthermore, for biologic NDA applications, proof of GMP compliance for the drug
substance must also be submitted in addition to the aforementioned GMP requirements.

All GMP certificates must be in English. Applicants should refer to section 6.4.1 for more
details on translation of non-English documents.

Patent declaration (1.12)

The Patent Declaration form is required for each NDA and GDA. Refer to Appendix 7 for
a copy of the Patent Declaration Form.

Under Section 1 Applicant Particulars, the name and address of the local applicant firm
is stated. Under Section 2 Product Particulars, the product name is stated and it should
be consistent with that stated in PRISM, the application form, all product labelling and all
other relevant documents in the dossier. Under Section 8 Declaration, the patent
declaration must be signed by the Company Director, Company Secretary as registered
with ACRA, or equivalent.

The patent declaration form needs to be submitted twice in original: at the time of dossier
submission and prior to issuance of the Product Licence, if the evaluation was deemed
satisfactory with respect to the products safety, efficacy and quality aspects.

13

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_manufacturers/
conformity_assessment/eServices_Forms.html
14
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/gmp/files_1.
Par.60707.File.dat/GUIDE-MQA-020-007.pdf

Declaration on rejection, withdrawal and deferral (1.13)

The document required for this section is a declaration letter that states that the
application as submitted to HSA or similar direction of use including indication(s), dosing
regimen(s) and patient population(s)
has not been rejected
has not been withdrawn
has not been approved via an appeal process, or
is not pending deferral
by any competent regulatory agency. If any of the conditions apply to the application,
details and reasons must be provided to HSA.

Declaration for NDA verification (1.14)

This section applies only to NDA verification dossiers.

A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the primary reference regulatory agency. Quality
aspects include, but are not limited to, formulation, manufacture site(s), release and shelf
life specifications, primary packaging and PI/PIL.

Registration status in other countries (1.15)

The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 6.1.4 of this document for further details.

In the event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered. The full details should
then be attached in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and in
hardcopy in section 1.15 of the CTD Module 1/Part 1. The document should be in the
format as seen in Table 3 on page 22, section 6.1.4 Registration Status in Other
Countries of this document.

6.4.3 CTD Overview and Summaries

The overview and summary documents are to be inserted into Module 2 of the ICH CTD
or into the relevant sections in Part 2, 3 and 4 of the ACTD.

A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part 2, section B of the ACTD, irrespective of
whether an ICH or ACTD QOS has been included in the application dossier. Take note
that the SQOS must be named and dated by the applicant prior to submission. The
electronic copy of the Singapore QOS should be in Microsoft Word format.

The SQOS for chemical and biologic drug products are given in Appendices 8 and 9,
respectively.

NOTE: the SQOS is only a summary of the technical information in the dossier.
Pages from the SQOS should not be used to replace documents required for the
application.

6.4.4 Quality Documents

The quality documents relate to Module 3 of the ICH CTD or Part 2 of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertaining to requirements specific to Singapore:

6.4.4.1 Body of Data Drug Substance

The ICH M4Q technical guideline and ASEAN Common Technical Requirements (ACTR)
provide details on the information to be included in the drug substance sections of an
application dossier.

For an NDA or GDA, if the drug substance sections of the application dossier are
incomplete, the dossier should make reference to a Drug Master File (DMF), Plasma
Master File (PMF) or Certificate of Suitability of Monographs of the European
Pharmacopoeia (CEP).

Drug Master File (DMF)

If a drug substance is manufactured by a manufacturer different from the product owner,
data on its manufacture, quality control and stability may be submitted via a Drug Master
File (DMF).

The DMF is divided into two parts: an open (or applicants) part and a closed (or
restricted) part. The open part contains most of the information in Module 3.2S (ICH
CTD) or Part 2.S (ACTD) i.e. S1, S2.1 and S3 to S7 sections. The closed part contains
the confidential information in section 3.2.S.2.

The documentary requirements for an application making a reference to a DMF are as
follows:

From Applicant:
the open part of the DMF from the applicant, as part of the submitted dossier;

From DMF Holder:
the complete (open and closed parts) DMF from the drug substance manufacturer
i.e. the DMF holder; and,
an original Letter of Access (see below).

The Letter of Access authorises HSA to refer to the DMF in support of the application for
a drug product. Thus, the Letter of Access must state the following:
the name of the drug product (product name, dosage form and product strength)
to be registered;
the local applicant responsible for product registration; and,
a declaration that the local applicant and HSA will be notified of any change in the
drug substance specification or in the manufacturing process that will likely affect
the products quality or safety.

NOTE: if a drug product contains more than one drug substance, the information
within Module 3.2.S (ICH CTD) or Part 2.S (ACTD) must be provided in its entirety
for each drug substance.

The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the restricted part of the Drug Master File will be
regarded as confidential and will only be evaluated in support of the applications
mentioned in the letter of access. The confidential information will not be disclosed to any
third party without a written authorisation from the Drug Master File holder.

Upon receipt of the DMF, HSA will assign a DMF number. For future correspondence, the
applicant and the DMF holder should make a reference to the assigned Drug Master File
number. Should there be deficiencies within the restricted part of the Drug Master File,
HSA will raise queries directly with the DMF holder.

Applicants are responsible to maintain and update the DMF. Applicants should file a
variation if there are changes to the DMF refer to the Post-Approval Process section of
this guidance for more information on filing variations.

Plasma Master File (PMF)

Plasma Master File (PMF) is required whenever a human plasma-derived product is used
either as a drug substance or as an excipient. The PMF is a stand-alone document that
contains information on the collection and control of source materials. Appendix 10 of the
guidance describes the PMF data requirements for submission.

The PMF should be filed separately from the application dossier for pre-marketing
evaluation. The applicant may cross-reference a currently registered PMF of HSA where
applicable.

Certificates of Suitability (CEP)

If reference is made to a CEP, the applicant should submit a copy of the valid CEP,
including all annexes, in lieu of a DMF or Section S of the CTD. However, the following
documents must accompany the CEP (and inserted into its corresponding CTD S
section):
results of batch analysis (S4.4) from the drug substance manufacturer*
demonstrating compliance with the Ph. Eur. Monograph and including any
additional tests/limits listed on the CEP; and,
additional data to address any relevant parameter(s) not addressed in the CEP,
such as stability data (S7), if a re-test period is not stated on the CEP and
physico-chemical characteristics (e.g. particle size, polymorphism, etc), if
applicable.

If there is a CEP for animal-derived material used in the drug product, the applicant may
submit the CEP in lieu of the documents stipulated in Appendix 11 Guideline on the
Registration of Human Medicinal Products Containing Materials of Animal Origin.

NOTE: if a Letter of Access does not fulfill these requirements, HSA reserves the
right to return the DMF to the DMF holder.
NOTE: HSA reserves the right to request for any additional information about the
drug substance if it is seemed appropriate.

It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from the European Directorate for the Quality of Medicines and
Healthcare (EDQM).

* If the drug substance manufacturer is CEP certified and drug product manufacturer
claims otherwise (USP, JP, In-House etc), data covering S4.1 to S4.5 from the drug
product manufacturer should be submitted instead.

Stability Data of Drug Substance (3.2.S.7)

At the time of submission, the minimum stability data required are as follows:
At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug substance;
The batches should be at least pilot scale-sized and manufactured by a method
that simulates the final commercial process.

If the drug substance is sourced from multiple sites, stability data from each site should
be provided.

HSA may request for additional stability data if deemed necessary for the evaluation of
the application.

6.4.4.2 Body of Data Drug Product

The ICH M4Q and ACTR also provide details on the information to be included in the
drug product sections of an application dossier.

Process Validation (3.2.P.3.5)

Applicants should refer to the ASEAN Guidelines on Submission of Manufacturing
Process Validation Data for Drug Registration
15
for the minimum data requirements on
Process Validation.

Control of Excipients (3.2.P.4)

This section refers to all excipients used in the drug product formulation, including
ingredients used in capsule shells and film coatings. The specifications and analytical
method(s) for each excipient should be described, with validation of any in-house test
method(s) if applicable.

Information on proprietary ingredients such as flavourings, colourants, perfumes and/or
printing inks should be as detailed as possible. Applicants are advised not to use internal
codes but rather give commercial names for such ingredients.

A CoA for an excipient may be submitted in lieu of the excipients specifications.

For ingredients derived from human plasma, the Checklist for Guideline on the
Registration of Human Plasma-derived Medicinal Products in Appendix 10 along with
supporting documents should be submitted under section 3.2.P.4.5. Appendix 10 also
describes additional requirements for registration of human plasma-derived medicinal
products.

15

For ingredients derived from animal sources, the TSE Checklist in Appendix 11 with
supporting documents should be submitted under section 3.2.P.4.5. Appendix 11 of this
document describes the guideline on the registration of human medicinal products
containing materials of animal origin.

Control of Drug Product (3.2.P.5)

The drug products release and shelf-life specifications should be declared in section
3.2.P.5.1.

Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section 3.2.P.5.4.

Stability Data of Drug Product (3.2.P.8)

At the time of submission, the minimum stability data required are as follows:
At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug product;
The primary batches should be manufactured by the same method(s) and
packaged in the same container closure system as that proposed for Singapore.
All submitted stability data must be site specific to the product proposed for Singapore.

If the drug substance is sourced from two different sites (e.g. site A and B), stability data
for the drug product must include one set of minimum requirements for the drug product
with drug substance from site A and one set for the drug product with drug substance
from site B i.e. a total of six batches at real time conditions and 6 batches at
accelerated conditions.

HSA has adopted the ASEAN Guideline on Stability of Drug Product
16
for guidance on the
conduct of stability studies for the ASEAN region. Applicants should familiarise
themselves with this guideline prior to submission. Applicants are also reminded that the
ASEAN stability requirements will be fully implemented with effect from 1
st
January 2009.

Product Interchangeability and Biowaiver request

Refer to Appendix 12 Product Interchangeability and Biowaiver Request for guidance
notes on acceptability criteria for product interchangeability and biowaiver request for
chemical generic drug applications.

Blank Production Batch Records

For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture should be provided.

6.4.5 Non-clinical Documents

The non-clinical documents relate to Module 4 of the ICH CTD or Part 3 of the ACTD.

The full set of non-clinical documents is required for a full dossier submission. For all
other dossier types, the non-clinical overview will suffice, unless the application
specifically pertains to non-clinical data. In those instances, the non-clinical summary,
non-clinical overview and relevant non-clinical study reports will be required.

16

Applicants should refer to the ICH CTD Guidelines M4S
17
(Safety) technical guidelines or
the ACTD Part 3: Nonclinical
18
guidelines for detailed information on the contents of non-
clinical documents for the application dossier.

6.4.6 Clinical Documents

The clinical documents relate to Module 5 of the ICH CTD or Part 4 of the ACTD.

Guidance on how to complete this Module/Part is provided in the ICH CTD Guideline
M4E
19
(Efficacy) technical guidelines, in particular the ICH E3 guidance document on
Structure and Contents of Clinical Study Reports, or the ACTD Part 4: Clinical
20

guidelines.

Pivotal clinical study reports are required for all NDAs. These studies should be
conducted using the drug product formulation submitted in the application and in the
appropriate patient population for the indication(s) and/or dosing regimen(s) as requested
in the NDA. Biopharmaceutic study reports are required if the commercial formulation for
the Singapore market differ from the clinical trial formulation used in the pivotal studies.

For a full dossier submission, the full set of clinical data is required i.e. the study reports
of all phase I-IV studies, whenever applicable, including the tables and appendices. For
abridged and verification dossiers, only the study reports of pivotal or relevant clinical
trials (without tables and appendices) and the list of key literature references are required.

7 APPLICATION SCREENING

After submission, the application will be screened to ensure that there are no deficiencies
that would hinder the evaluation. If any deficiencies are identified, a screening query letter
will be issued to the applicant.

The applicant will be required to submit all of the requested information and documents
within 30 calendar days from the date of the screening query letter. Any deficiencies
noted must be addressed before the dossier can be accepted for evaluation.

When the response to the screening query letter has been received, the requested
information and documents will be screened for completeness. The dossier will be
accepted when all requested information is found to be adequate.

If the applicant fails to provide the requested information, or the submitted information is
incomplete or contains unsolicited information, the application will be rejected. A non-
acceptance letter will be issued by HSA and the documents will be returned. If the
applicant wishes to resubmit the dossier at a future time, it will be processed as a new
application.

17
http://www.ich.org/cache/compo/276-254-1.html
18
19
http://www.ich.org/cache/compo/276-254-1.html
20
NOTE: Refer to the tables in section 6.3 and 6.4 of this document to see
the requirements for submission

Dossiers not submitted in the prevailing required format will be rejected at screening
without going through the screening process.

An acknowledgement notice will be issued to the applicant upon acceptance of an
application. The date of acceptance of the application will be considered as the start of
the evaluation timeline.

8 APPLICATION EVALUATION

Evaluation by HSA is based on the data set submitted by the applicant. A query letter will
be issued to the applicant if clarification or additional information is required.

The Stop-clock starts whenever HSA issues a query letter. Queries may be raised at any
time from the date of acceptance of the application to regulatory decision. The Stop-clock
ends when HSA receives complete and satisfactory response(s) from the applicant.

If the applicant anticipates difficulty in responding in full or within the specified timeframe,
HSA should be contacted to discuss the request for information as soon as possible after
receipt of HSAs query letter. An application will be considered withdrawn if the Stop-clock
time exceeds the deadline agreed upon by HSA and the applicant.

Additional supporting data submitted after acceptance of the application will not be
considered, unless requested by HSA or mutually agreed upon by HSA and the applicant
prior to acceptance.

During the evaluation process, HSA may determine that the application is more suitably
evaluated via an alternate route. Any re-routing of the application will be discussed with
the applicant.

HSA may engage external evaluators, experts and advisory committees in the evaluation
process, when necessary. These experts include scientists and clinicians from both local
and overseas institutions. All external evaluators and experts are bound by agreement to
protect the information made available to them. The identity of the external evaluators is
kept confidential.

9 REGULATORY DECISION

A regulatory decision is made based on the outcome of HSAs evaluation of the submitted
data package. The decision can be one of the following:

Approval the application has satisfied the registration requirements for quality,
safety and efficacy;
Approvable when the application has minor deficiencies;
Non-approvable when the application has major deficiencies; or
Rejection when the response provided by the applicant fails to address the
major deficiencies highlighted in HSAs non-approvable decision.

Approval and rejection are final decisions issued by HSA. Approvable and non-
approvable are intermediate regulatory decisions and applicants may withdraw their
applications at this stage.

In the event where an application is deemed approvable, the conditions for approval will
be stated in writing and the applicant is required to fulfill these conditions within the
stipulated timeframe.


For non-approvable applications, the applicant will be informed of the non-approvable
issues in writing. If the applicant wishes to address the non-approvable concerns raised
by HSA, a reply should be made within the specified timeframe. The reply should be
based on the original data set as submitted to HSA; additional data, which require
evaluation, will not be accepted. No extension of timeline will be considered, unless
mutually agreed between HSA and the applicant.

An application will be considered withdrawn if the applicant fails to reply within the
stipulated timeframe subsequent to an approvable or a non-approvable decision. Once an
application is withdrawn, the applicant is required to submit a new application according
to prevailing submission requirements.

Upon an approval regulatory decision, a Product Licence will be issued.

HSA may issue a product licence on the condition that certain documents/information
shall be submitted after the licence has been issued. Under such circumstances, an
official letter of commitment is required before the licence can be issued. The official letter
of commitment should be specific, i.e. addresses the particular issues of concern and
should provide details on how and when the post-approval licensing commitments will be
satisfied. Failure to comply with these commitments may result in the suspension or
revocation of the Product Licence.

Applicants should view the licensing conditions on-line
21
for specific details in order to be
reminded of any post-approval commitments associated with the Product Licence.

21
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism/drugs.html#history

POST-APPROVAL PROCESS

Throughout the life cycle of a medicinal product, changes to a products efficacy, quality
and/or safety are likely to occur.

HSA must be notified of any changes to a products safety, efficacy or quality through an
application process i.e. the variation application. Figure 4 below is a schematic diagram
of the variation application routes:

Figure 4. Schematic diagram of variation application routes.

10 POST-APPROVAL CHANGES

There are two types of variation applications: major variation application (MAV) and minor
variation application (MIV). The variations are described as follows:

MAV Major Variation application for an existing registered product.
MAV-1 : Any variation to the approved indication(s), dosing regimen(s), patient
group(s), and/or inclusion of clinical information extending the usage of
the product (e.g. clinical trial information related to an unapproved
indication, dosing regimen and/or patient population; additional bacterial
strains for antimicrobial products).
MAV-2 : A change in current approved forensic classification, also known as
reclassification.

MIV Minor Variation application for an existing registered product
MIV-1 : A minor variation, which requires regulatory approval.
MIV-2 : A minor variation or an administrative change, which does not require
regulatory approval; i.e. notification.

HSA reserves the right to re-categorise the application type if appropriate. Applicants are
to note that in PRISM, the re-categorisation of MIV to MAV-1, MIV-2 to MIV-1, or vice
versa, requires withdrawal of the original application. The applicant is required to resubmit
the application according to the correct category.

Except for administrative changes and some minor variations where notification to HSA is
sufficient, all applications require HSAs approval before the change(s) can be
implemented.

IS PRODUCT
REGISTERED?
YES
Change in safety,
efficacy or quality
aspect?
MAJOR VARIATION
MINOR VARIATION
MAV-1
MAV-2
MIV-1
MIV-2

10.1 DOSSIER FORMAT

As for applications for a new Product Licence, all submissions shall be submitted to HSA
in the CTD format, either the ICH CTD format or the ACTD format. The format used for a
variation application shall follow that used for the original application for new Product
Licence.

10.2 VARIATION APPLICATION PROCESS

The steps to submit an MAV or MIV is similar to submitting an NDA or GDA, as seen in
Figure 5 below:

a
An acceptance fax will be sent only for major variation applications.
b
A regulatory decision letter will not be sent for MIV-2 applications.

Figure 5. Schematic diagram of the variation application process.

However, each variation application has distinct differences and the applicant should be
familiar with the variation application process in order to facilitate the process.

10.2.1 Pre-Submission Preparation

For issues relating to an impending variation application, applicants may consult with
HSA in a pre-submission consultation. The request for a consultation should be made in
writing, with the purpose and agenda for the consult stated, via email to:
HSA_MedProd_Registration@hsa.gov.sg.

For a full dossier submission, the applicant is required to notify HSA two months prior to
the intended submission date of the application dossier.
PRE-SUBMISSION
PREPARATIONS
APPLICATION
SUBMISSION
APPLICATION
SCREENING
APPLICATION
EVALUATION
REGULATORY
DECISION
b
NON-ACCEPTANCE /
WITHDRAWAL
ACCEPTANCE
a

For issues relating to MIV submissions, the applicant may also opt to fax or email a
completed MIV Filing and Submission Inquiry Form, as seen in Appendix 13 of this
document. Upon receipt of an MIV Inquiry Form, an officer will process the inquiry and a
response will be faxed back to the named applicant with an Inquiry Reference Number. If
the MIV is submitted, a copy of the Inquiry Form, with the Inquiry Reference Number,
should be included in the submission.

Any advice given by HSA will be based on knowledge that is current at the time of the
enquiry. However, such advice is not binding and does not have direct bearing on the
eventual outcome of the application concerned.

10.2.2 Application Submission

Submission of a variation application consists of two parts: through on-line PRISM and
hardcopy submission.

Submitting the application through PRISM is similar to that stated in section 6.1 of this
guidance document. Some fields would not be editable for variation applications.

Hardcopy submission requirements differ amongst each variation type. Explanatory notes
on the requirements for each variation are described in subsequent sections of this
document. Applicants should be familiar with the requirements in order to facilitate the
application process.

Take note that hardcopy submission also includes softcopy submission of the required
documents, which may either be uploaded into PRISM section 7 or copied onto a CD.

10.2.3 Application Screening

The screening process is similar to that for an application for a new Product Licence a
query will be sent to the applicant to address any noted deficiencies in the submission
within a stipulated timeframe.

Upon acceptance of an application, an acknowledgement notice will be issued to the
applicant only for an MAV application. The date of acceptance of the application will be
considered as the start of the evaluation timeline.

10.2.4 Application Evaluation and Regulatory Decision

The evaluation process is similar to that for an application for a new Product Licence.

The regulatory decision process is also similar to that for an application for a new Product
Licence. However, a regulatory decision letter will not be issued for MIV-2 applications as
these are notifiable changes.

10.3 MAJOR VARIATION APPLICATIONS

The subsequent sections of this document will explain the different submission
requirements for each major variation application.


10.3.1 MAV-1 Applications

For an MAV-1 application, there are three evaluation routes with different dossier
requirements. The three evaluation routes are full, abridged and verification.

Full dossier

The full dossier evaluation route applies to a MAV-1 application that has not been
approved by any competent drug regulatory agency at the time of submission to HSA.

complete non-clinical documents, if applicable; and,
complete clinical documents; i.e. all study reports from phase I to phase III,
including tables and appendices.

Abridged dossier

The abridged evaluation route applies to the MAV-1 that has been evaluated and
approved by at least one competent drug regulatory agency. The proposed variation (i.e.
the proposed indication(s), dosing regimen(s), patient group(s) and/or clinical information)
should be the same as that approved by the regulatory agency that issued the proof of
approval.

a non-clinical overview, if applicable; and,
reports of the pivotal studies (the tables and appendices to the study reports may
be submitted upon request by HSA).

If the abridged MAV-1 is for a non-prescription medicine, the applicant may submit a
written request for a waiver of clinical data submission. Eligibility for waiver is subject to
the criteria defined in Appendix 4 Guideline on Submission Requirements for Non-
Prescription Medicines details the criteria for eligibility for waiver and the documentary
requirements. However, HSA reserves the right to request for the complete clinical data
set if it is deemed appropriate.

Verification dossier

Similar to an NDA, at least two of HSAs reference drug regulatory agencies i.e.
Australia TGA, Health Canada, EMEA, UK MHRA and US FDA must have evaluated
and approved the major variation.

One of the two reference drug regulatory agencies must be declared as the primary
reference agency. The proposed variation must be the same as that approved by the
chosen primary reference agency. The primary reference agency is defined as the
reference agency for which the qualifying supporting documents, as outlined in this
guidance document, will be submitted by the applicant.

However, note that approval by these reference regulatory agencies does not obligate
HSA to approve the application.

A verification dossier must be submitted within 3 years from the date of approval by the
chosen primary reference agency.


The approved variation must be similar across the reference regulatory agencies. If there
are apparent differences, the application will be re-routed to the abridged route. HSA
reserves the right to accept only the most stringent indication(s), dosing regimen(s),
patient group(s) and/or direction(s) of use amongst those approved by the reference
regulatory agencies.


The complete assessment report and other relevant supporting documents from the
primary reference agency must be submitted along with the relevant sections of the
application dossier. Refer to section 6.2.1.3 of this guidance for the required documents
to be submitted. The assessment reports must be unredacted or unedited. Reports
obtained from the public domain are deemed unacceptable.

Additional documents are also required at the time of submission to HSA:
an official approval letter, or equivalent document, from the relevant HSAs
reference regulatory agencies that certify the approval of the proposed
variation(s);
the SmPC/PI/PIL currently approved by the reference regulatory agencies that
issued the approval letters; and
an official letter declaring that the application as submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have
not been rejected, withdrawn, approved via appeal process, or pending deferral by
any competent regulatory agency, with reasons in each case if applicable.

Applicants must note that data submitted to HSA must be the same as the data package
submitted to the reference regulatory agencies. Differences between the dossier
submitted to HSA and data reviewed by the reference regulatory agencies will not only
delay processing of the application, but may also lead to re-routing of the dossier to the
abridged evaluation route if significant undisclosed differences have been discovered.

HSA will not accept a verification dossier if the application falls within one of the
categories listed below:
The proposed variation has been rejected, the application withdrawn from,
approved via appeal process or pending deferral by a competent drug regulatory
agency for safety and/or efficacy reasons; or,
The product needs a more stringent assessment as a result of differences in local
disease patterns and/or medical practices (e.g. blood products, vaccines and
some anti-infectives);

For a product with a proposed indication that has been designated as orphan drug by at
least one reference agency, or the proposed variation has been approved by at least one
reference agency via accelerated/fast-track approval, approval under exceptional
circumstances, or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.


10.3.1.1 Submission Requirements

The dossier types for an MAV-1 application are the same as those for an application for
an NDA.

Table 6 outlines the CTD Modules/Parts required for MAV-1 applications submitted as a
full, abridged or verification dossier:

Location in Module/Part required for
ICH CTD ACTD Full
MAV-1
Abridged MAV-1 Verification
MAV-1
Administrative
Documents and
Product Information
Module 1 Part 1 Yes Yes Yes
Common Technical
Document Overview
and Summaries
Module 2 Incorporated
in Parts 2, 3
and 4
Yes Yes Yes
Quality documents

Module 3 Part 2 No No No
Non-clinical
documents
Module 4 Part 3 No
No
#
No
#
Clinical documents Module 5 Part 4 Yes Study report(s) of
pivotal studies and
synopses of all
studies (phase I-
IV) relevant to
requested
indication, dosing
and/or patient
group
Study report(s)
of pivotal
studies and
synopses of all
studies (phase
I-IV) relevant to
requested
indication,
dosing and/or
patient group
If the proposed MAV-1 is related to non-clinical data, non-clinical summary and non-clinical overview as well
as relevant study reports is required.
#
Non-clinical overview only, if applicable.

Table 6. Dossier Submission Requirements for MAV-1.

The organisation, labelling and page numbering of the volumes should follow that as
described in section 6.3 of this guidance.

10.3.1.2 Hardcopy and Softcopy Requirements

The supporting documents should be arranged in accordance with the respective
checklists given in Appendix 2 or 3.

Applicants are required to submit one set of all documents at the time of submission as
outlined in Table 6.

An electronic copy of the complete submission dossier is required as described in section
6.3.1 of this guidance document.


Applicants should also note that hardcopy submission of all administrative documents in
CTD Module 1/Part 1 are also required for the application.


10.3.1.3 Documentary Requirements

Information in this section of this guidance explains the documentary requirements for
MAV-1 applications. The Application Checklist in Appendix 2 or 3 will serve as a guide to
the required documents.

Administrative Documents

The requirements for following sections are the same as for NDA or GDA applications,
unless otherwise specified:
Comprehensive Table of Contents;
Introduction including the Table of Amendment Details of PRISM section 0.5;
PRISM application form;
Labelling, Package Insert and Patient Information Leaflet both the proposed and
currently approved Singapore product labels and PI/PIL are required. For the
proposed labelling/PI/PIL, a pristine and an annotated version (which highlights
the changes made to the currently approved labelling) are required;
Approved SmPC/PI/PIL from the products Country of Origin, the drug regulatory
agency that issued the proof of approval, and from each of HSAs reference drug
regulatory agencies (where applicable) if the approved SmPC/PI/PIL from the
Country of Origin is not available, clarification on the registration status of the
MAV-1 is required in CTD section 1.16;
Assessment Report from Reference Agencies only for verification route;
Proof of Approval for an MAV-1, the GMP certificate(s) of the drug product
manufacturer(s) is (are) not required. However, the official approval letter(s) must
contain information on the requested Singapore variation i.e. proposed
indication(s), dosage regimen(s) and/or new patient group(s);
Declaration on rejection, withdrawal and deferral;
Registration Status in Other Countries; and,
Information about the Experts.

CTD Overview and Summaries

The following documents are to be submitted:
a clinical overview and summaries of clinical efficacy and clinical safety

Non-Clinical Documents

For a full dossier MAV-1 application related to non-clinical data, the full set of non-clinical
documents (non-clinical overview, non-clinical summary and relevant study reports) is
required.

Clinical Documents

Pivotal clinical study reports are required for all MAV-1 applications. These studies should
be conducted with the drug product formulation submitted in the application dossier and
in the appropriate patient population for the indication(s) and/or dosing regimens as
requested in the MAV-1.

For a full dossier submission, the full set of clinical data is required - i.e. the study reports
of all phase I-IV studies, whenever applicable, including the tables and appendices. For
abridged and verification dossiers, only the study reports of pivotal or relevant clinical
trials (without tables and appendices) and the list of key literature references are required.


10.3.2 MAV-2 Applications

A change of forensic classification of a POM drug product may be considered if basic
criteria are met:
The use of the product has been sufficiently extensive;
The POM has been marketed for a period of time sufficient to establish a post-
marketing adverse event profile; and,
The POMs safety profile gives no cause for concern during the marketing period.

Applicants who wish to submit a request for reclassification of a medicinal product shall
provide justification based on the following information:

The forensic classification and approved indication(s) and dosing regimen(s) of
the product in the UK, US, Canada and Australia;
The period of product registration in Singapore, UK, US, Canada and Australia,
with specific information on its forensic classification (i.e. POM, P and/or GSL) and
duration of sale in that classification;
The period of actual product sale in Singapore;
The rationale for requesting a change in the forensic classification;
Patient exposure of the product and its safety profile based on worldwide
spontaneous adverse drug reaction reports, data from post-marketing surveillance
studies, clinical trials, published literature and locally reported adverse drug
reactions; and,
Potential problems and hazards arising from the inappropriate use of the product.

10.3.2.1 Hardcopy and Softcopy Requirements

One set of documents, as outlined in the Application Checklists in Appendix 2 and 3,
should be submitted in softcopy.


Applicants should also note that harcopy submission of all administrative documents in
CTD Module 1/Part 1 are also required for the application.


10.3.2.2 Documentary Requirements

The documentary requirements for an MAV-2 submission are the same as for an NDA or
GDA, unless otherwise stated refer to the Appendix Checklist for guidance:

Comprehensive Table of Contents;
Introduction including the justification for re-classification , as listed above, and
the Table of Amendment Details of PRISM section 0.5;
PRISM Application Form;
Proposed PIL the proposed product labels/PIL should also be submitted, if
applicable;
Approved SmPC/PI/PIL;
Proof of Approval proof of the approved indication(s) and dosing regimen(s) for
the reclassified product in the UK, US, Canada and/or Australia;
Registration Status in Other Countries; and,
Summary of Clinical Safety the summary should include the following:

a) The forensic classification of the product in the UK, US, Canada and Australia,
with specific information on its forensic classification and duration of sale in
that classification;
b) The experience of patient exposure to the product e.g. sales volume,
patient-years;
c) A summary of the product safety profile based on worldwide and local
spontaneous adverse drug reaction reports, post-marketing surveillance data,
clinical trials and published literature ;
d) A list of the potential problems arising from using the product without medical
supervision ; and,
e) An analysis of the hazards arising from therapeutic misuse or drug abuse,
whether deliberate or accidental e.g. consequence of delay in seeking medical
attention.

A me-too reclassification application based on an analogous product, which has already
completed the reclassification procedure, may be submitted without the need to include
the summary of safety data as outlined above.

Reclassification may also be undertaken when experience gained shows that there is a
need to supervise the use of the product i.e. a GSL product may reclassified to a P or
POM product.

10.4 Minor Variation Applications

Applicants should be familiar with the guidelines for submitting minor variation
applications (MIVs). The guidelines and documentary requirements are described in
Appendix 14 (chemical) and 15 (biologics) of this document.

A minor variation application (MIV) is submitted via the Amendment to a Licence of
Western Drug Product form in PRISM:

If an MIV contains multiple proposed variations that belong to both MIV categories, the
MIV should be submitted as an MIV-1. If a proposed MIV-2 does not meet its specified
conditions, then the MIV should be submitted as an MIV-1.

HSA reserves the right to re-categorise the MIV, if deemed appropriate.

Applicants should ensure that all conditions and documentary requirements for the MIV
have been fulfilled prior to submission. For an MIV with multiple variations, all of the
requirements for each individual variation must be met. Applicants are advised to refer to
Appendix 14 or 15 for information on whether to submit documents in hardcopy or
softcopy.
NOTE: applicants are encouraged to fax or email the MIV Filing and
Submission Inquiry Form in Appendix 13 for any issues regarding MIV filing.

Any undisclosed variation(s) embedded in the submitted data, including any flow-on
changes, will not be considered. Evaluation will be based on the data relevant to the
proposed variation(s), unless HSA specifically requests for additional information.

It is the applicants responsibility to ensure the completeness of the application and
compliance with all specified requirements failure to do so may delay the MIV review
process.


OTHER INFORMATION

11 DATA PROTECTION AND DATA EXCLUSIVITY

Sections 19A and 19B were included in the Medicines Act in 1998 to enable Singapore to
comply with its obligations under Article 39 of the WTO TRIPS Agreement. Article 39
requires, amongst other things, countries to protect the test data of a pharmaceutical
product against disclosure and unfair commercial use.

Section 19D was introduced in July 2004, in order for Singapore to fulfil its obligations
under Article 16.8.1 of the US-Singapore Free Trade Agreement (FTA), stating that the
licensing authority may not grant marketing approval for a product on the basis of the
grant of an earlier approval for a period of 5 years from the date of the earlier approval,
unless with the consent of the holder of the earlier approval.

Applications that are based on safety and efficacy data of an earlier approval may be
submitted 18 months before the expiration of the 5-years data exclusivity period.
However, approvals can only be granted after the expiration of the 5-years period. Should
an applicant wish to submit a new drug application before the 5-years period is due, the
applicant is required to submit own non-clinical and clinical data for the proposed
directions of use and indications. The ICH and ASEAN guidelines on safety/non-clinical
and efficacy/clinical data provide information on the structure and content of the
respective modules/parts.

12 PATENT LINKAGE

Provisions for linkage between patent and marketing approval were introduced in July
2004, under Section 12A of the Medicines Act, in order for Singapore to fulfil its
obligations under Article 16.8.4(c) of the US-Singapore FTA.

The Medicines Act provides for a system of patent declaration by the applicant of a
product licence, and power for the licensing authority to revoke a product licence in
relation to patent infringement and patent declaration. Relevant parts include sections
12A, 16 and 20 of the Act, and paragraph 5B of the Medicines (Licensing, Standard
Provisions and Fees) Regulations.

All applications for new product licences shall be accompanied by patent declarations
required under Section 12A of the Medicines Act. The applicant is required to furnish the
patent declaration using the form set out in Part I of the Sixth Schedule of the Medicines
(Licensing, Standard Provisions and Fees) (Amendment) Regulations 2004 at the time of
application submission, and at such other time as HSA may require. As a general
guidance, a confirmatory declaration will be requested at the time when an approvable
regulatory decision is issued. The applicant is required to furnish the confirmatory
declaration within the timeframe stipulated by HSA.

All declarations required under Section 12A of the Medicines Act should be submitted in
hard copies on original letterhead, signed by the person authorised to make the
declaration on behalf of the applicant. The authorised person is ordinarily an officer of the
company such as a director, the company secretary as registered with ACRA, or
equivalent. Evidence of such authorisation by the applicant of that person to make the
declaration on its behalf shall be submitted together with the declaration. Examples of
evidence of authorisation resolution of board of directors, resolution of a general
meeting of the company, or an extract of the relevant portion of the companys articles of
association. Declaration forms must bear the original signatures of the authorised person
and the company stamp of the applicant.

Under Section 12A (3) of the Medicines Act, the licensing authority may, if the applicant
has declared that in his opinion and to the best of his belief the patent is invalid or will not
be infringed by the performing of the act for which the licence is sought (i.e. Category B
patent declaration), or if the licensing authority considers it appropriate in any particular
case, require the applicant to serve a notice to the proprietor of the patent, in the form
prescribed in Part II of the Sixth Schedule of the Medicines (Licensing, Standard
Provisions and Fees) (Amendment) Regulations 2004.

Applicants should take note that the information contained in this section is for the
purpose of guiding applicants in their patent declarations. Applicants requiring legal
advice shall seek the assistance of their own legal counsel.

13 RESPONSIBILITIES OF THE APPLICANT

The applicant shall:

a) Ensure that all particulars given in the application form and supporting documents
are true and valid, and that all current data, reports and information relevant to the
benefit/risk assessment of the medicinal product have been supplied at the time of
the application submission;

b) Ensure that all information and material included in the application dossier on
paper exactly matches the information and material included in the electronic
submission dossier. No information has been added, removed, or changed;

c) Declare at the time of submission to HSA that the application as submitted to HSA
or similar directions of use including indications have not been rejected, withdrawn
from, approved via appeal process or pending deferral by any competent
regulatory agency, with reasons in each case if applicable;

d) Notify HSA if the application as submitted to HSA or if similar directions of use
including indications have been rejected, withdrawn or deferred by any competent
regulatory agency, with reasons in each case if applicable, throughout the
products life cycle in the Singapore market;

e) Notify HSA of any change in the particulars submitted in the application and of any
new significant safety information during the course of evaluation and throughout
the products life cycle in the Singapore market;

f) Respond to HSAs queries on data submitted or requests for more data for review,
within timelines stipulated by HSA;

g) Ensure that the product will be sold, supplied and recommended for use in
accordance with the approved PI/PIL and in compliance with all licence
conditions, applicable legislation and guidelines;

h) Notify HSA of any manufacturing change(s) to the products quality, efficacy or
safety throughout the products life cycle in the Singapore market;

i) Notify HSA if the products marketing authorisation is withdrawn in any country,
with the reasons in each case, throughout the products life cycle in the Singapore
market;

j) Notify HSA if the product is no longer registered by any other country, throughout
the products life cycle in the Singapore market; and,


k) Ensure that all information provided to HSA is true and correct to the best of
his/her knowledge and that he/she has not wilfully suppressed any material fact.
The applicant is aware that if he/she makes any false statement, representation or
declaration in connection with an application submitted to HSA, he/she shall be
guilty of an offence under the Medicines Act (Chapter 176).

14 FEES

The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website
22
.

The screening fee per application is payable at the time of PRISM submission. Evaluation
fees are payable upon acceptance of the dossier for evaluation. The screening fees are
non-refundable once the application has been successfully submitted via PRISM. The
evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.

In PRISM, the re-categorisation of GDA to NDA, MIV to MAV-1, MIV-2 to MIV-1, or vice
versa requires withdrawal of the original application before acceptance and resubmission
of the application according to the correct application type. The screening fees for the
original application are non-refundable. As such, applicants are advised to consult HSA
on the correct application category when in doubt.

Applicants are advised to ensure that the dossier is compiled according to the required
format. Failure to arrange the submission dossier accordingly will lead to non-acceptance
of the dossier without screening. In these instances, the screening fees will be forfeited.

22

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/fees.html
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

LIST OF APPENDICES

APPENDIX 1 Target Processing Timelines

APPENDIX 2 Application Checklist (ICH CTD)

APPENDIX 3 Application Checklist (ACTD)

APPENDIX 4 Guideline on Submission for Non-Prescription Medicinal Products

APPENDIX 5 Flowchart for Translation of Non-English Documents

APPENDIX 6 Points to Consider for Singapore Labelling

APPENDIX 7 Patent Declaration Form

APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs

APPENDIX 9 Singapore Quality Overall Summary for Biologics

APPENDIX 10 Guideline on the Registration of Human Plasma-derived Medicinal
Products

APPENDIX 11 Guideline on the Registration of Human Medicinal Products Containing
Materials of Animal Origin

APPENDIX 12 Product Interchangeability and Biowaiver Request for Chemical
Generic Drug Applications

APPENDIX 12A Quick Reference for Acceptability of Bioequivalence Study

APPENDIX 13 MIV Filing and Submission Inquiry Form

APPENDIX 14 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for
Chemical Drugs

APPENDIX 14A Checklist for Minor Variation Applications (MIV-1) for Chemical Drugs

APPENDIX 14B Checklist for Minor Variation Applications (MIV-2) for Chemical Drugs

APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics

APPENDIX 15A Checklist for Minor Variation Applications (MIV-1) for Biologics

APPENDIX 15B Checklist for Minor Variation Applications (MIV-2) for Biologics



TARGET PROCESSING TIMELINES
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 1 - Page 1 of 1

APPENDIX 1 TARGET PROCESSING TIMELINES

Target processing timelines i.e. from the date of acceptance to regulatory decision,
excluding stop-clock for various evaluation routes as of 1 J anuary 2009 are as follows:

The timelines stated (in working days) are subject to change.

Dossier type NDA GDA MAV-1
Full 270 270
Abridged 180 240 180
Verification 60 60

The target processing timeline for screening dossiers (NDA, GDA, MAV-1, MIV-1) is 25
working days before the first query is issued. The screening timeline begins from the date
of the dossier submission, which should be within 2 working days after PRISM
submission to prevent delays in processing of the application. The date of submission will
be defined as the date when HSA receives the complete dataset for the application.

For MIV-1 applications, the target processing timeline to regulatory decision is 120
working days from the date of receipt of the complete dataset.

For MIV-2 applications, the notification timeline prior to implementation of the variation(s)
is 40 working days from the date of submission. The date of dossier submission should
be within 2 working days after PRISM submission. The date of submission will be defined
as the date when HSA receives the complete dataset for the application.

Take note that the stop-clock starts whenever HSA requests for clarification or additional
information with regard to a product application. Queries may be raised at any time from
the date of acceptance of the application to the regulatory decision. The stop-clock ends
when HSA receives complete and satisfactory response(s) from the applicant.

The stated processing timelines are intended for reference only and do not necessarily
represent the actual processing timelines for the applications. Applicants are advised to
contact the Pharmaceuticals & Biologics Branch, Therapeutic Products Division, for
updates on application status and processing time.



APPLICATION CHECKLIST (ICH CTD)

APPENDIX 2 APPLICATION CHECKLIST (ICH CTD)
This Application Checklist should be used to ensure submission of a complete dataset in the ICH CTD format.
To use this Checklist, check against the dossier and application type for your submission.
For NDA and MAV-1 applications, the document shown in the second column has to be submitted if the symbol representing the dossier type viz.
full dossier represented by , abridged dossier by and verification dossier by , and * (under application type) appear on the same row.
For GDA and MAV-2 applications, the Dossier Type column does not apply.

Application Type NDA GDA MAV-1 MAV-2
Dossier Type Full dossier Abridged dossier Verification dossier

Note: without the asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ICH technical guidance for explanatory notes on the
preparation of documents for a submission in ICH CTD format.


Module 1 Administrative Documentation

Application Type

Section Documents Dossier Type
NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)
1.1 Comprehensive Table of Contents * * * *
Include a complete list of all documents provided in the application dossier by Module
The location of each document should be identified by the Module number

For hardcopy submissions, the location of each document should be identified by the
volume number and tab identifiers (name of document or section heading according to
ICH CTD format)

1.2 Introduction * * * *
Provide a concise and precise summary of the application
Justify the lack of certain documents and deviation(s) from guidelines
1.3 PRISM Application Form * * * *
1.3.1 Section 1: Company Particulars * *
Company shall be based and registered in Singapore

1.3.2 Section 2: Applicant particulars * * * *

Applicant must be a permanent staff of the company and is residing in
Singapore. If the person making the application / correspondence person is
an external party (consultant) engaged by the applicant company, an original
letter of authorization from the applicant company must be submitted.

Company address and contact details can be entered instead of personal
residential address and contact details

1.3.3 Section 3: Application Details
3.1 Type of Application * * * *
3.2 Type of Product * *
3.3 Reference Product *

All GDA applications Specify Singapore Reference Products SIN
number


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)

If GDA-2 application not submitted at the same time as GDA-1
application Specify both the Singapore Reference Products and
the GDA-1 products SIN numbers

If NDA-3 applications not submitted at the same time as NDA-1/2
application Specify the NDA-1/2s SIN number

3.4 Product intended for export * *
3.5 Type of Dossier * *
3.6 Type of Format * *
1.3.4 Section 4: Product Information
4.1 Product name * *

Enter in the following format:
Product Name - Dosage Form Product Strength

Refer to Guidance document section 6.1.4 for additional pointers
4.2 Product Formula * *

Include the full composition of all active substances and excipients
(including water) that are present in the final pharmaceutical dosage
form

Ingredients related to the pharmaceutical dosage form, such as
tablet film coating or capsule shell, should be indicated within
parentheses before the ingredient name, e.g. (Film coating)
Ingredient Z

For active ingredients presented in the form of salts and chelate, the
quantity should be clearly stated, e.g., XX phosphate 32 mg
(equivalent to XX)


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)

Information on residual amounts of certain materials, such as
antibiotics, thiomersal and materials of biological origin (e.g. human
serum albumin), added or present in the drug product must be
declared. Information to declare includes the following:
o the materials name enter (Residual), followed by the
materials name in the Name of Substance field;
o the materials grade, if applicable;
o the materials limit in the product enter , followed by the limit
in the Strength field.

4.3 Ingredients derived from human blood or animal sources * *

Information to be provided in the following format: (Species &
product) (In manufacturing/drug substance/excipient) (Country)

4.4 ATC Code * *
4.5 Dosage Form * *
4.6 Route of Administration * *
Include all routes of administration proposed for the product
4.7 Packaging, Shelf Life & Storage Condition * *

Where more than one drug component is included in a drug product
(e.g., powder for injection with solvent as composite pack) and each
component has a different shelf life, the shorter shelf life is to be
used as the shelf life of the composite pack

4.8 Forensic Classification * * *
4.9 Registration Status in Other Countries * * *
For each country - State the application status and status date

For country of origin and all reference agencies - State the
application status, status date, application details and forensic
classification


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)

For products approved via an appeal process, following either a
negative opinion/rejection/non-approvable decision or an
approvable/conditional approvable decision Provide reasons for
the initial regulatory decision along with the subsequent approval

For applications submitted to the European Union agencies, the type
of application i.e. centralised, decentralised, mutual recognition or
national, should be identified; For decentralised and mutual
recognition applications, the reference member state should be
indicated

For applications approved by the UK MHRA Indicate whether
approval was granted through national procedure or whether MHRA
acted as RMS or CMS for decentralised and mutual recognition
procedures in European Union

For NDA & GDA, the registration status of the product in other
countries should be entered into PRISM

In the event that the PRISM text space does not allow input of full
details of the indication(s), dosing regimen(s), and/or reason(s), a
brief description may be entered; The full details should be attached
in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and
in hardcopy in section 1.16 of the CTD Module 1

For MAV-1, the registration status should be attached in softcopy
(PDF) in PRISM section 7 (Supporting Attachments) and in hardcopy
in section 1.16 of the CTD Module 1

4.10 Product Owner * *
1.3.5 Section 5: Manufacturers Particulars * *

All manufacturers of active substance(s), drug product and diluent used to
reconstitute the product (if packed and sold together with the drug product)
must be declared

For secondary packagers, enter (Secondary packager) after the name of the
manufacturer

All manufacturers names and addresses should be consistent throughout all
of the documents submitted in the application, such as GMP certificates,
CPPs, Letters of authorisation, Module 3 of the CTD and so forth


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)
1.3.6 Section 6: Batch Release Details * *

If there are multiple companies responsible for batch release, the applicant
must declare all of the sites

1.3.7 Supporting Documents * * * *
Attach all documents relating to Module 1 of the CTD

Other Modules Either attach in full in this PRISM section or submit soft
copies in CD

1.4
Labelling and PI/PIL proposed & currently approved in Singapore. For NDA and GDA
only proposed labelling and PI/PIL need to be submitted

Labelling must be in English; If non-English text is included in the labelling, applicants
must provide an official statement to declare that the non-English text is complete,
accurate and unbiased information and is consistent with the English text

Highlight any non-English country-specific labelling requirements on the artwork/drafts
if the labelling is shared with other countries

1.4.1 Outer/Carton Labels * *
1.4.2 Inner/Blister Labels * *
1.4.3 Package Insert (PI)
1.4.4 Patient Information Leaflet (PIL) *
1.5 Approved SmPC/PI/PIL

1.5.1 SmPC/PI/PIL approved by HSAs reference regulatory agencies *

The approved SmPC / PI / PIL currently approved by each of HSAs reference
agencies should be submitted, where applicable

1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture
1.5.3 PI / SmPC / PIL approved by other regulatory agency

The approved SmPC / PI / PIL from the drug regulatory agency that issued the
proof of approval, if different from the Country of Origin

1.5.4
If applicable: declaration that the translation of the SmPC/PI/PIL conforms to the
SmPC/PI/PIL currently approved


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)
1.6
Assessment report issued by HSAs reference regulatory
agency:

(Please specify)
* *
1.7 Description of batch numbering system * *
1.8
Proof of Approval from:
Country of Origin Reference Agency Others:
__________________________________________________

* * *
1.9
Proof of Approval from at least 2 of HSAs reference regulatory agencies
Please specify issuing agencies:
__________________________________________________

* *
1.10 Authorisation Letters

All submitted authorisation letters shall be hardcopy originals on the authorising
authorised person in the company

The names and addresses stated in the letters should be consistent with the
information provided in application form and dossier

1.10.1 Authorisation Letter from Product Owner to the Applicant firm * *

This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product

1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s) * *

This letter authorises the specified manufacturer to produce, pack and/or label
the drug product intended for Singapore

If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product

For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required

1.10.3 Authorisation Letter from Product Owner to the Batch Releaser * *

This letter authorises the specified company to test and batch release the drug
product


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)
1.11
GMP certification/proof of GMP compliance for each finished product manufacturer
inclusive secondary packer(s)
* *

For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided

Proof of GMP compliance must not expire within 6 months from the time of submission
to HSA

Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of the
supplied diluent(s) will follow the same requirements applicable to the drug product
e.g. proof of GMP compliance

The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form

1.12 Patent declaration form * *

The Patent Declaration form is required for each NDA and GDA

Under Applicant Particulars, name & address of the local applicant firm to be stated

Under Product Particulars, the product name is stated and it should be consistent with
that stated in PRISM, the application form, all product labelling and all other relevant
documents in the dossier

Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent

1.13 Declaration on rejection, withdrawal and deferral * * *

1.14
Declaration that Singapore product is identical to current approved product by reference
agency
*

Applies only to NDA verification dossier
1.15
Registration Status in Other Countries as separate attachment in PRISM under [7]
Supporting Attachments
*

For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments) and in hardcopy in section 1.15 of the CTD Module 1


Application Type

NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)

FOR MAV-1, registration status should be attached in this PRISM section (supporting
attachments) and in hardcopy in section 1.15 of the CTD Module 1


Module 2 Common Technical Document Summaries

Application Type

Section Document Dossier Type
NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page (Vol
__ Page __ to
__)
2.1 Overall CTD Table of Contents of Modules 2, 3, 4 and 5 * * *
2.2 Introduction * * *
2.3 Singapore Quality Overall Summary (QOS) & QOS in other format, if available * *
2.4 Non-clinical Overview *
2.5 Clinical Overview * *
2.6 Non-clinical Summary

2.6.1 Introduction *

2.6.2 Pharmacology Written Summary *

2.6.3 Pharmacology Tabulated Summary *

2.6.4 Pharmacokinetics Written Summary *

2.6.5 Pharmacokinetics Tabulated Summary *

2.6.6 Toxicology Written Summary *

2.6.7 Toxicology Tabulated Summary *

2.7 Clinical Summary

2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods *
2.7.2 Summary of Clinical Pharmacology Studies *
2.7.3 Summary of Clinical Efficacy * *
2.7.4 Summary of Clinical Safety * *
2.7.5 Synopses of Individual Studies * *


Module 3 Quality

Application Type
NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)
For verification dossier The submission should include Module 3 dossier as originally submitted to the
reference agency, and any documentations submitted to the same reference agency in subsequent
variations to the quality aspects of the product.

3.1 Module 3 Table of Contents * *
3.2 Body of Data
3.2.S Drug Substance (Acti ve Substance)

3.2.S.1 General Information

3.2.S.1.1 Nomenclature

* *

3.2.S.1.2 Structure

* *

3.2.S.1.3 General Properties * *

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s) * *

3.2.S.2.2 Description of Manufacturing Process and Process Controls * *

3.2.S.2.3 Control of Materials * *

3.2.S.2.4 Controls of Critical Steps and Intermediates * *

3.2.S.2.5 Process Validation and/or Evaluation * *

3.2.S.2.6 Manufacturing Process Development * *

3.2.S.3 Characterisation

3.2.S.3.1 Elucidation of Structure and other Characteristics * *

3.2.S.3.2 Impurities * *

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification of Drug Substance * *

Application Type
NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)
3.2.S.4.2 Analytical Procedures * *
3.2.S.4.3 Validation of Analytical Procedures * *
3.2.S.4.4 Batch Analyses * *
3.2.S.4.5 Justification of Specification * *

3.2.S.5 Reference Standards or Materials * *

3.2.S.6 Container Closure System * *

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions * *

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment * *

3.2.S.7.3 Stability Data * *

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product * *

3.2.P.2 Pharmaceutical Development

3.2.P.2.1 Components of the Drug Product

3.2.P.2.1.1 Drug Substance * *

3.2.P.2.1.2 Excipients * *

3.2.P.2.2 Drug Product

3.2.P.2.2.1 Formulation Development * *

3.2.P.2.2.2 Overages * *

3.2.P.2.2.3 Physicochemical and Biological Properties * *

3.2.P.2.3 Manufacturing Process Development * *

3.2.P.2.4 Container Closure System * *

Application Type
NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)

3.2.P.2.5 Microbiological Attributes * *

3.2.P.2.6 Compatibility * *

3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer(s) * *

3.2.P.3.2 Batch Formula * *

3.2.P.3.3 Description of Manufacturing Process And Process Controls * *

3.2.P.3.4 Controls of Critical Steps and Intermediates * *

3.2.P.3.5 Process Validation and/or Evaluation * *
3.2.P.4 Control of Excipients
3.2.P.4.1 Specifications * *
3.2.P.4.2 Analytical Procedures * *
3.2.P.4.3 Validation of Analytical Procedures * *
3.2.P.4.4 Justification of Specifications * *
3.2.P.4.5 Excipients of Human or Animal Origin * *
3.2.P.4.6 Novel Excipients * *
3.2.P.5 Control of Drug Product

3.2.P.5.1 Specification(s) of Drug Product * *
3.2.P.5.2 Analytical Procedures * *
3.2.P.5.3 Validation of Analytical Procedures * *
3.2.P.5.4 Batch Analyses * *
3.2.P.5.5 Characterisation of Impurities * *
3.2.P.5.6 Justification of Specification(s) * *

Application Type
NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)
3.2.P.6 Reference Standards or Materials * *

3.2.P.7 Container Closure System * *
3.2.P.8
Stability

3.2.P.8.1 Stability Summary and Conclusions * *

3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment * *

3.2.P.8.3 Stability Data * *
3.2.A Appendices

3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients
3.2.R Regional Information/Requirements

3.2.R.1 Checklist for Human Blood Product with required supporting documents
3.2.R.2 TSE Checklist with required supporting documents
3.2.R.3 Product Interchangeability (Bioequivalence Study Reports) *
3.2.R.4 Blank Production Batch Record
3.3 List of Literature References *

Module 4 Non-clinical Study Reports

Application Type

NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)
4.1 Module 4 Table of Contents *
4.2 Study Reports
4.2.1 Pharmacology

4.2.1.1 Primary Pharmacodynamics *

4.2.1.2 Secondary Pharmacodynamics *

4.2.1.3 Safety Pharmacology *

4.2.1.4 Pharmacodynamic Drug Interactions *

4.2.2 Pharmacokinetics

4.2.2.1 Analytical Methods and Validation Reports *

4.2.2.2 Absorption *

4.2.2.3 Distribution *

4.2.2.4 Metabolism *

4.2.2.5 Excretion *

4.2.2.6 Pharmacokinetic Drug Interactions (non-clinical) *

4.2.2.7 Other Pharmacokinetic Studies *

4.2.3 Toxicology

4.2.3.1 Single-Dose Toxicity *

4.2.3.2 Repeat-Dose Toxicity *

4.2.3.3 Genotoxicity *

4.2.3.4 Carcinogenicity *

4.2.3.5 Reproductive and Developmental Toxicity *

4.2.3.6 Local Tolerance *


Application Type

NDA MAV-1 GDA
ICH CTD
Vol/Page
(Vol __ Page
__ to __)
4.2.3.7 Other Toxicity Studies *

4.3 List of Literature References *


Module 5 Clinical Study Reports

Application Type

Section
Document
Dossier Type
NDA MAV-1 GDA MAV-2
ICH CTD
Vol/Page
(Vol __ Page __
to __)
5.1 Module 5 Table of Contents * *
5.2 Tabular Listings of All Clinical Studies * *

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

For Abridged and Verification Dossiers: only final study report(s) of
biopharmaceutic studies to establish bioequivalence between commercial
product formulation and clinical trial formulation used in pivotal studies should
be submitted, if applicable

For Full Dossier, all biopharmaceutic study reports are required
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials *
5.3.3 Reports of Pharmacokinetic (PK) Studies *
5.3.4 Reports of Pharmacodynamic (PD) Studies *
5.3.5 Reports of Efficacy and Safety Studies * *

For Full Dossier, reports of all clinical trials should be submitted, including the
appendices & tables

For Abridged and Verification Dossiers, only study reports of pivotal or
relevant clinical trials should be submitted (appendices & tables are required
upon request by HSA)

5.3.6 Reports of Post-marketing Experience * *
5.3.7
Case Report Forms and Individual Patient Listings (required upon request by
HSA)

5.4 List of Key Literature References * *

5.5 Other Supporting Documents



APPLICATION CHECKLIST (ACTD)


APPENDIX 3 APPLICATION CHECKLIST (ACTD)
This Application Checklist should be used to ensure submission of a complete dataset in the ASEAN CTD format.
To use this Checklist, check against the dossier and application type for your submission.
For NDA and MAV-1 applications, the document shown in the second column has to be submitted if the symbol representing the dossier type viz.
full dossier represented by , abridged dossier by and verification dossier by , and * (under application type) appear on the same row.
For GDA and MAV-2 applications, the Dossier Type column does not apply.

Application Type NDA GDA MAV-1 MAV-2
Dossier Type Full dossier Abridged dossier Verification dossier

Note: without the asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ASEAN guidance on ACTD for explanatory notes on the
preparation of documents for a submission in ACTD format.



Part I Administrative Documentation

Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)
1.1 Comprehensive Table of Contents * * * *
Include a complete list of all documents provided in the application dossier by Part
The location of each document should be identified by the Part number

For hardcopy submissions, the location of each document should be identified by the
volume number and tab identifiers (name of document or section heading according
to ACTD format)

1.2 Introduction * * * *
Provide a concise and precise summary of the application
Justify the lack of certain documents and deviation(s) from guidelines
1.3 PRISM Application Form * * * *
1.3.1 Section 1: Company Particulars * *
Company shall be based and registered in Singapore

1.3.2 Section 2: Applicant particulars * * * *

Applicant must be a permanent staff of the company and is residing in
Singapore. If the person making the application / correspondence person is
an external party (consultant) engaged by the applicant company, an original
letter of authorization from the applicant company must be submitted.

Company address and contact details can be entered instead of personal
residential address and contact details

1.3.3 Section 3: Application Details
3.1 Type of Application * * * *
3.2 Type of Product * *
3.3 Reference Product *

All GDA applications Specify Singapore Reference Products SIN
number



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)

If GDA-2 application not submitted at the same time as GDA-1
application Specify both the Singapore Reference Products and
the GDA-1 products SIN numbers

If NDA-3 applications not submitted at the same time as NDA-1/2
application Specify the NDA-1/2s SIN number

3.4 Product intended for export * *
3.5 Type of Dossier * *
3.6 Type of Format * *
1.3.4 Section 4: Product Information
4.1 Product name * *

Enter in the following format:
Product Name - Dosage Form Product Strength

Refer to Guidance document section 6.1.4 for additional pointers
4.2 Product Formula * *

Include the full composition of all active substances and excipients
(including water) that are present in the final pharmaceutical
dosage form

Ingredients related to the pharmaceutical dosage form, such as
tablet film coating or capsule shell, should be indicated within
parentheses before the ingredient name, e.g. (Film coating)
Ingredient Z

For active ingredients presented in the form of salts and chelate,
the quantity should be clearly stated, e.g., XX phosphate 32 mg
(equivalent to XX)



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)

Information on residual amounts of certain materials, such as
antibiotics, thiomersal and materials of biological origin (e.g. human
serum albumin), added or present in the drug product must be
declared. Information to declare includes the following:
o the materials name enter (Residual), followed by the
materials name in the Name of Substance field;
o the materials grade, if applicable;
o the materials limit in the product enter , followed by the limit
in the Strength field.

4.3 Ingredients derived from human blood or animal sources * *

Information to be provided in the following format: (Species &
product) (In manufacturing/drug substance/excipient) (Country)

4.4 ATC Code * *
4.5 Dosage Form * *
4.6 Route of Administration * *
Include all routes of administration proposed for the product
4.7 Packaging, Shelf Life & Storage Condition * *

Where more than one drug component is included in a drug
product (e.g., powder for injection with solvent as composite pack)
and each component has a different shelf life, the shorter shelf life
is to be used as the shelf life of the composite pack

4.8 Forensic Classification * * *
4.9 Registration Status in Other Countries * * *
For each country - State the application status and status date

For country of origin and all reference agencies - State the
application status, status date, application details and forensic
classification



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)

For products approved via an appeal process, following either a
negative opinion/rejection/non-approvable decision or an
approvable/conditional approvable decision Provide reasons for
the initial regulatory decision along with the subsequent approval

For applications submitted to the European Union agencies, the
type of application i.e. centralised, decentralised, mutual
recognition or national, should be identified; For decentralised and
mutual recognition applications, the reference member state should
be indicated

For applications approved by the UK MHRA Indicate whether
approval was granted through national procedure or whether MHRA
acted as RMS or CMS for decentralised and mutual recognition
procedures in European Union

For NDA & GDA, the registration status of the product in other
countries should be entered into PRISM

In the event that the PRISM text space does not allow input of full
details of the indication(s), dosing regimen(s), and/or reason(s), a
brief description may be entered; The full details should be attached
in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and
in hardcopy in section 1.16 of the CTD Part 1

For MAV-1, the registration status should be attached in softcopy
(PDF) in PRISM section 7 (Supporting Attachments) and in
hardcopy in section 1.16 of the CTD Part 1

4.10 Product Owner * *
1.3.5 Section 5: Manufacturers Particulars * *

All manufacturers of active substance(s), drug product and diluent used to
reconstitute the product (if packed and sold together with the drug product)
must be declared

For secondary packagers, enter (Secondary packager) after the name of
the manufacturer

All manufacturers names and addresses should be consistent throughout all
of the documents submitted in the application, such as GMP certificates,
CPPs, Letters of authorisation, Part II of the CTD and so forth



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)
1.3.6 Section 6: Batch Release Details * *

If there are multiple companies responsible for batch release, the applicant
must declare all of the sites

1.3.7 Supporting Documents * * * *
Attach all documents relating to Part I of the CTD

Other Parts Either attach in full in this PRISM section or submit soft copies
in CD

1.4
Labelling and PI/PIL proposed & currently approved in Singapore. For NDA and GDA
only proposed labelling and PI/PIL need to be submitted

Labelling must be in English; If non-English text is included in the labelling, applicants
must provide an official statement to declare that the non-English text is complete,
accurate and unbiased information and is consistent with the English text

Highlight any non-English country-specific labelling requirements on the
artwork/drafts if the labelling is shared with other countries

1.4.1 Outer/Carton Labels * *
1.4.2 Inner/Blister Labels * *
1.4.3 Package Insert (PI)
1.4.4 Patient Information Leaflet (PIL) *
1.5 Approved SmPC/PI/PIL

1.5.1 SmPC/PI/PIL approved by HSAs reference regulatory agencies *

The approved SmPC / PI / PIL currently approved by each of HSAs
reference agencies should be submitted, where applicable

1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture
1.5.3 PI / SmPC / PIL approved by other regulatory agency

The approved SmPC / PI / PIL from the drug regulatory agency that issued
the proof of approval, if different from the Country of Origin

1.5.4
If applicable: declaration that the translation of the SmPC/PI/PIL conforms to the
SmPC/PI/PIL currently approved



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)
1.6
Assessment report issued by HSAs reference regulatory
agency:

(Please specify)
* *
1.7 Description of batch numbering system * *
1.8
Proof of Approval from:
Country of Origin Reference Agency Others:
__________________________________________________

* * *
1.9
Proof of Approval from at least 2 of HSAs reference regulatory agencies
Please specify issuing agencies:
__________________________________________________

* *
1.10 Authorisation Letters

All submitted authorisation letters shall be hardcopy originals on the authorising
authorised person in the company

The names and addresses stated in the letters should be consistent with the
information provided in application form and dossier

1.10.1 Authorisation Letter from Product Owner to the Applicant firm * *

This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product

1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s) * *

This letter authorises the specified manufacturer to produce, pack and/or
label the drug product intended for Singapore

If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product

For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required

1.10.3 Authorisation Letter from Product Owner to the Batch Releaser * *

This letter authorises the specified company to test and batch release the
drug product



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)
1.11
GMP certification/proof of GMP compliance for each finished product manufacturer
inclusive secondary packer(s)
* *

For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided

Proof of GMP compliance must not expire within 6 months from the time of
submission to HSA

Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of
the supplied diluent(s) will follow the same requirements applicable to the drug
product e.g. proof of GMP compliance

The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form

1.12 Patent declaration form * *

The Patent Declaration form is required for each NDA and GDA

Under Applicant Particulars, name & address of the local applicant firm to be stated

Under Product Particulars, the product name is stated and it should be consistent
with that stated in PRISM, the application form, all product labelling and all other
relevant documents in the dossier

Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent

1.13 Declaration on rejection, withdrawal and deferral * * *

1.14
Declaration that Singapore product is identical to current approved product by reference
agency
*

Applies only to NDA verification dossier
1.15
Registration Status in Other Countries as separate attachment in PRISM under [7]
Supporting Attachments
*

For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments) and in hardcopy in section 1.15 of the CTD Part 1



Application Type

NDA MAV-1 GDA MAV-2
ACTD
Vol/Page
(Vol __ Page __
to __)

FOR MAV-1, registration status should be attached in this PRISM section (supporting
attachments) and in hardcopy in section 1.15 of the CTD Part 1



Part II Quality

Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
For verification dossier The submission should include Part II dossier as originally submitted to the
reference agency, and any documentations submitted to the same reference agency in subsequent
variations to the quality aspects of the product.

A Table of Contents of Part II * *
B Singapore Quality Overall Summary (QOS) & QOS in other format, if available * *
C Body of Data
Drug Substance (Acti ve substance)
S1 General Information

S1.1 Nomenclature * *

S1.2 Structure * *

S1.3 General Properties * *

S2 Manufacture

S2.1 Manufacturer(s) * *

S2.2 Description of Manufacturing Process and Process Controls * *

S2.3 Control of Materials * *

S2.4 Controls of Critical Steps and Intermediates * *

S2.5 Process Validation and/or Evaluation * *

S2.6 Manufacturing Process Development * *

S3 Characterisation

S3.1 Elucidation of Structure and other Characteristics * *

S3.2 Impurities * *

S4 Control of Drug Substance

S4.1 Specification of Drug Substance * *



Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
S4.2 Analytical Procedures * *

S4.3 Validation of Analytical Procedures * *

S4.4 Batch Analyses * *

S4.5 Justification of Specification * *

S5 Reference Standards or Materials * *

S6 Container Closure System * *

S7 Stability

S7.1 Stability Summary and Conclusions * *

S7.2 Post-approval Stability Protocol and Stability Commitment * *

S7.3 Stability Data * *

Drug Product
P1 Description and Composition of the Drug Product * *

P2 Pharmaceutical Development

P2.1 Information on Development Studies * *

P2.2 Components of the Drug Product

P2.2.1 Active Ingredients * *

P2.2.2 Excipients * *

P2.3 Finished Product

P2.3.1 Formulation Development * *

P2.3.2 Overages * *

P2.3.3 Physicochemical and Biological Properties

P2.4 Manufacturing Process Development * *

P2.5 Container Closure System * *



Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
P2.6 Microbiological Attributes * *

P2.7 Compatibility * *

P3 Manufacture

P3.1 Batch Formula * *

P3.2 Description of Manufacturing Process And Process Controls * *

P3.3 Controls of Critical Steps and Intermediates * *

P3.4 Process Validation and/or Evaluation * *

P4 Control of Excipients

P4.1 Specifications * *

P4.2 Analytical Procedures * *

P4.3 Excipients of Human and Animal Origin * *

P4.4 Novel Excipients * *

P5 Control of Drug Product (Finished Product)

P5.1 Specification of Drug Product * *

P5.2 Analytical Procedures * *

P5.3 Validation of Analytical Procedures * *

P5.4 Batch Analyses * *

P5.5 Characterisation of Impurities * *

P5.6 Justification of Specifications * *

P6 Reference Standards or Materials * *

P7 Container Closure System * *

P8 Stability

P8.1 Stability Summary and Conclusions * *



Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
P8.2 Post-approval Stability Protocol and Stability Commitment * *

P8.3 Stability Data * *

P9 Product Interchangeability *

D Key Literature References *

Q Country-specific Quality Requirements

Q1 Checklist for Human Blood Product with the required supporting documents

Q2 TSE Checklist with the required supporting documents

Q3 Blank Production Batch Record

Q4 Appendices

A.1 Facilities and Equipment

A.2 Adventitious Agents Safety Evaluation

A.3 Novel Excipients



Part III Non-clinical Data

Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
A Table of Content of Part III *
B Non-clinical Overview *
B1 General Aspect *
B2 Content and Structural Format *
C Non-clinical Summary (Written and Tabulated)
C1 Non-clinical Written Summary
C1.1 Pharmacology *
C1.2 Pharmacokinetics *
C1.3 Toxicology *
C2 Non-clinical Tabulated Summaries *
D Non-clinical Study Report
D1 Table of Content *
D2 Pharmacology
D2.1 Primary Pharmacodynamics *
D2.2 Secondary Pharmacodynamics *
D2.3 Safety Pharmacology *
D2.4 Pharmacodynamics Drug Interactions *
D3 Pharmacokinetics
D3.1 Analytical Methods and Validation Reports *
D3.2 Absorption *
D3.3 Distribution *
D3.4 Metabolism *


Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA
ACTD Vol /
Page (Vol __
Page __ to __)
D3.5 Excretion *
D3.6 Pharmacokinetics Drug Interaction (non-clinical) *
D3.7 Other Pharmacokinetics Studies *
D4 Toxicology
D4.1 Single-Dose Toxicity *
D4.2 Multiple-Dose Toxicity *
D4.3 Genotoxicity *
D4.4 Carcinogenicity *
D4.5 Reproductive and Developmental Toxicity *
D4.6 Local Tolerance *
D4.7 Other Toxicity Studies *
E List of Key Literature References *


Part IV Clinical Data

Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA MAV-2
ACTD Vol /
Page (Vol __
Page __ to __)
A Table of Content of Part IV * *

B Clinical Overview * *
C Clinical Summary

C1 Summary of Biopharmaceutic Studies and Associated Analytical Methods *
C2 Summary of Clinical Pharmacology Studies *
C3 Summary of Clinical Efficacy * *
C4 Summary of Clinical Safety * * *
C5 Synopses of Individual Studies * *
D Tabular Listing of All Clinical Studies * *

E Clinical Study Reports

E1 Reports of Biopharmaceutic Studies

For Abridged and Verification Dossiers: only final study report(s) of
biopharmaceutic studies to establish bioequivalence between commercial
product formulation and clinical trial formulation used in pivotal studies should be
submitted, if applicable

For Full Dossier, all biopharmaceutic study reports are required
E2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials *
E3 Reports of Human Pharmacokinetic (PK) Studies *
E4 Reports of Human Pharmacodynamic (PD) Studies *
E5 Reports of Clinical Efficacy and Safety Studies * *

For Full Dossier, reports of all clinical trials should be submitted, including the
appendices & tables

For Abridged and Verification Dossiers, only study reports of pivotal or relevant
clinical trials should be submitted (appendices & tables are required upon
request by HSA)



Application Type

Section Document
Dossier
Type
NDA MAV-1 GDA MAV-2
ACTD Vol /
Page (Vol __
Page __ to __)
E6 Reports of Post-marketing Experience *
E7 Case Reports Forms and Individual Patient Listing (required upon request by HSA)
F List of Key Literature References * *

G Other Supporting Documents



GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION MEDICINAL PRODUCTS


APPENDIX 4 GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION
MEDICINAL PRODUCTS

This document is intended to provide assistance in the submission of applications for
non-prescription medicinal products. It provides guidance on the eligibility criteria for a
reduced dataset submission and additional explanatory notes on documentary
requirements for drug registration

1 Eligibility for waiver of clinical documents

As stated in section 6.2.1.2 of the Guidance on Medicinal Product Registration in
Singapore, applicants may submit a written request for a waiver of clinical data
submission. The request may be made if the product fulfils the criteria below:

a) The active substance(s) must not be currently classified as a POM in Singapore.

b) The medicinal product should have been evaluated and approved as a non-
prescription medicine, as defined below, by at least one of the following reference
regulatory agencies:

Australia TGA non-prescription medicines refer to drugs substances listed in
Schedule 2 and 3 of SUSDP
1
.

Health Canada non-prescription medicines refer to medicinal products
classified under Schedule II, III or U.

US FDA non-prescription medicines. Products registered under the FDA OTC
Monograph (21 Code of Federal Regulations Chapter 1, Parts 300-499)
2
, which
are marketed without prior FDA clearance, are excluded.

UK MHRA non-prescription medicines refer to medicinal products classified as
P or GSL.

The approved classification by a reference regulatory agency does not obligate
HSA. HSA reserves the right to determine the products forensic classification
based on assessment of the products risk versus benefit profile as well as local
public health implications.

c) The use of each active substance contained in the product should be well-
documented in the following standard reference texts:

Martindale: The Complete Drug Reference. Sweetman SC (Ed.).
Pharmaceutical Press, UK.

Handbook of Non-prescription Drugs. American Pharmaceutical Association,
USA.

Remingtons Pharmaceutical Sciences. Gennaro AR (Ed.). American
Pharmaceutical Association, USA and Pharmaceutical Press, UK.

AHFS Drug Information. McEvoy GK (Ed.). American Society of Health System
Pharmacists, USA.

1
Standard for the Uniform Scheduling of Drugs and Poisons
2
http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfrv5_01.html
GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION MEDICINAL PRODUCTS


Handbook of Pharmaceutical Excipients. Kibbe AH (Ed.). American
Pharmaceutical Association, USA and Pharmaceutical Press, UK.

Other well-established reference texts may be accepted if deemed appropriate by
HSA.

If adequate documentation is provided, submission of clinical efficacy and safety data of
the product may not be required. Any use outside of the documented indication(s),
dosage(s) and route(s) of administration will require evidence of efficacy and safety
unless otherwise justified. It should be noted that anecdotal or limited clinical reports of
efficacy alone (for example, in Martindale, xxx has also been used in) will not be
accepted as evidence of safety and efficacy.

2 Documentary requirements

If the product fulfils the criteria as defined in section 1, the clinical data set in support of
the application may be reduced.

The documentary requirements are described in section 6.4 in the Guidance on Medicinal
Product Registration in Singapore, with following additional explanatory notes:

Administrative documents

The administrative documents required are the same as that for the abridged dossier
evaluation route.

Labelling (section 1.4) for non-prescription medicines should be provided in the form of a
Patient Information Leaflet (PIL). A PIL must be clear, simple and readable so that
consumers can understand information about the product, its benefits, its risks and how
the product should be used appropriately. For details on PIL labelling requirements,
please refer to the Appendix 6 Points to consider for Singapore labelling.

The Proof of Approval (section 1.8) by the drug regulatory agency should be an official
approval letter or equivalent document that also states the forensic classification of the
product. However, HSA may still request a CPP, if deemed appropriate.

Quality documents

The quality requirements for a non-prescription medicine are the same as that of a POM
product.

Non-clinical & clinical documents

The clinical part of the dossier should include a Clinical Overview and supporting
information from standard reference texts as listed in section 1(c) above. The supporting
documents should be inserted in section 2.5 of Module 2 (ICH CTD) or section B of Part
IV (ACTD).

HSA reserves all rights to request for the complete clinical data set if it is deemed
appropriate.
FLOWCHART FOR TRANSLATION OF NON-ENGLISH DOCUMENTS


APPENDIX 5 FLOW CHART FOR TRANSLATION OF NON-ENGLISH
DOCUMENTS

Non-English original document issued by a national drug regulatory agency (original bears seal and
signature)
e.g. GMP certificate, approval letter, CPP, SmPC/PIL (Product Information) and other documents
Applicable to product applications submitted to HSA:
1. Submit all original documents (including all translations, declarations & confirmations, where
applicable) to HSA; or
2. Submit certified true copy of all documents to HSA. Originals should be kept with the
applicant and should be provided upon request by HSA.
In languages other than Malay
(including Bahasa Indonesian),
Tamil or Chinese
In Malay (including Bahasa
Indonesian), Tamil or Chinese
Document translated at
Supreme Court (or Subordinate
Courts) in Singapore
Translated by non-
official source (e.g.
In-house translation)
Translation to be
endorsed/certified by a
responsible officer of
either the Embassy of the
Country of Origin in
Singapore OR the
Singapore Embassy in the
Country of Origin
Embassy of Country of
Origin is not available in
Singapore OR Singapore
Embassy is not available in
Country of Origin
Embassy of Country of
Origin is available in
Singapore OR Singapore
Embassy is available in
Country of Origin
Translator to make
declaration in presence of a
notary public
Notary public to be
authenticated by the relevant
authority in the Country of
Origin


POINTS TO CONSIDER FOR SINGAPORE LABELLING

APPENDIX 6 POINTS TO CONSIDER FOR SINGAPORE LABELLING

Labelling refers to any printed or graphic information on the immediate container, outer
packaging and any other form of printed material supplied together with the product.

Information provided in the labels should be consistent with the information submitted in
the application dossier. Any deviation should be highlighted and brought to HSAs
attention.

1 Outer/Carton Labels and Inner/Blister Labels

The Outer Carton refers to the product packaging in which the immediate packaging is
placed, e.g. the carton box containing blister strips. The Inner Label refers to the label
that is fixed onto the primary container closure system, e.g. the label affixed to a bottle,
vial or ampoule. The Blister Label refers to the foil backing of a blister strip.

In addition to the legal labelling requirements, the following information shall be present
on the labelling of the product:

Parameters
Outer
Carton
Inner
Label
Blister Label
1. Product Name
2. Dosage Form * NA
3. Name of Active Substance(s)
4. Strength of Active Substance(s)
5. Batch Number
6. Manufacturing Date*** * NA
7. Expiry Date
8. Route of Administration NA
9. Storage Condition * NA
10.
Name & Address of Product Owner
and/or Product Licence Holder***
*
Name/Logo of
Manufacturer/
Product Owner
11. Name & Address of Manufacturer** * NA
12. Warnings (if applicable) * NA
13. Pack Sizes (unit/volume) NA
14. Special Labelling (if applicable) * NA
15.
Name & Content of preservative(s) (if
applicable)
* NA

NA Not applicable
* Exempted for small labels such as an ampoule or vial with a nominal volume of 10 ml or less. Other
factors may be considered such as the amount of information which needs to appear on the label and
the font size necessary to achieve legibility of the information.
** The words Batch released by instead of Manufactured by may be used if the site named is
responsible for product release. The name and address of either the manufacturer or the batch releaser
should be present.
*** ASEAN labelling requirements


If the product is supplied without an outer carton, the information that is required on the
outer carton should be stated on the inner label.

Any handwritten information on the specimens, mock-ups or text is not acceptable, with
the exception of statements such as batch number and expiry dates will be printed or
similar.

Website addresses, email addresses and/or telephone numbers on the products labelling
may be considered if adequately justified, for example, in the case where the information
is intended for the purpose of adverse drug reaction reporting.

2 Package Insert (PI)

Package inserts are required for products classified as Prescription Only Medicines
(POMs).

The PI is regarded as a document that contains information that will ensure safe and
effective use of the drug product. It includes a scientific, objective account of the
medicines usefulness and limitations as shown by data submitted in the application.
Information in the PI shall be non-promotional in nature.

The following information is required for the PI:

i. Brand or Product Name as provided in the application.
ii. Name and Strength of Active Substance(s) the non-proprietary name of each
therapeutically active drug substance.
iii. Product Description a description of relevant physical and chemical
characteristics of the drug product and its formulation(s).
iv. Pharmacodynamics/Pharmacokinetics the pharmacokinetic and pharmacological
action(s), particularly in humans, of each drug substance. The ATC code should
be stated, if possible.
v. Indication the therapeutic indication(s) of the product.
vi. Recommended Dosage the information required include, as appropriate:
dosing regimen (dose and interval);
information on dose adjustments in special populations, e.g. elderly, children,
renal insufficiency, hepatic insufficiency and concomitant disease;
maximum recommended/tolerated daily dose and the maximum dose for an
entire course of therapy;
monitoring advice;
other pertinent information such as relationship to meals and compatibility with
other drugs and fluids; and,
reference to a dosing regimen for an unregistered product or unapproved
indication is not acceptable.
vii. Mode/Route of Administration only standard abbreviations should be used. Non-
standard or complicated routes of administration should be carefully explained in
full to avoid confusion, particularly when the product is made available for self-
selection.
viii. Contraindications situations where patients should never or generally not be
treated with the medicine. In rare cases where the medicine should never be
given, this must be explicitly stated.

ix. Warnings and Precautions circumstances where caution is required to ensure
safe and efficacious use of the drug.
x. Interactions with Other Medicines information on clinically relevant interactions
and other potentially serious interactions based on the pharmacology of the
medicine.
xi. Use during Pregnancy/Lactation
xii. Adverse Effects/Undesirable Effects provide an indication of severity, clinical
importance and frequency, whenever possible.
xiii. Overdose and Treatment symptoms, signs and recommended treatment of
overdose or accidental poisoning.
xiv. Incompatibilities (for injections only)
xv. Storage Condition if it is included in the PI, the storage condition must be
consistent with the product label and/or outer carton.
xvi. Dosage Forms or Presentation this refers to the available pack size(s) in
Singapore. The statement, Not all presentations may be available locally or
similar, must be included if this section includes listing of unregistered
presentations/pack sizes.
xvii. Name and Address of Manufacturer or Product Owner or Product Licence Holder
xviii. Date of Revision of Package Insert if a common PI is used for an internationally
marketed product, the date can follow the date of revision of the common PI.
However, if a Singapore-specific PI is used, the date of revision must reflect the
actual date that the local PI is revised.

3 Patient Information Leaflet (PIL)

Patient Information Leaflets (PILs) are required for Pharmacy Only (P) and General Sale
List (GSL) medicinal products. The PIL must be easily understood and be consistent with
the product labels and/or PI, as appropriate. The following information is required in the
PIL:

i. Name of Product
ii. Description of Product
iii. What is the medicine?
iv. Strength of the medicine
v. What is this medicine used for?
vi. How much and how often should you use this medicine?
vii. When should you not take this medicine?
viii. Undesirable effects/side effects
ix. What other medicine or food should be avoided whilst taking this medicine?
x. What should you do if you miss a dose?
xi. How should you keep this medicine?
xii. Signs & symptoms of overdose
xiii. What to do when you have taken more than the recommended dosage?
xiv. Name/logo of manufacturer/importer/product licence holder
xv. Care that should be taken when taking this medicine?
xvi. When should you consult your doctor?

If the product is sold without a PIL, the information that is required in the PIL must be
stated on the outer carton.


PATENT DECLARATION FORM

Appendix 7: Patent Declaration Form
(Version 28 June 2004: 2 pages)

PATENT DECLARATION FORM


REPUBLIC OF SINGAPORE
HEALTH SCIENCES AUTHORITY
MEDICINES ACT
(CHAPTER 176)
DECLARATION ON PATENT RELATED INFORMATION FOR
APPLICATION FOR PRODUCT LICENCE
Application No (for HSA use only):
SECTION 1: APPLICANT PARTICULARS
Name
Address
SECTION 2: PRODUCT PARTICULARS
Proprietary Name
Active Substance(s) and Strength
Dosage Form
SECTION 3: APPLICATION CATEGORY
Application Category (check one box)*
Category A1 (Proceed to Section 4)
Refers to an application where no patent is in force in respect of the medicinal product to which the application
relates.
Refers to an application where a patent is in force in respect of the medicinal product to which the application
relates; and the applicant is either the proprietor of the patent or, if the applicant is not the proprietor of the
patent, the proprietor has consented to or acquiesced in the grant of the product licence.
relates, the applicant is not the proprietor of the patent, the proprietor has not consented to nor acquiesced in
the grant of the product licence; and the applicant is requesting for grant of product licence after the expiry of
the patent. Such an application may not be made earlier than 18 months before the expiry of the patent.
Category B (Proceed to Section 7)
relates, the applicant is not the proprietor of the patent, the proprietor has not consented to nor acquiesced in
the grant of the product licence; and in the opinion and to the best belief of the applicant, the patent is invalid
or will not be infringed by the doing of the act for which the licence is sought.
SECTION 4: INFORMATION FOR CATEGORY A1 APPLICATIONS
I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that
there is no patent under the Patents Act (Cap. 221) in force in respect of the product stated in Section 2 on
the date of this declaration.
* For categories A2, A3 and B, please submit a separate declaration for each patent that is in force in respect of
the medicinal product.

I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that (check one box)
a patent under the Patents Act is in force in respect of the product stated in Section 2 on the date of this
declaration. I am the proprietor of the patent. The Singapore Patent No. for the patent is .
declaration. I am not the proprietor of the patent but the proprietor has consented to or acquiesced in the
grant of the product licence for the product stated in Section 2 to me. The name and address of the proprietor
of the patent or his authorised agent are . The Singapore Patent No. for the patent is .
declaration. I am not the proprietor of the patent and the proprietor has not consented to nor acquiesced in
the grant of the product licence for the product stated in Section 2 to me. I am requesting for the grant of the
product licence after the expiry of the patent. I am making the application not earlier than 18 months before
the expiry of the patent.
The name and address of the proprietor of the patent or his authorised agent are .
The Singapore Patent No. for the patent is .
The patent will expire on (dd/mm/yyyy), which is months from the date of my product licence
application.
SECTION 7: INFORMATION FOR CATEGORY B APPLICATIONS
declaration. I am not the proprietor of the patent and the proprietor has not consented to nor acquiesced in
the grant of the product licence for the product stated in Section 2 to me. In my opinion and to my best belief,
the patent (check one box)
is invalid; or
will not be infringed by the doing of the act for which the licence is sought.
The name and address of the proprietor of the patent or his authorised agent are .
The Singapore Patent No. for the patent is .
The patent will expire on (dd/mm/yyyy).
SECTION 8: DECLARATION
I am duly authorised by the applicant to make this declaration on behalf of the applicant, and enclose herewith
evidence of such authorisation
#
.
I,

the applicant/the authorised agent of the applicant on behalf of the applicant, declare that all information furnished
in this form is true. I am aware that a false declaration is an offence under the Medicines Act (Cap. 176). I further
undertake to notify the Health Sciences Authority of any change in the information furnished in this form.
Name: Designation:
Signature and Date: Applicants Stamp:
_______________________________

#
Please enclose appropriate evidence of authorisation. Delete this statement if applicant is a natural
person making the application personally.
SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS

APPENDIX 8 SINGAPORE QUALITY OVERALL SUMMARY
New Drug Applications and Generic Drug Applications (Chemicals)

The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e.,
Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) or a Generic Drug
Application (GDA) for a chemical drug product. Both hard copy and electronic copy of the Singapore QOS
shall be submitted for review.

The applicant is responsible for completing all sections and fields as much as possible. Sections and fields
that are not applicable should be indicated with NA. An explanatory note must immediately follow all NA
entries.

INTRODUCTION
Proprietary Name of Drug Product
INN Common Name of Drug
Substance

Product Owner Name
Licence Holder Name
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
Other introductory information:


S DRUG SUBSTANCE

S 1 GENERAL INFORMATION

Check appropriate box.
DMF (open) part is attached.
DMF (open and restricted) and Letter of Access to be submitted by DDMMYYYY (within
one month of PRISM submission),
OR
Letter of Access to the DMF filed with HSA (015:________) is provided.
* CEP (Certificate of Suitability from EDQM) for Drug Substance is attached.
CEP Number:
CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients is attached.
Drug Substance meets the current USP/PhEur/BP/JP (delete as appropriate)
requirements.
Drug Substance meets other pharmacopoeia standards.
Drug Substance meets in-house specifications.
Drug Substance meets other pharmacopoeia standards. Analytical methods and
appropriate analytical method validation data are included in the dossier.
Drug Substance meets in-house specifications. Analytical methods and appropriate
analytical method validation data are included in the dossier.
* If CEP is provided and Ph.Eur standard is claimed for drug substance, please fill in S1, S2.1, S4.4 and
#
S7
If CEP is provided and other standards are claimed for drug substance, please fill in S1, S2.1, S4.1 to S4.5 and
#
S7
(
#
To be provided if re-test period/shelf life is not stated on CEP)

S 1.1 Nomenclature

Hard Copy Location/Pages:
E-Copy Location/File Name:

Chemical Name:
Other names: (e.g. INN, BAN, USAN, common name)

Company or laboratory code:

Chemical Abstracts Service (CAS) registry number:

S 1.2 Structure


Structural formula (including stereochemistry): [insert structure]

Molecular formula:
Molecular Mass:

S 1.3 General Properties


Physical description (e.g., appearance, colour, physical state):
Physical form (e.g., polymorphic form, solvate, hydrate):
Solubilities (e.g., in common solvents, aqueous/non-aqueous
solubility profile):

pH and pKa values:
Other (e.g., partition coefficients, melting or boiling points,
optical rotation, refractive index (for a liquid), hygroscopicity,
UV absorption maxima and molar absorptivity):

S 2 MANUFACTURE

S 2.1 Manufacturer(s)

Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing:
Activity Name and Address *GMP Compliance (Please
indicate Approving Agency)
Site of Manufacture
Site of Release testing
Site of Batch Release
* For information only.

S 2.2 Description of Manufacturing Process and Process Controls


Typical production batch size:

Flow diagram of the synthetic process(es):


S 2.3 Control of Materials


S 2.4 Controls of Critical Steps and Intermediates


S 2.5 Process Validation and/or Evaluation


S 2.6 Manufacturing Process Development


S 3 CHARACTERISATION

S 3.1 Elucidation of Structure and other Characteristics


S 3.2 Impurities

Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation:
Chemical
Name/Laboratory Code
Origin/Type of Impurity Structure

[insert structure]


Process-related impurities (e.g., residual solvents):
Compound Name Step in Process

S 4 CONTROL OF THE DRUG SUBSTANCE

S 4.1 Specification

Standard Claimed for the Drug Substance (e.g., USP, BP,
etc.):

Test Method
(e.g., HPLC)
Source (e.g.,
USP, in-
house)
Acceptance Criteria


S 4.2 Analytical Procedures
S 4.3 Validation of Analytical Procedures

For each test, please indicate yes or no as appropriate
Test Name
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S 4.4 Batch Analyses

Batch Number Batch Size
Batch Type
(production/pilot)
Date of
Production
Site of Production

S 4.5 Justification of Specification


Test Justification of Specifications

S 5 REFERENCE STANDARDS OR MATERIALS


Batch Number Source (e.g., USP, in-house)
Primary Reference Standard
Working Standard

S 6 CONTAINER CLOSURE SYSTEM

Description of the container closure system(s) for the storage of the drug substance:


S 7 STABILITY

S 7.1 Stability Summary and Conclusions

Stability study details:
Storage
Conditions
(C, % RH, light)
Batch
Number
Batch Size Site of
Manufacture
Completed Test Intervals
(months)

Summary and discussion of all stability study results:


Proposed storage conditions and re-test period (or shelf life, as appropriate):
Container Closure
System
Storage Conditions Re-test Period (or Shelf Life, as
appropriate)

S 7.2 Post-approval Stability Protocol and Stability Commitment

Stability protocol for commitment batches (if applicable):
Protocol Parameter Description
Number of batches and batch sizes
Tests and acceptance criteria
Container closure system(s)
Testing frequency
Storage conditions (and tolerances) of samples
Other


S 7.3 Stability Data


P DRUG PRODUCT

P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

(1) Description of the dosage form:

(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis
(including overages, if any):
Strength (Label claim):
Components Quality Standard Quantity per unit % Function

Total

(3) Composition, i.e., qualitative list of all components of proprietary materials (e.g., capsule shells,
colouring blends, imprinting inks, etc.):
Proprietary Material Qualitative Composition Quantitative Composition

(4) Description of accompanying reconstitution diluent(s), if applicable:


P 2 PHARMACEUTICAL DEVELOPMENT

P 2.1 Components of the Drug Product


P 2.2 Drug Product

P 2.2.1 Formulation Development

P 2.2.2 Overages

P 2.2.3 Physicochemical and Biological Properties

P 2.3 Manufacturing Process Development

Discussion of the development of the manufacturing process of the drug product (e.g., optimization of
the process, selection of the method of sterilization, etc.):

P 2.4 Container Closure System

Discussion of the suitability of the container closure system (described in P 7) used for the storage,
transportation (shipping), and use of the drug product (e.g., physicochemical tests, biological reactivity
tests, leaching, etc.):

P 2.5 Microbiological Attributes

Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):


P 2.6 Compatibility

Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g.,
precipitation of drug substance in solution, sorption on injection vessels, etc.):

P 3 MANUFACTURE

P 3.1 Manufacturer(s)

production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
Site of Fabrication, Manufacturing
Site of Primary Packaging
Site of Secondary Packaging
Site of Release Testing

P 3.2 Batch Formula

List of all components of the dosage form to be used in the manufacturing process, and their amounts
on a per batch basis (including overages, if any):
Batch Size (Number of dosage units):
Component and Quality Standard (and Grade, if applicable) Quantity per batch


List of all components of the dosage form to be used in the manufacturing process, and their amounts
on a per batch basis (including overages, if any):
Batch Size (Number of dosage units):
Total

P 3.3 Description of Manufacturing Process and Process Controls


Flow diagram of the manufacturing process(es):

P 3.4 Controls of Critical Steps and Intermediates


P 3.5 Process Validation and/or Evaluation


Please check appropriate boxes.
Development Pharmaceutics Report Starting page #:
Ending page#:

Validation Scheme Starting page #:
Ending page#:

____ (e.g. 2) Pilot batches were used in the
validation study
Starting page #:
Ending page#:

____ (e.g. 3) full production batches were used in
the validation study
Starting page #:
Ending page#:

Type of Validation
Retrospective
Prospective
Concurrent*
Others; please specify:
* Prior consultation with HSA is required.


Manufacturing site at which the validation is carried out:
Batch Number (Batches must be consecutive) Batch Size
Batch Type
(production/pilot/experimental)

Post-Approval Commitment

(1) Validation protocol for commitment batches:
Number of batches per strength
Batch Size

P 4 CONTROL OF EXCIPIENTS

P 4.1 Specifications

Specifications for non-compendial excipients and for compendial excipients which include
supplementary tests not required by the monograph(s) may be found in:

P 4.2 Analytical Procedures


P 4.3 Validation of Analytical Procedures


P 4.4 Justification of Specifications

J ustification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria,
exclusion of certain tests, differences from compendial standard, etc.):


P 4.5 Excipients of Human or Animal Origin


P 4.6 Novel Excipients


P 5 CONTROL OF DRUG PRODUCT

P 5.1 Specification(s)

Standard Claimed for the Drug Product
(e.g., USP, Ph.Eur, BP, JP etc.):

Test Method (e.g.,
HPLC)
Source (e.g.,
USP, In-house)
Release
Specification
Shelf Life
Specification



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P 5.4 Batch Analyses

Batch Type
(production/pilot)
Date of
Production
Site of
Production
Site of Batch
Release

P 5.5 Characterisation of Impurities

Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary of
actual and potential degradation products, basis for setting the acceptance criteria, etc):
Chemical Name/Laboratory
Code
Origin/Type of Impurity

P 5.6 Justification of Specification(s)



P 6 REFERENCE STANDARDS OR MATERIALS

If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided Data of
studies performed on working standard against primary standard should be included, together with
appropriate Certificate of Analysis.


Working Standard

P 7 CONTAINER CLOSURE SYSTEM

Description of the container closure systems:
Description of Container Closure Quantity Per Container Pack Size

P 8 STABILITY

P 8.1 Stability Summary and Conclusions


Proposed Commercial Batch Size (kg):
Batch
Number
Batch Size Date of
Manufacture
Site of
Manufacture
Source of Active
Ingredient and
Batch Number
Container
Closure
System

Storage Conditions (C, % RH,
light)


In-use stability testing (where applicable):
In-use Storage Conditions
(C, % RH, light)
Length of Storage prior to Start
of In-use Stability Testing
Completed In-use Test Intervals
(e.g. minutes/ hours/ days)

Proposed storage conditions and shelf life:
Container Closure
System
Storage Conditions (and In-use
Storage Conditions, if
applicable)
Shelf Life (and In-use Period, if
applicable)

P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability protocol for commitment batches:
Number of batches per strength and batch
sizes

Testing frequency
Other

(2) Stability protocol for continuing (i.e., ongoing) batches:
Number of batches per strength per year and
batch sizes


(2) Stability protocol for continuing (i.e., ongoing) batches:
Testing frequency
Other

P 8.3 Stability Data

P 9 PRODUCT INTERCHANGEABILITY

P 9.1 Bioavailability / Bioequivalence Study

Details of the batches used
for BA/BE study
Generic Product Submitted to
HSA for Registration
Current Registered
Singapore Reference
Product
Product Name
Strength of Dosage Form
Site of Manufacture
Site of Batch Release N/A
Batch No.
Batch size N/A
Product formula
Same as section P.3.2
Yes
No, please provide justification
N/A

Study Report Number
BA/BE Study Site (Name & Address)
Date of Inspection of Study
Name of Inspecting Agency/Authority
Availability of Inspection Report (Yes/No)
Generic Product Used
in BA/BE Study
Reference Product Used
in BA/BE Study
Product Name
Site of Manufacture

Study Report Number
Country where the supply is
sourced for this study:

P 9.2 Comparative Dissolution Profile

Product 1: =
Product 2: =

Study Report Number:
Profile of Product 1 Profile of Product 2
Product Name
Site of Manufacture
Dissolution Method Used
Country where the supply is
sourced for this study:

Dissolution Test Results Profile of Product 1 Profile of Product 2
Medium 1
Range
Mean of 12 tablets
RSD
F2 Calculation
Medium 2
Range
Mean of 12 tablets
RSD
F2 Calculation
Medium 3
Range
Mean of 12 tablets
RSD
F2 Calculation
Graphical Presentation Presented in Pages ..

Statistical Analysis


Other Relevant Information:

A APPENDICES

A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)


A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM, MANUFACTURER)


A 3 NOVEL EXCIPIENTS


Applicants Name: Date:



SINGAPORE QUALITY OVERALL SUMMARY FOR BIOLOGICS

APPENDIX 9 SINGAPORE QUALITY OVERALL SUMMARY
New Drug Applications (Biologics)

The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e., Chemistry,
Manufacturing and Controls) portion of a New Drug Application (NDA) for a biologic drug product.
Both hard copy and electronic copy of the Singapore QOS shall be submitted for review.

The applicant is responsible for completing all sections and fields as much as possible. Sections and
fields that are not applicable should be indicated with NA. An explanatory note must accompany all
NA entries.

INTRODUCTION

Proprietary Name of Drug Product
Non-Proprietary or Common Name of
Drug Substance

Product Owner Name
License Holder Name
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)

Other introductory information:


S DRUG SUBSTANCE

S 1 GENERAL INFORMATION

Check appropriate box.
CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients is attached.
Plasma Master File (PMF)
Site Master File (SMF)

Drug Substance meets in-house specifications. Analytical methods and appropriate
analytical method validation data are included in the dossier.

S 1.1 Nomenclature


Substance Name:
Other names:
(e.g. INN, BAN, USAN, common name)

Company or laboratory code:

S 1.2 Structure


Schematic amino acid sequence indicating
glycosylation sites or other post-translational
modifications and relative molecular mass
should be provided, as appropriate:

S 1.3 General Properties


Physicochemical and other relevant properties
of the drug substance, including biological
activity


S 2 MANUFACTURE

S 2.1 Manufacturer(s)

Name and address, of each production site or facility involved in different manufacture and testing
activities:

2.1.1
Drug Substance Manufacture

2.1.2
Process Intermediates Manufacture
(e.g. Master Cell Bank, Working Cell
Bank)

2.1.3
Pilot/ Development Batches
Manufacture

2.1.4
Testing of Process Intermediates and
Drug Substance Release

2.1.5
Stability Study

2.1.6
Others (if applicable, please specify)

S 2.2 Description of Manufacturing Process and Process Controls


Typical production batch size:

Flow diagram of the manufacturing process:

S 2.3 Control of Materials



S 2.4 Controls of Critical Steps and Intermediates


S 2.5 Process Validation and/or Evaluation


S 2.6 Manufacturing Process Development


S 3 CHARACTERISATION

S 3.1 Elucidation of Structure and other Characteristics


S 3.2 Impurities

(1) Product-Related Impurities:
Name Description Control Method* & Acceptance Level

* Please indicate if it is controlled by in-process control test, product release test, or by validated
purification method.

(2) Process-Related Impurities:
Human plasma derived materials
Name Origin / Point of Entry Control Method* & Acceptance Level

Animal derived materials


Other materials

S 4 CONTROL OF THE DRUG SUBSTANCE

S 4.1 Specification

Standard Claimed for the Drug Substance (e.g., USP, BP, in-
house etc.):

Test Method
(e.g., HPLC)
Source/Ref #
or SOP #
Acceptance Criteria

Copy of official Drug Substance Release Specifications



S 4.2 Analytical Procedures
S 4.3 Validation of Analytical Procedures

Test Name
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S 4.4 Batch Analyses

Batch Type
(production/pilot)
Date of
Production
Site of Production

S 4.5 Justification of Specification



S 5 REFERENCE STANDARDS OR MATERIALS


Batch Number
Source (e.g., USP, in-
house)
Working Standard

S 6 CONTAINER CLOSURE SYSTEM


Description of the container closure system(s) for the storage of the drug substance:


S 7 STABILITY

S 7.1 Stability Summary and Conclusions

(1) Stability Study Details:
Storage Conditions
(C, % RH, light)
Batch
Number
Batch Size Site of
Manufacture
(months)

(2) Summary and Discussion of All Stability Study Results:

(3) Proposed Storage Conditions and Shelf Life:
Container Closure System Storage Conditions Shelf Life

S 7.2 Post-approval Stability Protocol and Stability Commitment

Stability protocol for commitment batches (if applicable):
Number of batches and batch sizes
Testing frequency
Other

S 7.3 Stability Data



P DRUG PRODUCT

P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

(1) Description of the Dosage Form (Type of container closure system used for the dosage
form and accompanying reconstitution diluent, if applicable):

(2) Composition (i.e., list of all components of the dosage form, and their amounts on a per unit
basis including overages):
Component

Quality Standard Quantity per unit
(incl. overages)
Function
Drug Substance

Excipients (Human Plasma Derived)

Excipients (Animal Derived)

Excipients (Others)

Residuals

Reconstitution Diluents


P 2 PHARMACEUTICAL DEVELOPMENT

P 2.1 Components of the Drug Product


P 2.2 Drug Product

P 2.2.1 Formulation Development

P 2.2.2 Overages

P 2.2.3 Physicochemical and Biological Properties

P 2.3 Manufacturing Process Development

Discussion of the development of the manufacturing process of the drug product
(e.g., optimization of the process, selection of the method of sterilization, etc.):

P 2.4 Container Closure System

Discussion of the suitability of the container closure system (described in P 7) used for the
storage, transportation (shipping), and use of the drug product and reconstitution diluent (e.g.,
physicochemical tests, biological reactivity tests, leaching, etc.):

P 2.5 Microbiological Attributes

Discussion of microbiological attributes of the dosage form where applicable (e.g., preservative
effectiveness studies):


P 2.6 Compatibility

Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage
devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, etc.):

P 3 MANUFACTURE

P 3.1 Manufacturer(s)

production site or facility involved in manufacture and testing of product intended for Singapore:

3.1.1
Drug Product Manufacture

3.1.2
Process Intermediates (e.g. Drug
Product bulk) Manufacture (if different
from 3.1.1)

3.1.3
Pilot/ Development Batches
Manufacture (if different from 3.1.1)

3.1.4
Testing for Process Intermediates and
Drug Product Release (if different from
3.1.1)

3.1.5
Stability Study (if different from 3.1.1)

3.1.6
Others (if applicable, please specify)


P 3.2 Batch Formula

List of all components of the dosage form to be used in the manufacturing process, and their
amounts on a per batch basis (including overages, if any):
Batch/ Lot Size (Number of dosage units):

Total

P 3.3 Description of Manufacturing Process and Process Controls


Flow diagram of the manufacturing process(es):

P 3.4 Controls of Critical Steps and Intermediates


P 3.5 Process Validation and/or Evaluation


Manufacturing site at which the validation is carried out:
Batch Number (Batches must be consecutive) Batch Size
Batch Type
(production/pilot/experimental)


P 4 CONTROL OF EXCIPIENTS

P 4.1 Specifications

supplementary tests not required by the monograph(s):





P 4.4 Justification of Specifications

J ustification of the specifications (e.g., evolution of tests, analytical procedures, and
acceptance criteria, exclusion of certain tests, differences from compendial standard, etc.):

supplementary tests not required by the monograph(s).

P 4.5 Excipients of Human or Animal Origin

Information regarding adventitious agents for excipients of human or animal origin (e.g.,
sources, specifications, description of the testing performed, viral safety data):

P 4.6 Novel Excipients



P 5 CONTROL OF DRUG PRODUCT

P 5.1 Specification(s)

Standard Claimed for the Drug Product
(e.g., USP, Ph.Eur, BP, JP, In-house etc.):

Test Method (e.g.,
HPLC)
Source/Ref #
or SOP #
Release
Specification
Shelf Life
Specification

Copy of Official Drug Product Release Specifications:



Test Name
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P 5.4 Batch Analyses

Batch Type
(production/pilot)
Date of
Production
Site of
Production
Site of Batch
Release

P 5.5 Characterisation of Impurities

Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary
of actual and potential degradation products, basis for setting the acceptance criteria, etc):

P 5.6 Justification of Specification(s)



P 6 REFERENCE STANDARDS OR MATERIALS

If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided Data
of studies performed on working standard against primary standard should be included, together
with a Certificate of Analysis.



Working Standard

P 7 CONTAINER CLOSURE SYSTEM

Description of the container closure systems:

Container Closure System Quantity per Container Pack Size

P 8 STABILITY

P 8.1 Stability Summary and Conclusions

(1) Summary and Conclusions:

(2) Stability Study Details:
Proposed Commercial Batch Size (e.g.
kg, litres) :

Batch
Number
Batch Size Date of
Manufacture
Site of
Manufacture
Source of Drug
Substance and
Batch number
Container
Closure
System



Storage Conditions (C, % RH,
light)

In-use stability testing (where applicable):
In-use Storage Conditions
(C, % RH, light)
Length of Storage prior to
Start of In-use Stability
Testing
Completed In-use Test Intervals
(e.g. minutes/ hours/ days)

(3) Proposed Storage Conditions and Shelf Life:
Container Closure
System
Storage Conditions (and In-use
Storage Conditions, if applicable)
Shelf Life (and In-use Period, if
applicable)

P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability Protocol for Commitment Batches:
Number of batches per strength and batch sizes
Testing frequency
Other
(2) Stability Protocol for Continuing (i.e., ongoing) Batches:


Number of batches per strength per year and
batch sizes

Testing frequency
Other

P 8.3 Stability Data


A APPENDICES

A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)


A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM,
MANUFACTURER)


A 3 NOVEL EXCIPIENTS


Applicants Name: Date:



GUIDELINE ON THE REGISTRATION OF HUMAN PLASMA-DERIVED MEDICINAL PRODUCTS


APPENDIX 10 GUIDELINE ON THE REGISTRATION OF HUMAN PLASMA-
DERIVED MEDICINAL PRODUCTS

This guideline
1
is applicable to all plasma-derived medicinal products containing an active
or inactive ingredient that is derived from human blood. Because such products carry the
risk of transmission of infectious agents, the safety of these products is assured through
the requirements as described in this appendix along with the main guidance document.

1 DOCUMENTARY REQUIREMENTS

Applications for human plasma-derived medicinal products will be evaluated on its quality,
safety and efficacy prior to marketing. This guideline outlines the requirements for the
Plasma Master File (PMF) and specific quality documentation to support registration of
these products.

The checklist in Annex 1 of this appendix may serve as a guide to the documentary
requirements.

1.1 Body of Data Drug Substance

1.1.1 Plasma Master File

Documents pertaining to the collection and control of source materials should be provided
as a PMF. The PMF is a stand-alone document and should be filed separately from the
application. Thus, one set of the PMF should be submitted together with the dossier
application for registration of a human plasma-derived product.

However, if the source of the plasma-derived ingredient(s) differs from the applicant, it is
the applicants responsibility to procure the PMF from the PMF holder for submission to
HSA. The applicant may also cross-reference a currently registered PMF to the
application, where applicable.

Take note that the applicant is responsible to update the registered PMF every two years.

PMF Data Requirements

The data must conform to the requirements recommended by HSAs reference drug
regulatory agencies and in particular, the following documents and their subsequent
revisions:
Note for Guidance on Plasma-Derived Medicinal Products (CPMP/BWP/269/95
rev. 3)
Guideline on the Scientific Data Requirements for a Plasma Master File (PMF)
(CPMP/BWP/3794/03)

The PMF document requirements include:

a) Documents that verify each donor of source material has undergone a proper
screening procedure and has met all established health criteria (including viral risks
requirements). The criteria used must conform to the recommendations on suitability

1
Adapted from CPMP NfG on Plasma-derived Medicinal Products (CPMP/BWP/269/95 rev. 3) and US FDA
Guidance for Industry for the Submission of Chemistry, Manufacturing and Controls and Establishment
Description Information for Human Plasma-derived Biological Products, Animal Plasma and Serum-derived
Products


of blood and plasma donors set out by the US FDA, the Council of Europe and the
Australian TGA. The following details need to be provided:

i Collection centres
Names and addresses of blood/plasma collection centres, including sub-
contractors and any separate site for testing of individual donations; and,
Audits:
- Internal audits (frequency and date of last audit); and,
- Audits by regulatory authority (frequency and date of last audit).

ii Data on epidemiology and blood-borne infections
Provide an assurance that there is a continuing evaluation of the epidemiology
at collection centres; and,
Data should be reported as:
- Incidence of confirmed seroconversion rates in regular donors (per number
of donors and number of donations); and,
- Prevalence of confirmed positives in new donors and known donors.

iii Selection/Exclusion criteria
Characteristics of donation:
- Indicate whether or not a plasma donor is remunerated;
- Clarify the nature of any compensation for donation; and,
- Outline the nature of the examination and interview of donors; and,
Exclusion criteria for donors:
- Confirm that centres do not collect blood/plasma from a population with a
high prevalence of infections transmitted by blood (HIV, HCV, HBV etc.);
- Confirm that there are measures taken to ensure viral safety for recipients
with respect to major pathogenic agents; and,
- Compliance with those exclusion criteria specified in appropriate
documents (Directives, Guidelines, Pharmacopoeial).

b) Documents that verify each unit of source material has been tested non-reactive for
Hepatitis B surface antigen, Anti-HIV-1&2 by NAT, Anti-HCV by NAT and other test
parameters as recommended by US FDA or an equivalent authority. There must be
no pooling of plasma for testing purposes. The following details need to be provided:

i Screening tests for markers of infection:
List of tests performed on individual donation;
Licence number for each test kit used;
Validation of these screening procedure methods; and,
Details of any inventory hold/ quarantine periods and procedures.

c) Documents that verify all steps in the processing of source material, including donor
examination, blood collection, plasmapheresis, laboratory testing, labelling, storage,
and issuing, are performed in centres that have been licensed by the US FDA or
equivalent authority for that purpose. The centres must conform to the requirements
for the collection of source materials as specified in The Collection, Fractionation,
Quality Control, And Uses of Blood and Blood Products published by the WHO. The
following details need to be provided:

i. System to trace the path of any donation:
Confirm that there is a system in place that ensures traceability from the
donation centre to finished product and vice versa; and,
Provide information on steps that would be taken if it is found retrospectively
that the donation(s) should have been excluded from processing.


d) Documents that verify all source materials are collected by aseptic techniques
designed to assure the integrity and minimise the risk of contamination of the source
material. The documents should also verify that the closure of the container used
maintains a hermetic seal. The following details need to be provided:

i. Blood bags
Information on the name of bag, manufacturer, anticoagulant solution,
composition and specification; and,
Indication on conformance to a particular standard (e.g. WHO, Ph. Eur.).

ii. Plasma quality
Information on storage conditions and maximum storage time with an
indication on how conditions are maintained from collection centre to the
manufacturer; and,
Confirmation of compliance with appropriate standard.

iii. Plasma specification
Information on specification(s) and confirm compliance to specification(s); and,
Information on in-process tests on the plasma pool, if any.

e) Documents that verify the source materials do not contain an additive other than
citrate or acid citrate dextrose anticoagulant solution, unless it has been shown that
the processing method yields a final product free of the additive to such an extent that
the continued safety, purity, potency, and effectiveness of the final product is not
adversely affected.

f) Documents that verify the fractionator/manufacturer and donation
centre(s)/organisation responsible for collecting plasma complies with PIC/S GMP
and procedures.

g) Letter of commitment from the Manufacturer stating that:
i. All collection centres have signed the contract; and,
ii. The national authority will be notified in the event of a serious failure of a blood
collection centre.

1.2 Body of Data Drug Product

1.2.1 Manufacturing Process and Control

The following data should be filed in the Quality section of the CTD (Module 3 of ICH CTD
or Part 2 of ACTD).

a) Documents that verify all steps in the manufacture of the final product are conducted
in establishments licensed by the US FDA or equivalent authority for that purpose. All
handling and processing techniques employed should conform with current relevant
international GMP guidelines of the US FDA, the Australian TGA, the EMEA CHMP or
WHO.

b) Documents that verify each batch of source material intended for manufacture has
been tested for Hepatitis B surface antigen, antibody to HIV-1&2 and antibody to
Hepatitis C Virus by tests approved for such use by the US FDA or an equivalent
authority. Each batch of source material must also be tested for HCV RNA by
genomic amplification testing. The following details need to be provided:

i. Plasma pooling


Information on the number of individual plasma units pooled together;
List of tests performed on these plasma pools; and,
Licence number for each test kit used.

c) Documents that verify the processing method used does not affect the integrity of the
product and has been demonstrated to consistently yield a product that is safe for use
in humans. Processing methods used for the manufacture of intravenous products
should have been shown to consistently yield a product that is safe for intravenous
injection.

d) Documents that verify processing steps are conducted to minimise risk of
contamination from pyrogens, micro-organisms, or other impurities. Preservatives to
inhibit growth of micro-organisms should not be used or added to the product at any
stage of processing. The following details need to be provided:

i. Manufacturing process
A detailed description of the manufacturing process and controls to
demonstrate proper quality control or prevention of possible contamination
with adventitious agents:
- Starting materials: Information on raw materials, intermediate products,
reagents and auxiliary materials with specifications or statements of quality
of each;
- Flowchart: A complete visual representation of the manufacturing process
flow. This flow should show the production steps, equipment, and materials
used, along with a complete list of the in-process controls and tests
performed on the product at each step. This diagram should also include
information on the methods used to transfer the product between steps;
- Detailed description: A detailed description of the fractionation, formulation,
sterilisation, purification and aseptic processes. This should include a
rationale for the chosen methods, and the precautions taken to assure
containment and prevention of contamination or cross-contamination. In-
process bioburden and endotoxin limits should be specified where
appropriate. Any reprocessing or related method should be fully validated
and described. The allowable conditions for reprocessing of all or parts of
any batch should be described; and,
- Batch record: A complete batch record of the process of production of the
biologic product should be included.

ii. Process control
A description of the control checks performed at various stages of the
manufacture, processing and packaging of the product;
A description of the in-process and final controls, including analytical tests and
appropriate data to support the specifications; and,
Validation data:
- A description of the validation studies, which identify and establish
acceptable limits for critical parameters to be used as in-process controls,
to assure the success of routine production;
- Validation studies for the purification process: a description of the
validation of the purification process to demonstrate adequate removal of
extraneous substances such as chemicals used in purification, column
contaminants, endotoxin, antibiotics, residual plasma proteins, non-viable
particulates and viruses; and,
- Validation studies for all sterilisation and aseptic processes (e.g.
formulation through filling and sealing).



iii. Notes on process steps for inactivation and removal of viruses
Procedures specifically designed to inactivate or remove infectious viruses
should be clearly defined, justified and documented. In addition, recent
transmissions of both enveloped and non-enveloped viruses by certain
plasma-derived products have highlighted the need for a strategy to further
increase the assurance of viral safety of these products;
When necessary, a viral risk assessment should be performed via calculation
of the estimated risk per dose, as outlined in the Guideline on Assessing the
Risk for Virus Transmission New Chapter 6 of the Notes for Guidance on
Plasma-derived Medicinal Products (CHMP/BWP/5180/03). The risk
assessment should demonstrate that the virus inactivation/removal capacity
clearly exceeds the potential amount of virus that could enter the production
process;
The following document, and its subsequent revisions, should also be referred:
- Note for Guidance on Virus Validation Studies: The Design, Contribution
and Interpretation of Studies Validating the Inactivation and Removal of
Viruses (CPMP/BWP/268/95); and,
The following notes are provided as a general guide:
- Albumin (Human Solution and Plasma Protein Fraction [Human] Solution)
the product must have undergone heat treatment or other established
viral inactivation procedures. Heat treatment should be conducted so that
the solution is heated continuously for not less than 10 or more than 11
hours at an attained temperature of 60 0.5
o
C.
- Clotting Factor Concentrate, Intravenous Immunoglobulin and
Intramuscular Immunoglobulin the product must have undergone
processing methods that include established and validated specific viral
inactivation capable of inactivating at least 10
5
infectious particles of HIV
per mL of solution (i.e. a 5 log
10
reduction in concentration of viable virus),
and not to transmit viral hepatitis.

1.2.2 Drug Product

The following data should also be filed in the Quality section of the CTD (Module 3 of ICH
CTD or Part 2 of ACTD).

The physical, chemical and pharmaceutical properties of the finished product must
comply with the relevant United States, British or European Pharmacopoeial
requirements. The following details need to be provided:

a) Product testing
i. Specifications and analytical methods used for release testing and expiration
dating to assure product identity, purity, strength, or potency and lot-to-lot
consistency;
ii. Validation protocol and results for non-compendial analytical systems to
demonstrate system suitability;
iii. Lot release protocols, including specification ranges of representative lots of the
product. Specifications may include, but not limited to, biochemical purity, safety,
appearance, pH, residual moisture, excipients, endotoxins, and sterility; and,
iv. Methods and standards of acceptance, including the sampling plan and the
accuracy and precision of the analytical methods in sufficient detail to permit
duplication and verification.
b) Container closure system/shipping containers
i. A description of the container and closure system with information on its
compatibility with the biological substance; and,
ii. Evidence of container and closure integrity.


c) Stability
i. Stability data for the product as packaged in the registered container closure
system;
ii. A description of the storage conditions, study protocols and results supporting the
stability of the product and any intermediates that are stored;
iii. An expiration date supported by the results of the stability study; and,
iv. When used as an excipient in medicinal products, the expiry date of the plasma-
derived product should not be earlier than that of the finished product. It is
recommended that the manufacturers have a system in place to maintain
traceability and notifications regarding post-collection information.

2 REGULATORY DECISION

When approved for registration, the product licence issued for a human plasma-derived
medicinal product will have the following post-approval conditions:

a) The import and sale of the product must be accompanied by a batch certification. The
batch certification and product movement records shall be maintained for 10 years
from the date of importation and be made available for inspection by HSA when
required.

b) The Product Licence Holder is responsible for ensuring that the product imported for
local sale and supply is identical, in all aspects, to that approved by HSA. The licence
holder should notify HSA of minor variations and obtain approval before
implementation as stipulated in Appendix 15 of the Guidance of Medicinal Product
Registration in Singapore.



ANNEX 1 CHECKLIST FOR THE REGISTRATION OF HUMAN PLASMA-DERIVED
MEDICINAL PRODUCTS

Appendix
Section
Document
Yes/No
(Encl. #)
For
official
use
1.1.1 Plasma Master File
1.1.1 (a) Documents that verify each donor of source material
has undergone a proper screening procedure to
ensure that all established health criteria (including
viral risks requirements) are met.

1.1.1 (a) (i) Details on collection centers

1.1.1 (a) (ii) Data on epidemiology and blood-borne infections

1.1.1 (a) (iii) Selection/ Exclusion criteria

1.1.1 (b) Documents that verify each unit of source material
has been tested non-reactive for Hepatitis B surface
antigen, Anti-HIV-1 & 2 and Anti-HCV.

1.1.1 (b) (i) Details of screening tests for markers of infection

1.1.1 (c) Documents that verify all steps in the processing of
source materials are performed in licensed centres
that conform to WHOs requirements.

1.1.1 (c) (i) Look back system to trace the path of any donation

1.1.1 (d) Documents that verify all source materials are
collected by aseptic techniques designed to assure
the integrity and to minimise the risk of contamination
of the source material and that the closure of the
container used maintains a hermetic seal.

1.1.1 (d) (i) Blood bags

1.1.1 (d) (ii) Plasma quality

1.1.1 (d) (iii) Plasma specification

1.1.1 (e) Documents that verify source materials do not contain
any additive other than citrate or acid citrate dextrose
anticoagulant solution unless it has been shown that
the processing method yields a final product free of
the additive to such an extent that the continued
safety, purity, potency and effectiveness of the final
product is not adversely affected.

1.1.1 (f) Documents that verify fractionator/ manufacturer and
donation centre(s)/organisation responsible for
collecting plasma complies with PIC/S GMP and
procedures.

1.1.1 (g) a) Manufacturers letter of commitment.



1.2.1 Manufacturing Process and Control
1.2.1 (a) Documents that verify all steps in the manufacture of
the final product are conducted in licensed
establishments for that purpose. All handling and
processing techniques employed should conform to
current relevant international GMP guidelines.

1.2.1 (b) Documents that verify each batch of source material
intended for manufacture has been tested for hepatitis
B surface antigen, antibody to HIV-1 & 2, antibody to
Hepatitis C Virus, and HCV RNA.

1.2.1 (b) (i) Details of plasma pooling

1.2.1 (c) Documents that verify the processing method used
does not affect the integrity of the product and has
been demonstrated to consistently yield a product.
Processing methods used for the manufacture of
products intended for IV use should have been shown
to consistently yield a product that is safe for IV
injection.

1.2.1 (d) Documents that verify processing steps are conducted
to minimise risk of contamination from pyrogens,
microorganisms, or other impurities. Preservatives to
inhibit growth of microorganisms are not used of
added to the product at any stage of processing.

1.2.1 (d) (i) Details of the manufacturing process

1.2.1 (d) (ii) Details of process control

1.2.1 (d) (iii) Details of assessing the risk for viral transmission

1.2.2 Drug Product
1.2.2 Statement on whether the physical, chemical and
pharmaceutical properties of the finished products
comply with the relevant United States, British or
European Pharmacopoeial requirements.

1.2.2 (a) Details of product testing

1.2.2 (b) Details of container closure system/shipping
containers

1.2.2 (c) Stability data

GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN

APPENDIX 11 GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL
PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN

Medicinal products containing animal-derived components animals carry the potential risk
of Transmissible Spongiform Encephalophathy (TSE). The safety of these products is
assured through the requirements as described in this appendix along with the main
guidance document.

This guideline
1
is applicable to all medicinal products containing an ingredient, whether
active or inactive, that is derived from animals. It applies to all materials of animal origin
that are used in the preparation of both active (e.g. insulin) and inactive ingredients (e.g.
gelatin, cell culture medium), and any other reagent that may come into contact with a
pharmaceutical product during its manufacturing process (e.g. cell culture serum and
enzymes).

Transmissible Spongiform Encephalopathy (TSE)

Transmissible Spongiform Encephalopathy (TSE) is a group of degenerative brain
diseases that includes scrapie in sheep and goats, Chronic Wasting Disease (CWD) in
deer and elk, Bovine Spongiform Encephalopathy (BSE) in cattle and Kuru and
Creutzfeldt-J akob Disease (CJ D) in humans. Agents causing these diseases replicate in
infected individuals generally without evidence of infection detectable by currently
available diagnostic tests. There is evidence to show that these agents may have
incubation periods of up to several years before causing observable disease (usually
neurological disorder) and eventually death. There is currently no treatment or vaccine for
the disease.

BSE is a food borne infection characterised by the presence of prion proteins, abnormal
infectious proteins in nervous tissue. The subsequent spongy degeneration of the brain
results in severe and fatal neurological signs and symptoms. There is evidence
suggesting that the new variant of human Creutzfeldt-J akob Disease (vCJ D) may be
caused by the same agent that is responsible for BSE in cattle.

The discovery of vCJ D has raised concerns that the BSE agent can be transmitted to
humans. Therefore caution is warranted if biological materials from animals known to be
affected by TSE are used in the manufacture of medicinal products.

1 DOCUMENTARY REQUIREMENTS

Applications for medicinal products containing animal-derived materials will be evaluated
on its quality, safety and efficacy prior to marketing. Documents with detailed information
must be submitted to support the registration of all the medicinal products that contain
animal-derived ingredients.

The documents listed below are to be submitted as part of Adventitious Agents Safety
Evaluation in section 3.2.A.2 of the ICH CTD or in section Q A.2 in the ACTD. The
checklist in Annex 1 may serve as a guide to the documentary requirements.

1
Adapted from CPMP-CVMP NfG on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Human and Veterinary Medicinal Products (EMEA/410/01 Rev. 2)

1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk
evaluation Certificate of Suitability (CEP)

Preference is accorded to animal-derived materials that have been awarded Certificates
of Suitability by the European Directorate for the Quality of Medicines & Healthcare
(EDQM). Applicant may refer to the European Pharmacopoeia and the EDQM website
2

for more information on TSE and the Certificate of Suitability.

Supporting documents to be submitted include:

a) A valid TSE Risk Evaluation Certificate of Suitability (CEP)

b) A brief description of the following:

i. Rationale for using animal-derived materials

When manufacturers choose to use animal-derived materials, the rationale for
using these materials instead of that from the non-animal origin should be given.

ii. Source of animals

A compulsory notification of BSE cases in the country of origin and a compulsory
clinical and laboratory verification of suspected cases are required for product
application.

The most satisfactory source of materials is from countries without any reported
case of BSE. The assessment of a countrys BSE status is based on the following:

Office International Des Episooties (OIE) classification
3

Opinions of the Scientific Steering Committee of the European Commission
4

As far as possible, animal-derived materials should be sourced from countries with
a negligible BSE risk in accordance to Terrestrial Animal Health Code (Chapter
2.3.13) of the World Organisation for Animal Health (OIE).

iii. Nature of animal tissue used and measures taken to minimise BSE risk

A declaration of the nature of the animal tissue used should be submitted.

In a TSE-infected animal, different organs and secretions have different
levels of infectivity. In accordance with the EMEA Note for Guidance,
selected ruminant tissues and fluids are classified into the three main
categories as follows:

Category A (High Infectivity): brain, spinal cord, retina, optic nerve, spinal
ganglia, trigeminal ganglia, pituitary gland and dura mater.

Category B (Low Infectivity): peripheral nerves, enteric plexuses, lymph
nodes, nictitating membrane, thymus, oesophagus, forestomach,
stomach/abomasums, duodenum, jejunum, ileum, large intestine, lung,
liver, kidney, spleen, tonsil, placenta, cerebrospinal fluid, adrenal,

2
http://www.edqm.eu
3
http://www.oie.int/eng/info/en_esbmonde.htm
4
http://ec.europa.eu/food/fs/sc/ssc/outcome_en.html

pancreas, bone marrow, blood vessels, olfactory mucosa, gingival tissue,
salivary gland, cornea, blood.

Category C (No detectable Infectivity): faeces, heart/pericardium,
mammary gland/udder, milk, semen, placenta fluids, ovary, saliva,
prostate/epididymis/seminal vesicle, skeletal muscle, testis, uterus (non-
gravid), foetus, embryos, tongue, tendon, trachea, adipose tissue, thyroid
gland, colostrum, cord blood, sweat, tears, nasal mucus, bone, skin, urine.

As a general rule, ruminant-derived raw materials that have been classified
as Category A and Category B tissues or fluids must be sourced from
countries with a negligible BSE risk.

In certain situations, there could be cross-contamination of tissues from
different categories of infectivity, e.g. direct contact between different
materials, or the use of penetrative brain stunning as a method of
slaughtering the animals.

Thus, in such cases, procedures used in collecting the intended animal
tissues/organs and the measures in place to avoid cross-contamination with a
higher risk material must also be described in detail.

iv. Nature and quantity of each animal-derived material used

Detailed information must be provided on the nature and quantity of each animal-
derived material used for the preparation of:

Drug substance;
Excipients and adjuvants;
Raw and starting materials and reagents used in production e.g. bovine
serum albumin, enzymes and culture media including those used to
prepare working cell banks or new master cell banks.

Materials that come into direct contact with the equipment used in the
manufacture of the medicinal product or that come in contact with the medicinal
product and therefore have the potential for contamination should also comply
with these guidelines. Likewise, materials used in the qualification of plant and
equipment, such as culture media used in media fill experiments to validate the
aseptic filling process shall be considered in compliance with these guidelines.

As far as possible, information on the residual amount of animal-derived
materials present in the drug product should be clearly stated as follows:

For example: Foetal bovine serum (residual) 0.350 mcg/mL

1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE risk

The use of animal-derived materials that have NOT been awarded Certificates of
Suitability by the European Directorate for the Quality of Medicines & Healthcare (EDQM)
may still be acceptable, subjected to the risk assessment of the TSE in the form of a
detailed assessment report.


Supporting documents to be submitted includes:

a) Detailed Assessment Report for the risk of TSE

i. The scope of this report should include section 1.1 (b) as well as the risk factors
associated with the route of administration and the maximum therapeutic dosage
(daily dosage and duration of treatment) of the product.

ii. Production process steps for inactivation of TSE agents

Controlled sourcing is the most important criterion in achieving acceptable safety of
the product due to the documented resistance of TSE agents to most inactivation
procedures. The production process, wherever possible, should be designed to
take into consideration all available information on methods that are thought to
inactivate or remove TSE agents.

If claims are made that inactivation of TSE agents occurs during the manufacturing
process, then relevant information on the process should be submitted for
evaluation.

b) Certificate of analysis for each animal-derived material used.

2 RESPONSIBILITY OF PRODUCT LICENSE HOLDER

The Product Licence holder is responsible for ensuring that the product imported for local
sale and supply is identical, in all aspects, to that approved by the licensing authority. The
licence holder should notify HSA of variations and obtain approval before implementing
the variation if necessary (for example, change of source materials for manufacturing).

3 CONCLUSION

The acceptability of a medicinal product containing animal-derived ingredients, or which
as a result of manufacture could contain these materials, will be influenced by a number
of factors, including:

Documented and recorded source of animals;
Nature of animal tissue used in the manufacture;
Production process;
Route of administration;
Quantity of tissue used in the medicinal products;
Maximum therapeutic dosage; and/or,
Intended use of the product.

The above guidelines only serve as guidance. Pharmaceutical manufacturers and owners
are required to observe international best practices at all times and to comply with the
requirements of the EMEA, USA, Australia, Canada, in particular, the requirements set
down in the given references and their subsequent revisions.


4 REFERENCES

a) CPMP & CVMPs Note for Guidance on Minimising the Risk of Transmitting Animal
Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products,
EMEA/410/01 Rev 2)

b) Guidance for Industry The Sourcing and Processing of Gelatin to Reduce the
Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated
Products for Human Use, by US FDA

c) Ph. Eur. general monograph on Product with risk of transmitting agents of animal
spongiform encephalopathies

d) Guidelines on the Investigation of Manufacturing Processes for Plasma-Derived
Medicinal Products with regard to vCJ D risk (EMEA/BWP/5136/03)

e) CPMP/BWP/337/02/Public/Final, Risk and regulatory assessment of lactose and other
products prepared using calf rennet

f) CPMP/BWP/1793/02/Guidance on the use of Bovine Serum in the manufacture of
human biological medicinal products.

g) Terrestrial Animal Health Code, World Organisation for Animal Health (OIE)


ANNEX 1 CHECKLIST FOR THE REGISTRATION OF HUMAN MEDICINAL
PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN

Appendix
section
Document Yes/No
(Encl. #)
For
official
use
1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk
1.1 (a) TSE Risk Evaluation Certificate of suitability (CEP)
Basic information providing a brief description of the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.1 (b) (iii) Description of the tissue/organ-collection procedures
and measures in place to avoid cross-contamination.

Nature and quantity of each animal-derived material
used:

As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a
drug substance/excipient.

As a reagent or culture media component used in
manufacture.

establishing master/working cell banks.

1.1 (b) (iv)
Others, give details.
1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE
risk evaluation Certificate of Suitability (CEP)
Detailed Assessment Report for the risk of TSE.
The scope of this assessment report should include the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.

Appendix
section
Document Yes/No
(Encl. #)
For
official
use
1.1 (b) (iii) Description of the tissue/organ-collection procedures
and measures in place to avoid cross-contamination.

1.2 (a) Details of the risk factors associated with the route of
administration and maximum therapeutic dosage of
the product.

Nature and quantity of each animal-derived material
used:

As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a
drug substance/excipient.

manufacture.

establishing master/working cell banks.

1.1 (b) (iv)
Others, give details.
1.2 (a) (ii) Relevant information to support the claim that the
manufacturing process is capable of inactivating TSE
agents.

1.2 (b) Certificates of analysis for each animal-derived
materials used



PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS

APPENDIX 12 PRODUCT INTERCHANGEABILITY AND BIOWAIVER
REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS

Applicants are advised to be familiar with The ASEAN Guideline on the Conduct of
Bioavailability and Bioequivalence Studies
1
on the conduct of bioavailability (BA) and
bioequivalence (BE) studies for the purposes of drug registration. Applicants are also
advised to consult the relevant international guidelines from EMEA CHMP
2
, US FDA
3
or
WHO for the conduct and analysis of bioavailability and bioequivalence studies.

The report of a BA/BE study should include the complete documentation of its protocol,
conduct and evaluation in compliance with GCP and related ICH E3
4
guideline.
Deviations, additions, or omissions from existing guidelines must be explained, either by
introductory remarks or within each relevant module/part of the submission, whichever is
more appropriate.

With effect from 1
st
April 2004, in vivo bioequivalence (BE) data are required for
Prescription Only Medicines (POM) in oral solid dosage forms. Also, GDA-2 applications
will require bioequivalence data if the application is for a Prescription Only Medicine
(POM) in an oral solid dosage form, even if the first strength (GDA-1) application was
submitted to HSA before 1 April 2004. Applicants are advised to consult HSA for
guidance to determine whether the GDA-2 application requires in vivo bioequivalence
data. This requirement may be extended to other dosage forms in the future.

For generic products containing a different salt or ester form of the active substance
compared to the Singapore reference product, applicants are required to submit data to
demonstrate that the different salt/ester form does not affect the pharmacokinetic,
pharmacodynamic, efficacy or toxicity profile of the active substance in the reference
product.

Product Interchangeability

The generic or test product used in the BA/BE study should be the same as the
Singapore drug product submitted for registration. The generic product should also be
manufactured at the same drug substance and drug product manufacturing sites by the
same manufacturing processes as submitted in the Singapore application dossier.

It is recommended that the reference product used in the BE study be the same as the
Singapore reference product. i.e. the BE reference product should be of the same
strength as the generic product and manufactured from the Singapore registered drug
product manufacturing site. Details of the manufacturing source of the Singapore
reference product can be found by searching HSAs online database
5
.

If the BE reference product was manufactured by a non-Singapore registered
manufacturer, the following criteria must be fulfilled in order to accept the submitted BE
study:
a) The reference product is registered in and obtained from a country with a competent
regulatory system as defined by the WHO;

1
2
http://www.emea.europa.eu/htms/human/humanguidelines/background.htm
3
http://www.fda.gov/cder/guidance/index.htm
4
http://www.ich.org/
5
APPLICATIONS

b) It is documented that the reference product is marketed in the country of origin
i. by the same innovator company or corporate entity that markets the same drug
product (same dosage form and strength) in Singapore; or,
ii. through a licensing arrangement with the innovator company or corporate entity
that markets the same product in Singapore;
c) The reference product is a conventional, immediate-release oral dosage form (tablet,
capsule) or an enteric coated tablet or capsule formulation that releases the drug
substance promptly once the enteric coating has dissolved;
d) The ingredients in the BE reference product are qualitatively identical to those used in
the Singapore reference product, with exception of minor excipients that are unlikely
to affect the bioavailability of the product (e.g. colourants and inks);
e) The sponsor shall provide Certificates of Analysis for both the BE reference and
Singapore reference products, analysed under the proposed specifications for the
generic product;
f) The active ingredient has a well-described dose response curve and does not exhibit
the following:
i. a narrow therapeutic range or safety margin e.g. does not require careful
dosage titration or patient monitoring;
ii. a steep dose-response relationship;
iii. a risk of serious undesired effects; and/or,
iv. complicated or variable pharmacokinetics (PK) e.g. non-linear PK, variable or
incomplete absorption, site-specific absorption and substantial first-pass
metabolism (>40%); and,
g) The BE reference product
i. contains the same nominal quantity of active ingredient as the innovator product
marketed in Singapore;
ii. is the same as the Singapore reference product with respect to size, weight and
type of coating (e.g. uncoated, film-coated or enteric-coated); and,
iii. exhibits individual and mean dissolution profiles comparable to the Singapore
reference product.

Dissolution profiles should be determined in at least three dissolution media within the
physiological range (pH 1 to 7.5), including 0.1 N HCl, a pH 4.5 buffer and a pH 6.8
buffer. One of the dissolution media should be described in the BP or USP monograph, if
one exists. Thus, for comparative in-vitro dissolution studies, the following data should be
submitted:
a) individual dissolution data in each of the media;
b) mean, range and RSD values of 12 units conducted in the three different media; and,
c) statistical comparison using a procedure described in relevant international guidelines
e.g. F
2
calculations.

For more information on the conduct and reporting of comparative dissolution studies,
applicants are advised to refer to the ASEAN Guideline on the Conduct of Bioavailability
and Bioequivalence Studies
6
and other relevant international guidelines, as appropriate.

Only one bridging step is allowed for a BE study that deviates from the optimal BA/BE
study design (i.e., using the generic product submitted in the application and the
Singapore reference product of corresponding strength, pharmaceutical dosage form and
Singapore registered manufacturing site).
A quick reference on the acceptability of a BE study is given in Appendix 12A. If the
acceptability of a BE study is still in doubt, applicants are advised to email HSA at

6
APPLICATIONS

HSA_MedProd_Registration@hsa.gov.sg with the completed Appendix 12A. HSA will
respond to the applicants inquiry once a decision has been reached.

Biowaiver Request

Results from comparative bioavailability studies should be provided in support of the
safety and efficacy of each proposed product and proposed strength included in a GDA
submission. In the absence of such studies, a justification supporting a waiver of this
requirement should be provided for each product and strength.

In general, BE data or a justification for not providing such data are not required for the
following:
a) Simple or complex solutions that do not contain any ingredient which can be regarded
as a pharmacologically active substance;
b) Haemodialysis and peritoneal dialysis solutions;
c) Simple aqueous solutions intended for intravenous injection or infusion containing the
same active substance(s) in the same concentration as currently registered products.
Simple solutions do not include complex solutions such as micellar or liposomal
solutions;
d) Solutions for injection that contain the same active ingredients and excipients in the
same concentrations as currently registered products and which are administered by
the same route(s);
e) Products that are powder for reconstitution as a solution and the solution meets either
criterion (c) or (d) above;
f) Oral immediate release tablets, capsules and suspensions containing drug
substances with high solubility and high permeability and where the medicinal product
has a high dissolution rate, provided that the applicant submits an acceptable
justification for not providing BE data in terms of the CHMP/FDA guidelines;
g) Oral solutions containing the same active ingredient(s) in the same concentration as a
currently registered oral solution and not containing excipients that may significantly
affect gastric passage or absorption of the active ingredient(s);
h) Products for topical use provided the product is intended to act without systemic
absorption when applied locally;
i) Products containing therapeutic substances, which are not systemically or locally
absorbed (e.g., barium sulphate enemas, powders in which no ingredient is
absorbed). If there is doubt as to whether absorption occurs, a study or justification
may be required; and,
j) Otic or ophthalmic products prepared as aqueous solutions and containing the same
drug substance(s) in the same concentration.

For example, when a product is to be marketed in several strengths, if the formulation of
each strength contains the same medicinal and non-medicinal ingredients in the same
proportion, the results of a single comparative bioavailability study may be extrapolated to
all strengths in the series. In all cases, however, if comparative bioavailability data is not
provided for each formulation, the sponsor should provide a scientific justification for not
conducting studies on each strength. This justification may address issues such as the
nature of the kinetics of the drug (e.g., linear versus non-linear), and the proportionality of
the strengths for which a waiver is sought to the strength on which a comparative
bioavailability study was conducted. Similarly, if the submission involves a solution (e.g.,
oral solution, syrup, topical), which the sponsor believes should not require a comparative
bioavailability study, a scientific justification must be presented for the waiver of this
requirement.

APPLICATIONS

In preparing a justification, the sponsor should address at least the following issues, as
applicable:
the nature of the dosage form;
the solubility of the drug substance(s)/active ingredient(s);
the comparative dissolution profiles across the physiological pH range (1-7.5) of
the products being considered;
the pharmacokinetic characteristics of the active ingredient(s), such as
permeability (or absolute bioavailability), linearity or otherwise, first pass effect (if
any) and its significance;
the clinical consequences of any potential differences in bioavailabilities of the
products under consideration (for example, increased dose leading to toxicity or
decreased dose leading to lack of efficacy);
the width of the margin between the minimum effective and minimum toxic plasma
concentration; and/or,
the similarities of, or differences between, the formulations being considered.

If the justification is not considered adequate, the sponsor will be required to provide
relevant biopharmaceutic data.

This document reflects the current thinking of HSA on the minimum data necessary for
assessment. HSA reserves the right to request additional information if deemed
appropriate.

QUICK REFERENCE ON ACCEPTABILITY OF BIOEQUIVALENCE STUDY

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12A - Page 1 of 1

APPENDIX 12A QUICK REFERENCE ON ACCEPTABILITY OF BIOEQUIVALENCE STUDY

Generic Product submitted to HSA
(include all proposed strengths in this application)
Singapore Reference Product
(include all registered strengths)
Product Name Product Name
Proposed
strength(s)
Registered
strength(s)

Manufacturing site
(name & address)
Manufacturing site
(name & address)

Generic Product used in BE study
Manufacturing Site
Reference product used in BE study
Manufacturing Site
Reference Product used in BE study
Strength
Manufacturing site Generic Product used in BE
same as proposed site for Singapore GDA
Manufacturing site Reference Product in BE
same as registered Singapore site
Strength of Reference Product used in BE
same as registered Singapore strength
from different manufacturing site is not available in Singapore from different manufacturing site
(not acceptable, test product used in BE study
must be from same manufacturing site as the
proposed Singapore product)
One RED tick box: BE study acceptable with bridging data (comparative dissolution)
More than one RED tick box BE study not acceptable; considered two steps



MIV FILING AND SUBMISSION INQUIRY FORM


APPENDIX 13 MIV FILING AND SUBMISSION INQUIRY FORM

FAX completed form to Pharmaceuticals & Biologics Branch: 65 6478 9032 OR
Email to HSA_MedProd_Registration@hsa.gov.sg

Name of applicant: Date:
Designation:
Company:
Tel: Fax:
Product name: License no:
Product type: Chemical (Appendix 14) or Biologic (Appendix 15)
Proposed change(s):
1.
2.
Proposed section(s) for submission, and provide justification as needed: (Must complete)
e.g. Appendix 15 - Section B3, MIV-2, cannot find appropriate section, etc...
1.
2.
Additional comments/information: (e.g. type of application submitted to other agencies)

Below for Official Use Only
Inquiry reference number:
Inquiry response officer:
Difficulty of the
inquiry?
easy - applicant kindly reminded to review guidance documents
Medium
hard - proposed guidance update(s): section_____________________

Recommended Course of Action for the Applicant: (Check all that apply)
Include a copy of this form in the submission, attach any relevant correspondence
Submit documents/sections as proposed Submit as an MIV-2 Submit as an MIV-1
Submit the following documents/sections in support of the proposed changes
(HSA reserves the right to request additional information during the course of evaluation.)



GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &MIV-2) FOR CHEMICAL DRUGS

APPENDIX 14 GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &
MIV-2) FOR CHEMICAL DRUGS

TABLE OF CONTENTS

PART A: INTRODUCTION.............................................................................................. 3

PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION.................................... 5

B1 Change or Inclusion of Manufacturing Site(s) of Drug Substance....................... 5
B2 Major Change of Manufacturing Process of Drug Substance ............................. 5
B3 Change of Specification of Drug Substance or Drug Product ............................. 6
B4 Change or Inclusion of Manufacturing Site(s) of Drug Product........................... 6
B5 Change of Manufacturing Process and/or Test Methods of Drug Product.......... 7
B6 Change or Inclusion of Score/Break Line of Tablet............................................. 7
B7 Change of Batch Size of Drug Product................................................................ 7
B8 Change or Inclusion of Primary Packaging Site(s).............................................. 8
B9 Change or Inclusion of Container Closure System of Drug Product ................... 8
B10 Change of Shelf Life or Storage Condition of Drug Product................................ 8
B11 Change of Shelf Life After Reconstitution or First Opening................................. 9
B12 Change of Pack Size (Volume) or Inclusion of New Pack Size for Sterile Drug
Product................................................................................................................ 9
B13 Change of Product Labelling............................................................................... 9

PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION.................................. 10

C1 Change of Contact Person................................................................................ 10
C2 Change of Product Name.................................................................................. 10
C3 Change of Product Owner................................................................................. 11
C4 Change of Batch Numbering System................................................................ 11
C5 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug
Substance.......................................................................................................... 11
C6 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Product
........................................................................................................................... 11
C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product,
Packager or Batch Releaser) ............................................................................ 12
C8 Deletion of Pack Size for Drug Product............................................................. 12
C9 Minor Change of Manufacturing Process of Drug Substance ........................... 12
C10 Change of Batch Size of Drug Substance......................................................... 13
C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance....... 13
C12 Change of Test Procedure of Drug Substance.................................................. 13
C13 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s)
of Drug Substance............................................................................................. 14
C14 Extension of Shelf Life or Retest Period of Drug Substance............................. 14

C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing on
Capsules Including Addition or Change of Inks Used for Product Marking....... 14
C16 Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without
Change in Qualitative and Quantitative Composition and Mean Mass ............. 15
C17 Minor Qualitative Change of Excipient .............................................................. 15
C18 Minor Quantitative Change or Deletion of Existing Excipient............................ 16
C19 Change of Colouring System of Drug Product (Addition, Deletion or
Replacement of Colourant(s)) ........................................................................... 17
C20 Change of Flavouring System of Drug Product (Addition, Deletion or
Replacement of Flavourant(s)).......................................................................... 17
C21 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell.. 18
C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging.......... 18
C23 Change or Inclusion of Site(s) Responsible for Batch Release......................... 18
C24 Change of Batch Size of Drug Product.............................................................. 19
C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product19
C26 Minor Change of Manufacturing Process of Drug Product................................ 20
C27 Change to Comply with Pharmacopoeia for Excipient ...................................... 20
C28 Change of Test Procedure for Excipient............................................................ 21
of Excipient........................................................................................................ 21
C30 Change of Test Procedure of Drug Product...................................................... 21
C31 Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter(s) and Limit(s) of Drug Product........................................................ 22
C32 Minor Change or Inclusion of Container Closure System of Drug Product ....... 22
C33 Change in Shape of Container Closure System................................................ 22
C34 Change or Inclusion of Pack Size for Drug Product.......................................... 23
C35 Addition or Replacement of Measuring Device for Oral Liquid and Other
Dosage Forms................................................................................................... 23
C36 Change of Product Labelling due to Safety Updates......................................... 24
C37 Change of Product Labelling Relating to:.......................................................... 24
C38 Change of Product Labelling of Language(s) Other Than English.................... 24


PART A: INTRODUCTION

This document describes the requirements of a Minor Variation Application (MIV)
submitted for an existing registered chemical drug product in Singapore. Applicants
should be familiar with the contents of this document, the Guidance on Medicinal Product
Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.

Minor Variation Applications are divided into two sub-categories:
MIV-1: A minor variation which requires regulatory approval
MIV-2: A minor variation or an administrative change which does not require
regulatory approval; i.e., notification.

MIV should be categorized as an MIV-1. If a proposed MIV-2 does not meet its
specified conditions, then the MIV must be categorized as an MIV-1 with supporting
documents. HSA reserves the right to re-categorise the MIV if deemed appropriate.

Registration Process

Western Drug Product form in PRISM.

Applicants should fully disclose all proposed change(s) in Section 0 Licence Summary
under Section 0.4 Amendment Summary, and in the Table of Amendment Details,
downloaded via the link indicated in Section 0.5 Amendment Details. Any undisclosed
variation(s) embedded in the submitted data, or any follow-on changes not specifically
requested by HSA, will not be considered for evaluation.

NOTE: Applicants are encouraged to fax or email the MIV Filing and

Documentary Requirements

The following documents must be submitted with each MIV submission, as given in Table
A below:

Hard Copy E-Copy
PRISM application form Yes N/A
Table of Contents Yes Optional*
Checklist for MIV applications Yes Optional*
Table of Amendment Details Yes PRISM
MIV-specific Supporting documents
- Administrative (Module 1/Part 1)
- Other supporting documents

Yes
Optional

PRISM
PRISM/CD
Current and proposed product labelling (annotated and
pristine copies), where applicable
Yes PRISM
* E-copies may be submitted via PRISM or CD-ROM.

Table A. MIV Application Hard Copy and Electronic Copy Requirements

The Checklist for Minor Variation Applications for Chemical Drugs is located in Appendix
14A of this guidance document. This Checklist serves as a guide for submitting the
required documents relevant to each proposed MIV. When submitting the Checklist, the
following should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission;
and,
The Declaration for the MIV with the submission date and the local applicants name
and signature.

The Table of Amendment Details concisely describes the proposed MIV(s). The following
information must be stated in the Table:
Section of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason for the change(s); and,
Registration status and date of the proposed change(s) in other countries.

The required documents for each proposed MIV-1 or MIV-2 variation are specified in Part
B or Part C of this document respectively. For an MIV application with multiple related
or unrelated variations, all of the supporting documents for each individual
variation should be submitted. If the required documents have not been submitted,
justification must be provided.

assessment. Applicants are responsible for ensuring that all necessary validations were
conducted to demonstrate that the change does not adversely affect the quality, safety or
efficacy of the product concerned. HSA reserves the right to request additional
information if deemed appropriate.
NOTE: For unstable drug substances or critical dosage forms, whenever stability data is
required, a minimum of three batches (at least two pilot scale or larger) must be submitted.

PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION

B1 Change or Inclusion of Manufacturing Site(s) of Drug Substance

Supporting Documents
1) CTD Section S, European Pharmacopoeia Certificate of Suitability (CEP) for the
drug substance, or both the open and closed portions of the Drug Master File;
2) Tabulation of the differences compared with the registered manufacture
information (if applicable);
3) Batch analysis data (in a comparative tabular format) for at least two batches
(minimum pilot scale) of the drug substance from the current and proposed
manufacturers/sites;
4) A letter of commitment to conduct the appropriate stability study for the drug
product manufactured with the drug substance from the proposed manufacturer.

B2 Major Change of Manufacturing Process of Drug Substance

For any changes not covered by MIV2 C9 (e.g. alternative synthetic route)

1) Relevant CTD section S;
2) Tabulation of the current and proposed process with changes highlighted;
3) Batch analysis data (in a comparative table) of at least two batches (pilot scale or
production scale) manufactured according to the currently approved and proposed
process;
4) A declaration from the applicant that no new impurities have been introduced at or
above the accepted threshold for qualification of impurities or that there is no
increase in the level of impurities, which require further safety studies;
5) If any potential new impurities are detectable at an acceptable limit of detection,
appropriate evidence must be provided;
6) A declaration from the applicant that the specification of the drug substance has
not changed or if there is any change to the specification (i.e. tightening), the texts
of the current and proposed specifications should be provided (in a comparative
table where possible);
7) Relevant stability studies of the drug substance in accordance with the relevant
guidelines should be provided;
8) A letter of commitment to conduct the appropriate stability study for the drug
product manufactured with the drug substance from the new manufacturing
process, and report if any results fall outside shelf life specification (with proposed
action).


B3 Change of Specification of Drug Substance or Drug Product

For any changes not covered by MIV2 C13 and C31

1) Scientific and/or historical data used to support the change;
2) Currently registered version of the release and/or shelf life specifications with the
proposed change(s) clearly highlighted, underscored, or otherwise indicated (in a
comparative table);
3) Release and shelf-life specifications;
4) Batch analysis for all tests in the new specification;
5) Description of any new analytical method and summary of the validation data, if
applicable;
6) Results of appropriate real time stability studies of at least two production scale
batches of the drug product with undertaking to continue the stability studies up till
the proposed shelf life and to report if any results fall outside shelf life
specification.

B4 Change or Inclusion of Manufacturing Site(s) of Drug Product

1) Proof that the proposed site is appropriately authorised for the
pharmaceutical form concerned: a GMP certificate;
2) Official letter authorising the proposed site to manufacture the product;
3) Product formula;
4) Specification of drug substance;
5) Release and shelf life specifications of drug product;
6) Batch numbering system;
7) Appropriate stability data of at least 6 months on 2 batches (pilot/production) with
undertaking to conduct on-going stability study and report if any results fall outside
shelf life specification (with proposed action);
8) Batch analysis data on a minimum two production batches (or one production
batch and two pilot batches) simulating the production process and comparative
data on the last 3 batches from the current site; batch analysis data on the next 2
full production batches should be available upon request or reported if outside
release and shelf life specifications (with proposed action);
9) For sterile or parenteral products, validation data of the manufacturing process
and sterilization process at the proposed site for products should be provided.
10) Official letter declaring that the formulation, drug substance source & specification,
manufacturing process, analytical test methods, release and shelf life
specifications have not changed.


B5 Change of Manufacturing Process and/or Test Methods of Drug Product

For any change in the procedure of the current registered manufacturing process at
any stage during manufacture drug product not covered by MIV2 C25 or C26.

3) Batch analysis data of at least two production batches (or one production batch
and two pilot batches) manufactured according to currently registered and
proposed processes;
4) For solid dosage forms, comparative dissolution profile data of at least one
representative pilot/production batch of the drug product of the currently registered
and proposed processes;
5) J ustification for not submitting a new bioequivalence study according to the
current Bioavailability and Bioequivalence guidance;
6) Tabulation of the changes and differences;
7) Validation scheme and data on manufacturing process and/or analytical method
(where applicable).

B6 Change or Inclusion of Score/Break Line of Tablet

1) Detailed drawing or written description of the current and proposed tablet;
2) J ustification to support the change or inclusion of score/break line;
3) Data on uniformity of content of the subdivided parts of the tablets;
4) Official letter of commitment to inform users of the relevant changes, and that the
current product stocks will be exhausted before the new product is marketed;
5) Current and proposed release and shelf life specifications.

B7 Change of Batch Size of Drug Product

For any change in the scale of the current registered manufacturing process at any
stage during manufacture drug product not covered by MIV2 C24.

1) Amended relevant CTD Section P.3;
3) Batch analysis data (in a comparative table) of at least two production batches (or
one production batch and two pilot batches) manufactured according to currently
registered and proposed batch sizes;

4) Release and shelf life specifications of the drug product;
5) For solid dosage forms, comparative dissolution profile data of at least one
representative pilot/production batch of the drug product of the currently registered
6) Validation scheme and data on proposed manufacturing process and/or analytical
method.

B8 Change or Inclusion of Primary Packaging Site(s)

1) Proof that the proposed site is appropriately authorised for the packaging activity
concerned: GMP certificate;
2) Official letter authorising the proposed site to package the product and stating the
types of activity performed by the packager;
3) Validation data on manufacturing process (for suspensions and emulsions);
4) A declaration from the applicant that the appropriate stability studies have been
started on at least two pilot or production scale batches and that the relevant
stability studies will be finalised; data should be provided only if outside shelf life
specification (with proposed action) or when requested.

B9 Change or Inclusion of Container Closure System of Drug Product

For any changes not covered by MIV2 C32

1) Amended section P.7 and technical information;
2) Appropriate stability study of at least 6 months on 2 production batches of the
proposed primary packaging material with undertaking to continue the stability
studies up till the proposed shelf life and report if any results fall outside shelf life
specification (with proposed action) or when requested;
3) A declaration from the applicant that the release and shelf life specifications of the
drug product are not affected if applicable;
4) For sterile products, validation data of the relevant manufacturing and sterilization
process.

B10 Change of Shelf Life or Storage Condition of Drug Product

batches of the drug product in the authorised packaging material covering the
duration of the proposed/approved shelf life;
drug product are not affected if applicable.


B11 Change of Shelf Life After Reconstitution or First Opening

batches of the product after reconstitution or first opening in the authorised
packaging material covering the duration of the proposed shelf life;
2) Results of appropriate microbiological testing if applicable;

B12 Change of Pack Size (Volume) or Inclusion of New Pack Size for Sterile Drug
Product

1) J ustification that the proposed pack size is consistent with the dosage regimen
and duration of use as is approved in the package insert;
2) Validation data of the manufacturing process, sterilization and container closure
system (where applicable);
3) Results of the stability study for at least 6 months on 2 production batches of the
proposed pack size with undertaking to continue the stability studies up till the
proposed shelf life and to report if any results fall outside shelf life specification
(with proposed action);

B13 Change of Product Labelling

Conditions
- The change is not a major variation (MAV);
- For safety-related changes of product labelling, refer to MIV-2 C36

1) J ustification and clinical documents to support proposed changes.

PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION

An MIV-2 application is a variation for which only a notification is required to be submitted
to HSA. Each MIV-2 notification shall be submitted at least 2 months in advance of the
commencement date.

If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.

C1 Change of Contact Person

Condition
- The product licence holder remains the same.

1) Particulars of the contact person updated in the on-line PRISM application.

C2 Change of Product Name

Conditions
- There is no change to the product (formulation, release and shelf life specifications,
manufacturing source and process) except the product name change;
- No confusion with another drug product either when spoken or written;
- New name does not imply (a) greater safety or efficacy than supported by clinical
data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic
use for the product, or (d) the presence of substance(s) not present in the product.

1) Official letter authorising the change of product name;
2) A declaration from the applicant that there is no change to the product except
name;
current product stocks will be exhausted before the product labelled with the new
name is marketed;
4) CPP.


C3 Change of Product Owner

Condition

1) Official letter from the new product owner declaring the change, and authorising
the local licence holder to be responsible for the product licence in Singapore;
2) If the new product owner is not the manufacturer of the drug product, an official
letter by the new product owner authorising the manufacturer to manufacture the
drug product on its behalf;

C4 Change of Batch Numbering System

Document Required
1) Description of batch number system;
2) Official letter stating the commencement date of the change

Substance

Condition
- The manufacturing site of the drug substance remains at the same physical
location.

1) Updated information of the manufacturer of the drug substance;
2) A declaration from the applicant that manufacturing site remains the same and
that the renaming does not involve changes of the manufacturing process and/or
quality of the product.

Product

Condition
- The manufacturing site remains at the same physical location.

1) Official letter authorising the manufacturer with new name/address to manufacture
the drug product (not required if the manufacturer is the product owner);
2) GMP certificate with new name or address;

3) A declaration from the applicant that the manufacturing site remains the same,
and that the renaming does not involve changes of the manufacturing process
and/or quality of the product;

C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product,
Packager or Batch Releaser)

1) Reason for withdrawal/deletion

C8 Deletion of Pack Size for Drug Product

1) Reason for deletion.

C9 Minor Change of Manufacturing Process of Drug Substance

Conditions
- The synthetic route remains the same;
- Specification of the drug substance remains the same;
- No change in the physical properties;
- No new impurities or change in level of impurities which would require further
qualifications in safety studies.

3) Batch analysis data (in a comparative table) of at least two batches (pilot scale or
production scale) manufactured according to the currently approved and proposed
process;
increase in the level of impurities, which require further safety studies;
not changed or if there is any change to the specification (i.e. tightening), the texts
of the current and proposed specifications should be provided (in a comparative
table where possible);
6) A declaration from the applicant that the relevant stability studies of the drug
substance in accordance with the relevant guidelines have been started and that
the relevant stability studies will be finalised; data should be provided only if
outside specification (with proposed action).


C10 Change of Batch Size of Drug Substance

Condition
- The change does not affect the reproducibility of the process.

1) Amended relevant CTD Section S;
2) Batch analysis data (in a comparative table) on a minimum of one production
batch manufactured to both the currently approved and the proposed batch sizes.
Batch data on the next 2 full production batches should be available on request or
reported if outside specification (with proposed action);
3) Specification of the drug substance.

C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance

Pharmacopoeias accepted by HSA are EP, USP, BP, and J P.

Conditions
- Change is made exclusively to comply with an update of the relevant monograph of
the pharmacopoeia;
- Excludes change from one accepted pharmacopoeia to another.

1) Tabulation of the current and revised specifications with changes highlighted;
2) Revised specification of the drug substance;
3) Batch analysis of the drug substance for all tests in the new specification

C12 Change of Test Procedure of Drug Substance

Condition
- Results of method validation show new test procedure to be at least equivalent to
the former procedure.

1) Description of the analytical methodology, a summary of validation data, and
comparative analytical results between the current test and the proposed one, if
appropriate;
2) Specification of the drug substance;
not changed.


of Drug Substance

Condition
- New test method does not concern a novel non-standard technique or a standard
technique used in a novel way

1) Tabulation of the current and revised specification of drug substance with changes
highlighted;
2) Revised specification of drug substance;
3) Batch analysis of the drug substance for all tests in the new specification.
applicable.

C14 Extension of Shelf Life or Retest Period of Drug Substance

Condition
- The studies must show compliance with specification

1) Stability data of the drug substance should be presented on at least two pilot or
production scale batches of the requested shelf life or retest period;

C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing on
Capsules Including Addition or Change of Inks Used for Product Marking

Conditions
- New markings do not cause confusion with other tablets or capsules;
- The inks have not been rejected for pharmaceutical use;
- Release and shelf life specifications of the drug product have not changed (except
for appearance).
- For changes involving the score/break line, refer to MIV1 B6.

1) Details of the proposed new inks (where applicable);
2) Detailed drawing or written description of the current and proposed
imprint/bossing/markings/ink;
name is marketed;
product have not changed (except for appearance).

Change in Qualitative and Quantitative Composition and Mean Mass
C16.1 Conventional dosage form, suppository and pessary
C16.2 Critical dosage form and scored tablet

Conditions
- No change in dissolution profile;
- Release and shelf life specifications of the drug product have not changed (except
for dimensions).

1) Detailed drawing or written description of the current and proposed appearance;
3) Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).

4) In addition to C16.1 Documents 1 to 3;
5) Comparative dissolution data on at least one pilot/production batch of the current
and proposed dimensions in accordance with HSAs drug registration guidelines;
current Bioavailability and Bioequivalence guidelines;
7) Where applicable, data on the test for uniformity of content of the subdivided parts
of tablets at release should be submitted and commitment to conduct the test at
the end of shelf life, data should be provided only if outside the release and shelf
life specifications (with proposed action).

C17 Minor Qualitative Change of Excipient

Conditions
- Replacement of an excipient with a comparable excipient;
- Same functional characteristics of the excipient;
- No change in dissolution profile for solid dosage forms;
- The release and shelf life specifications of the drug product have not changed (or
have tightened), except for the replacement of the excipients;
- For change of preservatives, refer to MIV B3;
- For changes affecting release and shelf life specification, refer to MIV1 B3.

1) J ustification for the change of excipients must be given by appropriate
development pharmaceutics (including stability aspect and antimicrobial
preservation where appropriate);

3) Tabulation of the current and revised product formulation with changes
highlighted;
4) Revised product formulation;
5) Release and shelf life specifications and batch analysis of the drug product;
6) Specifications of new excipient;
7) Comparative dissolution profile data of at least one representative pilot/production
batch of the drug product in the new and old composition for solid dosage forms in
accordance with HSAs drug registration guidelines;
8) A declaration from the applicant that the new excipient does not interfere with the
drug product release and shelf life specifications test method;
drug product have not changed;
10) A declaration from the applicant that the relevant stability studies in accordance
with the relevant guidelines have been started (on at least two pilot scale or
production scale batches) and that the relevant stability studies will be finalised;
data should be provided only if outside the shelf life specification (with proposed
action) or when requested.

C18 Minor Quantitative Change or Deletion of Existing Excipient

Conditions
- Total quantitative change within 5% (w/w), inclusive of the following:
Disintegrant: Starch ( 3%), other ( 1%);
Binder ( 0.5%);
Lubricant: Ca or Mg Stearate ( 0.25%), other ( 1%);
Glidant: Talc ( 1%), other ( 0.1%); and/or,
Film Coat ( 1%);
- No change in the dissolution profile for solid dosage forms;
- Release and shelf life specifications of the drug product have not changed.

1) J ustification for the change must be given by appropriate development
pharmaceutics (including stability aspect and antimicrobial preservation where
appropriate);
2) Comparative dissolution profile data of at least one representative pilot/production
batch of the drug product in the new and old composition for solid dosage forms in
accordance with HSAs drug registration guidelines;
4) Tabulation of the current and revised product formulation with changes
highlighted;
6) Release and shelf life specifications and batch analysis of drug product;
7) A declaration from the applicant that the change of excipient does not interfere
with the drug product release and shelf life specifications test method;

started (on at least two pilot scale or production scale batches) and that the
relevant stability studies will be finalised; data should be provided only if outside
the shelf life specification (with proposed action) or when requested.

C19 Change of Colouring System of Drug Product (Addition, Deletion or
Replacement of Colourant(s))

Conditions
- Same functional characteristics, no change in dissolution profile for solid dosage
forms;
- The colouring system must not have been rejected for pharmaceutical use;
- The release and shelf life specifications of the drug product have not changed,
except for the change in appearance/colour.

1) Qualitative and quantitative information of the colourant;
current product stocks will be exhausted before the product with the proposed
variation is marketed;
5) A declaration from the applicant that the change in the colouring system does not
interfere with the drug product release and shelf life specifications test methods;
6) A declaration from the applicant that the release and shelf life specifications have
not changed (except for appearance);

C20 Change of Flavouring System of Drug Product (Addition, Deletion or
Replacement of Flavourant(s))

Conditions
- Proposed flavour must not have been rejected for pharmaceutical use;
- The release and shelf life specifications of the drug product have not changed,
except for the change in flavour.

1) Qualitative and quantitative information of the flavouriant;

current product stocks will be exhausted before the product with the proposed
variation is marketed;
5) A declaration from the applicant that the change of flavour(s) does not interfere
product have not changed (except for flavour);

C21 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell

Conditions
- The product release and shelf life specifications have only been updated in respect
of weight and dimensions, if applicable.

1) Comparative dissolution profile data of at least one pilot/production batch of the
drug product in the new and old composition in accordance with HSAs drug
registration guidelines (for modified release products, to provide in vitro data
which has been correlated with in vivo data);
3) Revised release and shelf life specifications of the drug product;
4) A declaration from the applicant that the change does not interfere with the drug
product specifications test method;
drug product have not changed (except for average weight).

C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging

1) Official letter authorising the proposed manufacturer to perform secondary
packaging;
2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is
appropriately authorised for the packaging activity concerned.

C23 Change or Inclusion of Site(s) Responsible for Batch Release

Condition
- The manufacturer of the drug product remains the same;

1) Official letter authorising the company/manufacturer with new name/address
responsible for batch release;
2) GMP certificate with name or address of the new site (where appropriate);

C24 Change of Batch Size of Drug Product

Conditions
- The change does not affect consistency of production;
- The change only applies to standard immediate release oral dosage forms and to
non-sterile liquid forms, refer to MIV1 B9;
- Up to a 10-fold change when compared to the batch size currently registered with
HSA;
- Validation scheme is available or validation of the manufacture has been
successfully carried out according to protocol with at least three batches at the
proposed new batch size in accordance with the relevant guidelines.

2) Batch analysis data (in a comparative table) on a minimum of one production
batch manufactured to both the currently approved and the proposed batch sizes.
Batch data on the next 2 full production batches should be available on request or
reported if outside the shelf life specification (with proposed action);
4) Official letter of commitment to put the product manufactured according to the
proposed batch size under stability studies in accordance with relevant stability
guidelines.

C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product

Condition
- In-process limits are tightened or addition of new tests.

1) A description of the analytical methodology and summary of validation data must
be provided for all new analytical methods (where applicable);
2) Tabulation of the in-process controls and the relevant changes;
3) Batch analysis data of one production batch of the drug product for all tests in the
proposed specification (if applicable).


C26 Minor Change of Manufacturing Process of Drug Product

Conditions
- Release and shelf life specifications of the drug product are not adversely affected;
- New process must lead to an identical or better product regarding all aspects of
quality, safety and efficacy;
- No change in the dissolution profile;
- For major changes in the manufacturing process such as from wet granulation to
direct compression of dry powder, refer to MIV B5.

1) Amended relevant CTD section P;
2) Tabulation of the present process and the new process with changes highlighted;
3) Appropriate justification and validation of the change should be provided where
appropriate, especially for sterilisation process;
4) For solid dosage forms, dissolution profile data of one representative production
batch in accordance to HSAs drug registration guidelines
5) Release and shelf life specifications of the drug product. If there is any change of
the specifications (i.e. tightening), the texts of the current and proposed
specifications should be provided (in a comparative table where possible);
7) Batch analysis data (in a comparative table) of at least one batch manufactured
according to the currently approved and proposed process;
8) A declaration from the applicant that the appropriate stability studies of the drug
product have been started and that the relevant stability studies will be finalised;
data should be provided only if outside specification (with proposed action).

C27 Change to Comply with Pharmacopoeia for Excipient

Pharmacopoeias accepted by HSA are EP, USP, BP, and J P.

Conditions
- Change is made exclusively to comply with an update of the relevant monograph of
the Pharmacopoeia.

1) Tabulation of the current and revised specifications with changes highlighted;
2) Specification of the excipient;
3) Batch analysis of the excipient for all tests in the new specification;
4) Declaration that the quality of the drug product is not adversely affected.


C28 Change of Test Procedure for Excipient

Conditions
- Appropriate validation studies have been performed in accordance with the relevant
guidelines;
the former procedure;
- Any new test method does not concern a novel non-standard technique or a
standard technique used in a novel way.

1) Description of the analytical methodology, a summary of validation data;
2) Revised specification for impurities (if applicable);
3) Comparative validation results showing that the current test and the proposed one
are equivalent.

of Excipient

Condition
technique used in a novel way.

1) Tabulation of the current and revised specification of the excipient with changes
highlighted;
2) Revised specification of the excipient;
applicable.

C30 Change of Test Procedure of Drug Product

Condition
the former procedure.

1) Description of the analytical methodology, appropriate validation data, and
comparative analytical results between the current test and the proposed one;
2) Comparative release and shelf life specifications of the drug product.


C31 Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter(s) and Limit(s) of Drug Product

Condition
technique used in a novel way.

1) Tabulation of the current and revised release and shelf life specifications of the
drug product with changes highlighted;
3) Batch analysis of the drug product for all tests in the new specification.
4) Details of any new analytical method and summary of validation data, if
applicable.

C32 Minor Change or Inclusion of Container Closure System of Drug Product

Conditions
- The proposed packaging material must be at least equivalent or better than the
current approved material in respect of its relevant properties;
- The change only concerns the same packaging (for example blister to blister);
- For changes related to sterile products, refer to MIV1 B9.

1) J ustification for the change in packaging material and appropriate scientific
studies on the new packaging;
2) For semisolid and liquid dosage forms, proof must be provided that no interaction
between the content and the packaging material occurs (e.g. no migration of
components of the proposed material into the content and no loss of components
of the product into the pack);
3) Specifications of the immediate packaging material;
action) or when requested;
5) A declaration from the applicant that the product will meet the release and shelf
life specifications.

C33 Change in Shape of Container Closure System

Conditions
- No change in the qualitative and quantitative composition of the container and
stability of the product in the container;

- The change does not concern a fundamental component of the packaging material
which affects the delivery or use of the product;
- The change does not relate to sterile preparations.

1) Details/description of the new container shape;
2) A declaration from the applicant that the specifications of the container (except for
shape) have not changed;
drug product have not changed;
started with at least two pilot scale batches and that the relevant stability studies
will be finalised (for change in the headspace or a change in the surface/volume
ratio); data should be provided only if outside the shelf life specification (with
proposed action).

C34 Change or Inclusion of Pack Size for Drug Product

Conditions
- Does not apply to sterile preparations, unless the change only concerns the number
of containers in the outer packaging, otherwise refer to MIV-1 B12;
- Release and shelf life specifications of the drug product are not affected;
- The new size is consistent with the dosage regimen and duration of use as
approved in the PI;
- The packaging material remains the same.

1) J ustification that the new size is consistent with the dosage regimen and duration
of use as is approved in the PI;
drug product are not affected, the container and closure composition is
unchanged;
3) A declaration from the applicant that stability studies on at least 2 production
batches will be conducted for products where stability parameters could be
affected. Data to be reported only if outside specifications (with proposed action).

C35 Addition or Replacement of Measuring Device for Oral Liquid and Other
Dosage Forms

Conditions
- The size and, where applicable, the accuracy of the proposed measuring device
must be compatible with the approved posology;
- The new device is compatible with the drug product.


1) Description of the device (including a drawing), where appropriate;
2) The composition of the device material; where applicable, the materials should
comply with the Pharmacopoeia;
3) J ustification that size and accuracy of the device are adequate for the posology as
is approved in the product labelling;

C36 Change of Product Labelling due to Safety Updates

Conditions
- Tightening of the products target-patient population; or,
- Add warnings, precautions, contraindications or adverse events/effects to the
approved product labelling.

1) Official letter outlining: (a) the reasons for the notification, (b) the status of the
proposed changes in other countries;
2) A declaration from the applicant that no other changes have been made to the
labelling and that the changes are supported by data.

C37 Change of Product Labelling Relating to:
Addition/deletion of bar code
Replacement of distributor details
Layout without altering text or meaning
Deletion of indication (Note: Re-inclusion of the deleted indication in the future
should be submitted as MAV-1 according to the prevailing requirement.)
Addition/deletion/replacement of pictures or diagrams that do not imply an
unapproved indication

Conditions
- No change to the text or meaning of the wordings;
- The change is not an MAV or does not contain promotional information.

labelling.

C38 Change of Product Labelling of Language(s) Other Than English

Conditions
- No change to the text or meaning of the English wordings;
- The change is not an MAV or contains promotional information.

1) A declaration from the applicant that the information in non-English language(s)
provides complete, accurate and unbiased information on the product and is
consistent with the English information.



CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

APPENDIX 14A CHECKLIST FOR MINOR VARIATION APPLICATIONS
(MIV-1) FOR CHEMICAL DRUGS

Applicants should be familiar with the documentary requirements for MIV submissions
refer to Table A in Appendix 14 for the list.

The following documents must be submitted with each MIV submission, as given below:

Hard Copy E-Copy

Yes
Optional

PRISM
PRISM/CD
Yes PRISM

When submitting the Checklist for Minor Variation Applications (MIV-1) for Chemical
Drugs, applicants must make the following declaration:

Declaration of the applicant for MIV-1
I hereby submit an application for the concerned product to be varied in accordance with
the proposals given above. I declare that

There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.

NOTE: When submitting the Checklist, please delete the MIV-1 checklist
category(ies) that do not relate to the MIV application.

DOSSIER REQUIREMENTS FOR MIV-1 VARIATION

the proposals given above. I declare that (please tick the appropriate declarations)

Summary;

____________________ ______________________ _______________
Applicants Name Applicants Signature Date

B1 Change or Inclusion of Manufacturing Site(s) of Drug Substance
1)
CTD Section S, European Pharmacopoeia Certificate of Suitability (CEP) for
the drug substance or both the open and closed portions of the Drug Master
File;

2)
Tabulation of the differences compared with the registered manufacture
information (if applicable);

3)
Batch analysis data (in a comparative tabular format) for at least two batches
(minimum pilot scale) of the drug substance from the current and proposed
manufacturers/sites;

4)
A letter of commitment to conduct the appropriate stability study for the drug
product manufactured with the drug substance from the proposed
manufacturer.

B2 Major Change of Manufacturing Process of Drug Substance
For any changes not covered by MIV2 C9 (e.g. alternative synthetic route)
3)
Batch analysis data (in a comparative tabulation form) of at least two
batches (pilot scale or production scale) manufactured according to the
currently approved and proposed process.

4)
A declaration from the applicant that no new impurities have been introduced
at or above the accepted threshold for qualification of impurities or that there
is no increase in the level of impurities, which require further safety studies;

5)
If any potential new impurities are detectable at an acceptable limit of
detection, appropriate evidence must be provided;

6)
A declaration from the applicant that the specification of the drug substance
has not changed or if there is any change to the specification (i.e.
tightening), the texts of the current and proposed specifications should be
provided (in a comparative tabulation form where possible);


7)
Relevant stability studies of the drug substance in accordance with the
relevant guidelines should be provided;

8)
A letter of commitment to conduct the appropriate stability study for the drug
product manufactured with the drug substance from the new manufacturing
process, and report if any results fall outside shelf life specification (with
proposed action).

B3 Change of Specification of Drug Substance or Drug Product
For any changes not covered by MIV2 C13 and C31
2)
Currently registered version of the release and/or shelf life specifications with
the proposed change(s) clearly highlighted, underscored, or otherwise
indicated (in a comparative tabulation form);

3) Release and shelf-life specifications;
4) Batch analysis for all tests in the new specification;
5)
Description of any new analytical method and summary of the validation
data, if applicable;

6)
Results of appropriate real time stability studies of at least two production
scale batches of the drug product with undertaking to continue the stability
studies up till the proposed shelf life and to report if any results fall outside
shelf life specification.

B4 Change or Inclusion of Manufacturing Site(s) of Drug Product
1)
Proof that the proposed site is appropriately authorised for the
pharmaceutical form concerned: a GMP certificate;

2) Official letter authorising the proposed site to manufacture the product;
3) Product formula;
4) Specification of drug substance;
6) Batch numbering system;
7)
Appropriate stability data of at least 6 months on 2 batches (pilot/production)
with undertaking to conduct on-going stability study and report if any results
fall outside shelf life specification (with proposed action);

8)
Batch analysis data on a minimum two production batches (or one
production batch and two pilot batches) simulating the production process
and comparative data on the last 3 batches from the current site; batch
analysis data on the next 2 full production batches should be available upon
request or reported if outside release and shelf life specifications (with
proposed action);

9)
For sterile or parenteral products, validation data of the manufacturing
process and sterilization process at the proposed site for products should be
provided.

10)
Official letter declaring that the formulation, drug substance source &
specification, manufacturing process, analytical test methods, release and
shelf life specifications have not changed.


B5 Change of Manufacturing Process and/or Test Methods of Drug Product
For any change in the procedure of the current registered manufacturing process
at any stage during manufacturing drug product not covered by MIV2 C25 or C26

2)

3)
Batch analysis data of a least two production batches (or one production
batch and two pilot batches) manufactured according to currently registered

4)
For solid dosage forms, comparative dissolution profile data of at least one
representative pilot/production batch of the drug product of the currently
registered and proposed processes;

5)
J ustification for not submitting a new bioequivalence study according to the

6) Tabulation of the changes and differences;

7)
Validation scheme and data on manufacturing process and/or analytical
method (where applicable).

B6 Change or Inclusion of Score/Break Line of Tablet
1) Detailed drawing or written description of the current and proposed tablet;
2) J ustification to support the change or inclusion of score/break line;
3) Data on uniformity of content of the subdivided parts of the tablets;
4)
Official letter of commitment to inform users of the relevant changes, and
that the current product stocks will be exhausted before the new product is
marketed;

5) Current and proposed release and shelf life specifications.

B7 Change of batch size of drug product
For any change in the scale of the current registered manufacturing process at any
stage during manufacture drug product not covered by MIV2 C24.

2)

3)
Batch analysis data (in a comparative tabulated format) of at least two
production batches (or one production batch and two pilot batches)
manufactured according to currently registered and proposed batch sizes;

5)
For solid dosage forms, comparative dissolution profile data of at least one
representative pilot/production batch of the drug product of the currently
registered and proposed processes;

6)
Validation scheme and data on proposed manufacturing process and/or
analytical method.


B8 Change or Inclusion of Primary Packaging Site(s)
1)
Proof that the proposed site is appropriately authorised for the packaging
activity concerned: GMP certificate;

2)
Official letter authorising the proposed site to package the product and
stating the types of activity performed by the packager;

3) Validation data on manufacturing process (for suspensions and emulsions);
4)
A declaration from the applicant that the appropriate stability studies have
been started on at least two pilot or production scale batches and that the
relevant stability studies will be finalised; data should be provided only if
outside shelf life specification (with proposed action) or when requested.

B9 Change or Inclusion of Container Closure System of Drug Product
For any changes not covered by MIV2 C32
1) Amended section P.7 and technical information;
2)
Appropriate stability study of at least 6 months on 2 production batches of
the proposed primary packaging material with undertaking to continue the
stability studies up till the proposed shelf life and report if any results fall
outside shelf life specification (with proposed action) or when requested;

3)
A declaration from the applicant that the release and shelf life specifications
of the drug product are not affected if applicable;

4)
For sterile products, validation data of the relevant manufacturing and
sterilization process.

B10 Change of Shelf Life or Storage Condition of Drug Product
1)
scale batches of the drug product in the authorised packaging material
covering the duration of the proposed/approved shelf life;

2)
of the drug product are not affected if applicable.

B11 Change of Shelf Life After Reconstitution or First Opening
1)
scale batches of the product after reconstitution or first opening in the
authorised packaging material covering the duration of the proposed shelf
life;

2) Results of appropriate microbiological testing if applicable;
3)

B12
Change of Pack Size (Volume) or Inclusion of New Pack Size for Sterile Drug
Product


1)
J ustification that the proposed pack size is consistent with the dosage
regimen and duration of use as is approved in the package insert;

2)
Validation data of the manufacturing process, sterilization and container
closure system (where applicable);

3)
Results of the stability study for at least 6 months on 2 production batches of
the proposed pack size with undertaking to continue the stability studies up
till the proposed shelf life and to report if any results fall outside shelf life
specification (with proposed action);

4)

B13 Change of Product Labelling
Condition
- The change is not a major variation (MAV);
- For safety-related changes of product labelling, refer to MIV-2 C36
1) J ustification and clinical documents to support proposed changes.

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 14B - Page 1 of 14

APPENDIX 14B CHECKLIST FOR MINOR VARIATION APPLICATIONS
(MIV-2) FOR CHEMICAL DRUGS


The following documents must be submitted with each MIV submission, as given below:

Hard Copy E-Copy

Yes
Optional

PRISM
PRISM/CD
Yes PRISM

When submitting the Checklist for Minor Variation Applications (MIV-2) for Chemical
Drugs, applicants must make the following declaration:


Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the notification(s) concerned are fulfilled; and,
The required documents for the notification(s) have been submitted.


DOSSIER REQUIREMENTS FOR MIV-2 VARIATION


Summary;
product;
The required documents for the notification(s) have been submitted.

____________________ ______________________ _______________

Condition
1) Particulars of the contact person updated in the on-line PRISM application.

Conditions
-
There is no change to the product (formulation, release and shelf life
specifications, manufacturing source and process) except the product name
change;

- No confusion with another drug product either when spoken or written;
-
New name does not imply (a) greater safety or efficacy than supported by
clinical data, (b) superiority over a similar product in Singapore, (c) imply a
therapeutic use for the product, or (d) the presence of substance(s) not
present in the product.

1) Official letter authorising the change of product name;
2)
A declaration from the applicant that there is no change to the product
except name;

3)
that the current product stocks will be exhausted before the product labelled
with the new name is marketed;

4) CPP.

Condition

1)
Official letter from the new product owner declaring the change, and
authorising the local licence holder to be responsible for the product licence
in Singapore;

2)
If the new product owner is not the manufacturer of the drug product, an
official letter by the new product owner authorising the manufacturer to
manufacture the drug product on its behalf;

1) Description of batch number system;
2) Official letter stating the commencement date of the change.

C5
Renaming (e.g. street name, postal code) of Manufacturing Site of Drug
Substance

Condition
-
The manufacturing site of the drug substance remains at the same physical
location.

1) Updated information of the manufacturer of the drug substance;
2)
A declaration from the applicant that manufacturing site remains the same
and that the renaming does not involve changes of the manufacturing
process and/or quality of the product.

C6
Renaming (e.g. street name, postal code) of Manufacturing Site of Drug
Product

Condition
-
The manufacturing site of the drug product remains at the same physical
location.

1)
Official letter authorising the manufacturer with new name/address to
manufacture the drug product (not required if the manufacturer is the
product owner);

2) GMP certificate with new name or address;

3)
A declaration from the applicant that the manufacturing site remains the
same, and that the renaming does not involve changes of the manufacturing
process and/or quality of the product.

C7
Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product,
Packager or Batch Releaser)


1) Reason for withdrawal/deletion.


1) Reason for deletion.


C9 Minor Change of Manufacturing Process of Drug Substance
Conditions
- The synthetic route remains the same;
- Specification of the drug substance remains the same;
- No change in the physical properties;
-
No new impurities or change in level of impurities, which would require
further qualifications in safety studies.

2) Tabulation of the current and new process with changes highlighted;
3)
Batch analysis data (in a comparative table) of at least two batches (pilot
scale or production scale) manufactured according to the currently
approved and proposed process.

4)
A declaration from the applicant that no new impurities have been
introduced at or above the accepted threshold for qualification of impurities
or that there is no increase in the level of impurities, which require further
safety studies;

5)
has not changed or if there is any change to the specification (i.e.
tightening), the texts of the current and proposed specifications should be
provided (in a comparative table where possible);

6)
A declaration from the applicant that the relevant stability studies of the drug
substance in accordance with the relevant guidelines have been started and
that the relevant stability studies will be finalised; data should be provided
only if outside specification (with proposed action).

C10 Change of Batch Size of Drug Substance
Condition
- The change does not affect the reproducibility of the process.
1) Amended relevant CTD Section S;
2)
Batch analysis data (in a comparative table) on a minimum of one
production batch manufactured to both the currently approved and the
proposed batch sizes. Batch data on the next 2 full production batches
should be available on request or reported if outside specification (with
proposed action);


C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance
Pharmacopoeias accepted by HSA are EP, USP, BP, and JP.
Conditions
-
Change is made exclusively to comply with an update of the relevant
monograph of the pharmacopoeia;

- Excludes change from one accepted pharmacopoeia to another.
1)
Tabulation of the current and revised specifications with changes
highlighted;

2) Revised specification of the drug substance;


C12 Change of Test Procedure of Drug Substance
Condition
-
Results of method validation show new test procedure to be at least
equivalent to the former procedure.

1)
Description of the analytical methodology, a summary of validation data,
and comparative analytical results between the current test and the
proposed one, if appropriate;

2) Specification of the drug substance;

3)
has not changed.

C13
Tightening of Specification or Addition of New Test Parameter(s) and Limit(s)
of Drug Substance

Conditions
-
New test method does not concern a novel non-standard technique or a

1)
Tabulation of the current and revised specification of drug substance with
changes highlighted;

2) Revised specification of drug substance;

4)
data, if applicable.

C14 Extension of Shelf Life or Retest Period of Drug Substance
Condition
- The studies must show compliance with specification.
1)
Stability data of the drug substance should be presented on at least two
pilot or production scale batches of the requested shelf life or retest period;


C15
Change of Imprints, Bossing or Other Markings on Tablet or Printing on
Capsule Including Addition or Change of Inks Used for Product Marking

Conditions
- The inks have not been rejected for pharmaceutical use;
-
Release and shelf life specifications of the drug product have not changed
(except for appearance).

- For changes involving the score/break line, refer to MIV1 B6.
1) Details of the proposed new inks (where applicable);
2)
Detailed drawing or written description of the current and proposed
imprint/bossing/markings/ink;

3)
that the current product stocks will be exhausted before the product labelled
with the new name is marketed;


4)
of the product have not changed (except for appearance).

C16
Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without

Conditions
-
(except for dimensions).

1)
appearance;

3)
Revised drafts of the package insert and labelling incorporating the
proposed variation (where applicable).

5)
Comparative dissolution data on at least one pilot/production batch of the
current and proposed dimensions in accordance with HSAs drug
registration guidelines;

6)

7)
Where applicable, data on the test for uniformity of content of the
subdivided parts of tablets at release should be submitted and commitment
to conduct the test at the end of shelf life, data should be provided only if
outside the release and shelf life specifications (with proposed action).

C17 Minor Qualitative Change of Excipient
Conditions
- Replacement of an excipient with a comparable excipient;
- Same functional characteristics of the excipient;
- No change in dissolution profile for solid dosage forms;
-
The release and shelf life specifications of the drug product have not
changed (or have tightened), except for the replacement of the excipients;

- For change of preservatives, refer to MIV B3;
1)
J ustification for the change of excipients must be given by appropriate
development pharmaceutics (including stability aspect and antimicrobial
preservation where appropriate);

2)

3)
Tabulation of the current and revised product formulation with changes
highlighted;

5) Release and shelf life specifications and batch analysis of the drug product;

6) Specifications of new excipient;

7)
Comparative dissolution profile data of at least one representative
pilot/production batch of the drug product in the new and old composition for
solid dosage forms in accordance with HSAs drug registration guidelines;

8)
A declaration from the applicant that the new excipient does not interfere

9)
of the drug product have not changed;

10)
A declaration from the applicant that the relevant stability studies in
accordance with the relevant guidelines have been started (on at least two
pilot scale or production scale batches) and that the relevant stability studies
will be finalised; data should be provided only if outside the shelf life

Minor Quantitative Change or Deletion of Existing Excipient
Conditions
C18
-
Total quantitative change within 5% (w/w), inclusive of the following:
Disintegrant: Starch ( 3%), other ( 1%);
Binder ( 0.5%);
Lubricant: Ca or Mg Strearate ( 0.25%), other ( 1%);
Glidant: Talc (1%), other ( 0.1%); and/or
Film Coat ( 1%);

- No change in the dissolution profile for solid dosage forms;
- Release and shelf life specifications of the drug product have not changed.
1)
J ustification for the change must be given by appropriate development
pharmaceutics (including stability aspect and antimicrobial preservation
where appropriate);

2)
Comparative dissolution profile data of at least one representative
pilot/production batch of the drug product in the new and old composition for
solid dosage forms in accordance with HSAs drug registration guidelines;

3)

4)
Tabulation of the current and revised product formulation with changes
highlighted;

6) Release and shelf life specifications and batch analysis of drug product;
7)
A declaration from the applicant that the change of excipient does not
interfere with the drug product release and shelf life specifications test
method;

8)
A declaration from the applicant that the appropriate stability studies have
been started (on at least two pilot scale or production scale batches) and
only if outside the shelf life specification (with proposed action) or when
requested.

C19
Change of Colouring System of Drug Product (Addition, Deletion or
Replacement of Colourant(s))

Conditions
-
Same functional characteristics, no change in dissolution profile for solid
dosage forms;


-
changed, except for the change in appearance/colour.

1) Qualitative and quantitative information of the colourant;
4)
that the current product stocks will be exhausted before the product with the
proposed variation is marketed;

5)
A declaration from the applicant that the change in the colouring system
does not interfere with the drug product release and shelf life specifications
test methods;

6)
have not changed (except for appearance);

7)

C20
Change of Flavouring System of Drug Product (Addition, Deletion or
Replacement of Flavourant(s))

Conditions
- Proposed flavour must not have been rejected for pharmaceutical use;
-
changed, except for the change in flavour.

1) Qualitative and quantitative information of the flavourant;
4)
that the current product stocks will be exhausted before the product with the
proposed variation is marketed;

5)
A declaration from the applicant that the change of flavour(s) does not
interfere with the drug product release and shelf life specifications test
method;

6)
of the product have not changed (except for flavour);

7)

Conditions
-
The product release and shelf life specifications have only been updated in
respect of weight and dimensions, if applicable.


1)
Comparative dissolution profile data of at least one pilot/production batch of
the drug product in the new and old composition in accordance with HSAs
drug registration guidelines (for modified release products, to provide in vitro
data which has been correlated with in vivo data);

2)

4)
A declaration from the applicant that the change does not interfere with the
drug product specifications test method;

5)
of the drug product have not changed (except for average weight).

C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging
1)
Official letter authorising the proposed manufacturer to perform secondary
packaging;

2)
Evidence (i.e. GMP certificate) demonstrating that the proposed site is

C23 Change or Inclusion of Site(s) Responsible for Batch Release
Conditions
- The manufacturer of the drug product remains the same;
1)
Official letter authorising the company/manufacturer to be responsible for
batch release;

2) GMP certificate of the proposed site;

C24 Change of Batch Size of Drug Product
Conditions
- The change does not affect consistency of production;
-
The change only applies to standard immediate release oral dosage forms
and to non-sterile liquid forms, refer to MIV1 B9;

-
Up to a 10-fold change when compared to the batch size currently registered
with HSA;

-
Validation scheme is available or validation of the manufacture has been
successfully carried out according to protocol with at least three batches at
the proposed new batch size in accordance with the relevant guidelines.

2)
Batch analysis data (in a comparative table) on a minimum of one production
batch manufactured to both the currently approved and the proposed batch
sizes. Batch data on the next 2 full production batches should be available
on request or reported if outside the shelf life specification (with proposed
action);


4)
Official letter of commitment to put the product manufactured according to
the proposed batch size under stability studies in accordance with relevant
stability guidelines.


C25
Change of In-Process Control(s) Applied During Manufacture of Drug
Product

Condition
- In-process limits are tightened or addition of new tests.
1)
A description of the analytical methodology and summary of validation data
must be provided for all new analytical methods (where applicable);

2) Tabulation of the in-process controls and the relevant changes;

3)
Batch analysis data of one production batch of the drug product for all tests
in the proposed specification (if applicable).

C26 Minor Change of Manufacturing Process of Drug Product
Conditions
-
Release and shelf life specifications of the drug product are not adversely
affected;

-
New process must lead to an identical or better product regarding all aspects
of quality, safety and efficacy;

- No change in the dissolution profile.
-
For major changes in the manufacturing process such as from wet
granulation to direct compression of dry powder, refer to MIV B5.

1) Amended relevant CTD section P;
2)
Tabulation of the present process and the new process with changes
highlighted;

3)
Appropriate justification and validation of the change should be provided
where appropriate, especially for sterilisation process;

4)
For solid dosage forms, dissolution profile data of one representative
production batch in accordance to HSAs drug registration guidelines;

5)
Release and shelf life specifications of the drug product. If there is any
change of the specifications (i.e. tightening), the texts of the current and
proposed specifications should be provided (in a comparative table where
possible);

6)

7)
Batch analysis data (in a comparative table) of at least one batch
manufactured according to the currently approved and proposed process.

8)
A declaration from the applicant that the relevant stability studies of the drug
product in accordance with the relevant guidelines have been started and
only if outside specification (with proposed action).

C27 Change to Comply with Pharmacopoeia for Excipient
Pharmacopoeias accepted by HSA are EP, USP, BP, and JP.
Conditions
-
Change is made exclusively to comply with an update of the relevant
monograph of the Pharmacopoeia;

1)
Tabulation of the current and revised specifications with changes
highlighted;

2) Specification of the excipient;

4) Declaration that the quality of the drug product is not adversely affected.

C28 Change of Test Procedure for Excipient
Conditions
-
Appropriate validation studies have been performed in accordance with the
relevant guidelines;

-
equivalent to the former procedure;

-
Any new test method does not concern a novel non-standard technique or a

1) Description of the analytical methodology, a summary of validation data;
2) Revised specification for impurities (if applicable);

3)
Comparative validation results showing that the current test and the
proposed one are equivalent.

C29
Tightening of Specification or Addition of New Test Parameter(s) and Limit(s)
of Excipient

Conditions
-

1)
Tabulation of the current and revised specification of the excipient with
changes highlighted;

2) Revised specification of the excipient;

4)
data, if applicable.

C30 Change of Test Procedure of Drug Product
Condition
-
equivalent to the former procedure.

1)
Description of the analytical methodology, appropriate validation data, and
comparative analytical results between the current test and the proposed
one;

2) Comparative release and shelf life specifications of the drug product.

C31
Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter(s) and Limit(s) of Drug Product

Condition
-

1)
Tabulation of the current and revised release and shelf life specifications of
the drug product with changes highlighted;


3) Batch analysis of the drug product for all tests in the new specification.
4)
Details of any new analytical method and summary of validation data, if
applicable.

C32 Minor Change or Inclusion of Container Closure System of Drug Product
Conditions
-
The proposed packaging material must be at least equivalent or better than
the current approved material in respect of its relevant properties;

-
The change only concerns the same packaging (for example blister to
blister);

- For changes related to sterile products, refer to MIV1 B9.
1)
J ustification for the change in packaging material and appropriate scientific
studies on the new packaging;

2)
For semisolid and liquid dosage forms, proof must be provided that no
interaction between the content and the packaging material occurs (e.g. no
migration of components of the proposed material into the content and no
loss of components of the product into the pack);

3) Specifications of the immediate packaging material;

4)
specification (with proposed action) or when requested;

5)
A declaration from the applicant that the product will meet the release and
shelf life specifications.

C33 Change in Shape of Container Closure System
Conditions
-
No change in the qualitative and quantitative composition of the container
and stability of the product in the container;

-
The change does not concern a fundamental component of the packaging
material which affects the delivery or use of the product;

- The change does not relate to sterile preparations.
1) Details/description of the new container shape;
2)
A declaration from the applicant that the specifications of the container
(except for shape) have not changed;

3)
of the drug product have not changed;

4)
accordance with the relevant guidelines have been started with at least two
pilot scale batches and that the relevant stability studies will be finalised (for
change in the headspace or a change in the surface/volume ratio); data
should be provided only if outside the shelf life specification (with proposed
action).

C34 Change or Inclusion of Pack Size for Drug Product
Conditions
-
Does not apply to sterile preparations, unless the change only concerns the
number of containers in the outer packaging, otherwise refer to MIV1 B12;


- Release and shelf life specifications of the drug product are not affected;
-
The new size is consistent with the dosage regimen and duration of use as
approved in the PI;

- The packaging material remains the same.
1)
J ustification that the new size is consistent with the dosage regimen and
duration of use as is approved in the PI;

2)
of the drug product are not affected, the container and closure composition
is unchanged;

3)
A declaration from the applicant that stability studies on at least 2 production
batches will be conducted for products where stability parameters could be
affected. Data to be reported only if outside specifications (with proposed
action).

C35
Addition or Replacement of Measuring Device for Oral Liquid and Other
Dosage Forms

Conditions
-
The size and, where applicable, the accuracy of the proposed measuring
device must be compatible with the approved posology;

- The new device is compatible with the drug product.
1) Description of the device (including a drawing), where appropriate;
2)
The composition of the device material; where applicable, the materials
should comply with the Pharmacopoeia;

3)
J ustification that size and accuracy of the device are adequate for the
posology as is approved in the product labelling;

C36 Change of Product Labelling due to Safety Updates
Conditions
- Tightening of the products target-patient population; or,
-
Add warnings, precautions, contraindications or adverse events/effects to
the approved product labelling.

1)
Official letter outlining: (a) the reasons for the notification, (b) the status of
the proposed changes in other countries;

2)
A declaration from the applicant that no other changes have been made to
the labelling and that the changes are supported by data.

C37
Change of Product Labelling Relating to:
Addition/deletion of bar code
Replacement of distributor details
Layout without altering text or meaning
Deletion of indication (Note: Re-inclusion of the deleted indication in the
future should be submitted as MAV-1 according to the prevailing
requirement.)
Addtion/deletion/replacement of pictures or diagrams that do not
imply an unapproved indication

Conditions
- The change is not an MAV or does not contain promotional information.

1)
A declaration from the applicant that no other changes have been made to
the labelling.

Conditions
- The change is not an MAV or contains promotional information.
1)
A declaration from the applicant that the information in non-English
language(s) provides complete, accurate and unbiased information on the
product and is consistent with the English version.

GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &MIV-2) FOR BIOLOGICS

APPENDIX 15 GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &
MIV-2) FOR BIOLOGICS

TABLE OF CONTENTS

PART A: INTRODUCTION.............................................................................................. 2

PART B: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1 ................................... 2

B1 Change of Manufacturing Site............................................................................4
B2 Change of Testing Laboratory............................................................................4
B3 Change of Manufacturing Process .....................................................................4
B4 Change of Test Procedure .................................................................................5
B5 Change of Specifications....................................................................................5
B6 Change of Container Closure System................................................................5
B7 Change of Shelf Life and/or Storage Condition..................................................6
B8 Change of Excipient ...........................................................................................6
B9 Change of Product Label....................................................................................6
B10 Seasonal Variation of Influenza Strains for Vaccine...........................................7

PART C: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-2 .................................... 8

C1 Change of Contact Person.................................................................................8
C2 Change of Product Name...................................................................................8
C3 Change of Product Owner..................................................................................9
C4 Change of Batch Numbering System.................................................................9
C5 Renaming of Manufacturing Site........................................................................9
C6 Change of Batch Release Site ...........................................................................9
C7 Addition or Replacement of Secondary Packaging Site...................................10
C8 Withdrawal of Manufacturer or Manufacturing Site ..........................................10
C9 Deletion of Pack Size for Drug Product............................................................10
C10 Change of Secondary Packaging.....................................................................10
C11 Change of Impirints, Bossing, or Other Markings (except Score/Break Line on
Tablet or Printing on Capsule Including Addition or Change or Inks Used for
Product Marking................................................................................................10
Change in Qualitative and Quantitative Composition and Mean Mass .............11
C13 Change in Colouring or Flavouring System of Product Including Addition,
Deletion or Replacement of Colourant(s) or Flavourant(s)................................12
C14 Quantitative Change in Coating Weight of Tablet or Weight of Capusle Shell.12
C15 Change of Product Labelling due to Safety Updates........................................12
C16 Change of Product Labelling............................................................................13
C17 Change of Product Labelling of Language(s) Other Than English...................13

PART A: INTRODUCTION

This document describes the requirements of a Minor Variation Application (MIV)
submitted for an existing registered biologic drug product in Singapore. Applicants
should be familiar with the contents of this document, the Guidance on Medicinal Product
Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.

Minor Variation Applications are divided into two sub-categories:
MIV-1: A minor variation which requires regulatory approval
MIV-2: A minor variation or an administrative change which does not require
regulatory approval; i.e., notification.

MIV should be categorized as an MIV-1. If a proposed MIV-2 does not meet its
specified conditions, then the MIV must be categorized as an MIV-1 with supporting
documents. HSA reserves the right to re-categorise the MIV if deemed appropriate.

Registration Process

Western Drug Product form in PRISM.

Applicants should fully disclose all proposed change(s) under Section 0.4 Amendment
Summary in Section 0 Licence Summary, and in the Table of Amendment Details. The
Table template can be downloaded via the link indicated in Section 0.5 Amendment
Details. Any undisclosed variation(s) embedded in the submitted data, or any flow-on
changes not specifically requested by HSA, will not be considered for evaluation.


Documentary Requirements

A below:

Hard Copy E-Copy

Yes
Optional

PRISM
PRISM/CD
Relevant CTD section(s) of the currently registered
version with the proposed change(s) clearly annotated
Optional PRISM/CD
Yes PRISM

Table A. MIV Application Hard Copy and Electronic Copy Requirements

The Checklist for Minor Variation Applications for Biologic Drugs is located in Appendix
15A and 15B of this guidance document. This Checklist serves as a guide for submitting
the required documents relevant to each proposed MIV. When submitting the Checklist,
the following should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission;
and,
The Declaration for the MIV with the submission date and the local applicants
name and signature.

The Table of Amendment Details concisely describes the proposed MIV(s). The following
information must be stated in the Table:
Section of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason for the change(s); and,
Registration status and date of the proposed change(s) in other countries.

The required documents for each proposed MIV-1 or MIV-2 variation are specified in Part
B or Part C of this document respectively. For an MIV application with multiple related
or unrelated variations, all of the supporting documents for each individual
variation should be submitted. If the required documents have not been submitted,
justification must be provided.

assessment. Applicants are responsible for ensuring that all necessary validations were
conducted to demonstrate that the change does not adversely affect the quality, safety or
efficacy of the product concerned. HSA reserves the right to request additional
information if deemed appropriate.


PART B: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1

B1 Change of Manufacturing Site

For any change, including addition to or replacement, of currently registered
manufacturing site(s) of drug substance, drug product, process intermediates, and/or
primary packager. If there are any changes in the manufacturing process, include
documents listed under B3.

1) Official letter authorising the proposed site to perform the related activity;
2) GMP certificate;
3) Validation study reports and/or summaries of the manufacturing process at the
proposed manufacturing site;
4) Release and/or shelf life specifications;
5) Batch analysis data (in a comparative tabular format) of at least three batches
manufactured at the currently registered and proposed site;
6) Results of appropriate stability studies of at least three batches produced at the
proposed manufacturing site in accordance with the relevant stability guidelines;
7) Batch numbering system.

B2 Change of Testing Laboratory

For any addition or replacement of the current registered laboratories for stability tests
or any quality control (QC) tests.

2) Analytical assays at the proposed site;
3) Validation study reports and/or summaries at the proposed site;
4) Release specification;
5) Batch analysis data (in a comparative tabular format) of at least two batches
tested at the currently registered and proposed site

B3 Change of Manufacturing Process

For any change in the procedure and/or scale of the current registered manufacturing
process at any stage during manufacture of drug substance and/or drug product.

1) Validation study reports and summaries of the proposed manufacturing process;
manufactured according to the currently registered and proposed process;

4) Results of appropriate stability studies of at least three batches produced with the
proposed manufacturing process in accordance with the relevant stability
guidelines;
increase in the level of impurities, which require further safety studies.

B4 Change of Test Procedure

For any change of test procedure of drug substance, drug product, in-process tests,
excipients, product release tests, and/or stability tests.

1) Validation study reports and summaries of the proposed test procedure.

B5 Change of Specifications

For any change of release and/or shelf life specifications of drug substance, drug
product, in-process tests, product release tests, and/or stability tests.

2) Currently registered version of the release and/or shelf life specifications with the
proposed change(s) clearly highlighted, underscored, or otherwise indicated.

B6 Change of Container Closure System

For any change of the container closure system that is in immediate contact with the
drug substance, drug product, process intermediates, and/or diluent used for
reconstitution.

1) Information on construction materials and design features of the proposed
container closure system;
2) Study reports and/or summaries on compatibility, leaching materials, leak tests,
etc. for demonstrating the suitability of using the proposed container closure
system;
3) Release and shelf life specifications;
4) Results of appropriate stability studies of at least three batches produced with the
proposed container closure system in accordance with the relevant stability
guidelines.


B7 Change of Shelf Life and/or Storage Condition

For any change of shelf life and/or storage condition of drug substance, drug product,
and/or process intermediates after initial opening or after reconstitution.

2) Results of appropriate stability studies of at least three batches covering the
duration of the proposed shelf life under the proposed storage conditions in
accordance with the relevant stability guidelines.

B8 Change of Excipient

For any change of the qualitative or quantitative formulation of excipients of drug
substance and/or drug product.

manufactured according to the currently registered and proposed formulation;
3) Results of appropriate stability studies of at least three batches with the proposed
formulation in accordance with the relevant stability guidelines.

B9 Change of Product Label

For any change of product labelling of the package insert (PI), patient information
leaflet (PIL), unit carton label, inner label, and/or blister strips which cannot be
classified as an MAV or an MIV-2.

1) J ustification for the proposed change(s) and supporting clinical documents, where
applicable;
2) Currently registered product label with the proposed change(s) clearly highlighted,
underscored, or otherwise indicated;
3) Proposed product label with all change(s) incorporated;

B10 Seasonal Variation of Influenza Strains for Vaccine

Change of only influenza strains for the formulation of an influenza vaccine according
to WHO Recommendations for Influenza Vaccine Composition may be expedited.
Additional changes other than strain changes will require additional supporting
documents, and may delay the evaluation timeline.

Document Required In Addition to MIV-1 Compulsory Documents:
1) CTD Module 2 - Section 2.3 Quality Overall Summary;

2) CTD Module 3 - Section 3.2.P.8 Stability (Summary & Conclusion) of at least 6
months of the vaccine from the preceding year or season;
3) Currently registered product label with the proposed change(s) clearly highlighted,
underscored, or otherwise indicated;
5) A commitment from the applicant to perform stability studies up to the proposed
shelf-life of the product.


PART C: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-2

An MIV-2 application is a variation for which only a notification is required to be submitted
to HSA. Each MIV-2 notification shall be submitted at least 2 months in advance of the
commencement date.

If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.


Condition

1) Particulars of the contact person updated in the on-line PRISM application form.


Conditions
- There is no change to the product (formulation, specifications, manufacturing
source and process) except the product name;
- No perceived conflict, confusion, or similarity to name(s) of existing medicinal
products;
- New name does not imply (a) greater safety or efficacy than supported by clinical
data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic
use for the product, or (d) the presence of substance(s) not present in the product.

1) Official letter authorising change of product name;
2) A declaration from the applicant that there is no change to the product except
name;
name is marketed;
4) CPP.



Condition

1) Official letter by the new product owner declaring the change, and authorising the
local licence holder to be responsible for the product licence in Singapore;
2) If the new product owner is not the manufacturer of the drug product, an official
letter by the new product owner authorising the manufacturer to produce the drug
product on its behalf.


1) Official letter stating the commencement date of the change;
2) Description of batch number system.

C5 Renaming (e.g. street name, postal code) of Manufacturing Site

Condition
- The current manufacturing site(s) of drug substance, drug product, process
intermediates, packaging, and/or batch release remains unchanged and at the
same physical location.

1) Official letter authorising the site to perform the related activity (not required if the
manufacturer is the product owner);
2) A declaration from the applicant that the manufacturing site remains the same,
4) GMP certificate with new name or address.

C6 Change of Batch Release Site

Condition
- Batch release procedure is equivalent between the current and new site.

1) Official letter authorising the site for batch release;
2) GMP certificate of the new site.


C7 Addition or Replacement of Secondary Packaging Site

1) Official letter authorising the proposed manufacturer to perform secondary
packaging;
2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is

C8 Withdrawal of Manufacturer or Manufacturing Site

1) Official letter stating the withdrawal or deletion of the manufacturer or
manufacturing site to perform the related activity.


1) No additional documents required.

C10 Change of Secondary Packaging

Conditions
- Conformance to current drug product release and shelf life specifications;
- The change is consistent with the dosage regimen and duration of use as
approved in the PI.

1) Official letter stating that release and shelf life specifications, the container and
closure system compositions have not been changed;
2) J ustification that the change is consistent with the dosage regimen and duration of
use as approved in the PI.

C11 Change of Imprints, Bossing or Other Markings (except Score/Break Line) on
Tablet or Printing on Capsule Including Addition or Change of Inks Used for
Product Marking

Conditions
- The inks are acceptable for pharmaceutical use;
- Conformance to current drug product release and shelf life specifications except
for appearance.


1) A declaration from the applicant that that the release and shelf life specifications
(except appearance) of the drug product have not been changed;
3) Detailed drawings and/or written descriptions of the current AND new imprint/
bossing/ markings/ink/etc.;
4) Drug product release and shelf life specifications.

C12.1 Conventional Dosage Form, Suppository and Pessary

Conditions
for dimensions.

1) Detailed drawing or written description of the current and proposed appearance;
3) Revised drafts of the package insert and labelling incorporating the proposed

5) Comparative dissolution data on at least one pilot/production batch of the current
and proposed dimensions in accordance with HSAs drug registration guidelines;
7) Where applicable, data on the test for uniformity of content of the subdivided parts
of tablets at release should be submitted and commitment to conduct the test at
the end of shelf life, data should be provided only if outside the release and shelf
life specifications (with proposed action).

C13 Change in Colouring or Flavouring System of Product Including Addition,
Deletion or Replacement of Colourant(s) or Flavourant(s)

Conditions
- Same functional characteristics, no change in dissolution profile for solid dosage
forms;
for colour/flavour.

(except colour and/or flavour) of the drug product have not been changed;
3) Official letter of commitment to conduct the appropriate stability studies of at least
three batches produced with the revised formulation in accordance with the
relevant stability guidelines;
4) Detailed information of the colouring or flavouring agent;


Conditions
for weight.

(except weight) of the drug product have not been changed;
2) Comparative dissolution data of at least one pilot or production batch of the
current version versus the proposed version in accordance with HSAs drug
registration guidelines; for modified release products, also provide correlative data
comparing in vitro and in vivo data;
3) J ustification for waiving requirements for a new bioequivalence study according to
the relevant guidelines;
4) Drug product release specification.

C15 Change of Product Labelling due to Safety Updates:

Note: Changes to safety information on product labels and package insert may be
allowed without prior approval from HSA provided the changes fulfil the conditions
stipulated below. Companies that need to disseminate safety information urgently
can continue to do so through Dear Healthcare Professionals Letters, in consultation
with HSA. Thereafter, product labelling should be updated in accordance with the
labelling safety-related update notification system.

Conditions
- Addition of warnings, precautions, contraindications or adverse events/effects to
the current product labelling, or
- Tightening of the target-patient population.


labelling and that the change is supported by data.

C16 Change of Product Labelling Relating to:
Addition/Deletion of Bar Code
Replacement of Distributor Details
Layout without Altering Text or Meaning
Deletion of Indication (Note: Re-inclusion of the deleted indication in the future
should be submitted as MAV-1 according to the prevailing requirement.)
Addition/Deletion/Replacement of Pictures or Diagrams that do not Imply
an Unapproved Indication

Conditions
- No unapproved indications, usages, dosage regimens or promotional information.

labelling.


Conditions
- No unapproved indications, usages, dosage regimens or promotional information.

1) A declaration from the applicant that the information in other language(s) provides
complete, accurate and unbiased information on the product and is consistent
with the English version.


CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR BIOLOGICS

APPENDIX 15A CHECKLIST FOR MINOR VARIATION APPLICATIONS
(MIV-1) FOR BIOLOGICS


A below:

Hard Copy E-Copy
Administrative (Module 1/Part 1)
Other supporting documents

Yes
Optional

PRISM
PRISM/CD
Optional PRISM/CD
Yes PRISM

When submitting the Checklist for Minor Variation Applications for Biologic Drugs,
applicants must make the following declaration:


Summary;


DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1


Summary;

____________________ ______________________ _______________

B1 Change of Manufacturing Site
For any change, including addition to or replacement, of currently registered
manufacturing site(s) of drug substance, drug product, process intermediates,
and/or primary packager. If there are any changes in the manufacturing process,
include documents listed under B3.

2) GMP certificate;
3)
Validation study reports and/or summaries of the manufacturing process at
the proposed manufacturing site;

5)
Batch analysis data (in a comparative tabular format) of at least three
batches manufactured at the currently registered and proposed site;

6)
Results of appropriate stability studies of at least three batches produced at
the proposed manufacturing site in accordance with the relevant stability
guidelines.

7) Batch numbering system.

B2 Change of Testing Laboratory
For any addition or replacement of the current registered laboratories for stability
tests or any quality control (QC) tests.

2) Analytical assays at the proposed site;
3) Validation study reports and/or summaries at the proposed site;
4) Release specification;

5)
Batch analysis data (in a comparative tabular format) of at least two batches
tested at the currently registered and proposed site.


B3 Change of Manufacturing Process
For any change in the procedure and/or scale of the current registered
manufacturing process at any stage during manufacture of drug substance and/or
drug product.

1)
Validation study reports and summaries of the proposed manufacturing
process;

3)
manufactured according to the currently registered and proposed process;

4)
Results of appropriate stability studies of at least three batches produced
with the proposed manufacturing process in accordance with the relevant
stability guidelines;

5)
A declaration from the applicant that no new impurities have been introduced
at or above the accepted threshold for qualification of impurities or that there
is no increase in the level of impurities, which require further safety studies.

B4 Change of Test Procedure
For any change of test procedure of drug substance, drug product, in-process
tests, product release tests, and/or stability tests.

1) Validation study reports and summaries of the proposed test procedure.

B5 Change of Specifications
For any change of release and/or shelf life specifications of drug substance, drug
product, in-process tests, product release tests, and/or stability tests.

2)
Currently registered version of the release and/or shelf life specifications with
the proposed change(s) clearly highlighted, underscored, or otherwise
indicated.

B6 Change of Container Closure System
For any change of the container closure system that is in immediate contact with
the drug substance, drug product, process intermediates, and/or diluent used for
reconstitution.

1)
Information on construction materials and design features of the proposed
container closure system;

2)
Study reports and/or summaries on compatibility, leaching materials, leak
tests, etc. for demonstrating the suitability of using the proposed container
closure system;


4)
Results of appropriate stability studies of at least three batches produced
with the proposed container closure system in accordance with the relevant
stability guidelines.


B7 Change of Shelf Life and/or Storage Condition
For any change of shelf life and/or storage condition of drug substance, drug
product, and/or process intermediates after initial opening or after reconstitution.

2)
Results of appropriate stability studies of at least three batches covering the
duration of the proposed shelf life under the proposed storage conditions in
accordance with the relevant stability guidelines.

B8 Change of Excipient
For any change of the qualitative or quantitative formulation of excipients of drug
substance and/or drug product.

2)
manufactured according to the currently registered and proposed
formulation;

3)
Results of appropriate stability studies of at least three batches with the
proposed formulation in accordance with the relevant stability guidelines.

B9 Change of Product Label
For any change of product labelling of the package insert (PI), patient information
leaflet (PIL), unit carton label, inner label, and/or blister strips which cannot be
classified as an MAV or an MIV-2.

1)
J ustification for the proposed change(s) and supporting clinical documents,
where applicable;

2)
Currently registered product label with the proposed change(s) clearly
highlighted, underscored, or otherwise indicated;


B10 Seasonal Variation of Influenza Strains for Vaccine
Change of only influenza strains for the formulation of an influenza vaccine
according to WHO Recommendations for Influenza Vaccine Composition may be
expedited. Additional changes other than strain changes will require additional
supporting documents, and may delay the evaluation timeline.

Document Required In Addition to MIV-1 Compulsory Documents:
1) CTD Module 2 - Section 2.3 Quality Overall Summary;
2)
CTD Module 3 - Section 3.2.P.8 Stability (Summary & Conclusion) of at least
6 months of the vaccine from the preceding year or season;

3)
Currently registered product label with the proposed change(s) clearly
highlighted, underscored, or otherwise indicated;

4) Proposed product label with all change(s) incorporated.

5)
A commitment from the applicant to perform stability studies up to the
proposed shelf-life of the product.


APPENDIX 15B CHECKLIST FOR MINOR VARIATION APPLICATIONS
(MIV-2) FOR BIOLOGICS


A below:

Hard Copy E-Copy
Administrative (Module 1/Part 1)
Other supporting documents

Yes
Optional

PRISM
PRISM/CD
Optional PRISM/CD
Yes PRISM

When submitting the Checklist for Minor Variation Applications for Biologic Drugs,
applicants must make the following declaration:


Summary;
product;
The required documents as specified for the notification(s) have been submitted.


DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-2


Summary;
product;
The required documents as specified for the notification(s) have been submitted.

____________________ ______________________ _______________

Condition
1)
Particulars of the contact person updated in the on-line PRISM application
form.

Conditions
-
There is no change to the product (formulation, specifications, manufacturing
source and process) except the product name;

-
No perceived conflict, confusion, or similarity to name(s) of existing medicinal
products;

-
New name does not imply (a) greater safety or efficacy than supported by
clinical data, (b) superiority over a similar product in Singapore, (c) imply a
therapeutic use for the product, or (d) the presence of substance(s) not present
in the product.

1) Official letter authorising change of product name;
2)
A declaration from the applicant that there is no change to the product except
name;

3)
Official letter of commitment to inform users of the relevant changes, and that
the current product stocks will be exhausted before the product labelled with
the new name is marketed;

4) CPP.

Condition

1)
Official letter by the new product owner declaring the change, and authorising
the local licence holder to be responsible for the product licence in Singapore;

2)
If the new product owner is not the manufacturer of the drug product, an official
letter by the new product owner authorising the manufacturer to produce the
drug product on its behalf.

2) Description of batch number system.

C5 Renaming (e.g. street name, postal code) of Manufacturing Site
Condition
-
The current manufacturing site(s) of drug substance, drug product, process
intermediates, packaging, and/or batch release remains unchanged and at the
same physical location.

1)
Official letter authorising the site to perform the related activity (not required if
the manufacturer is the product owner);

2)
A declaration from the applicant that the manufacturing site remains the same,


4) GMP certificate with new name or address.

C6 Change of Batch Release Site
Condition
- Batch release procedure is equivalent between the current and new site.
1) Official letter authorising the site for batch release;
2) GMP certificate of the new site.

C7 Addition or Replacement of Secondary Packaging Site
1)
Official letter authorising the new manufacturer to perform secondary
packaging;

2)
Evidence (i.e. GMP certificate) demonstrating that the proposed site is

C8 Withdrawal of Manufacturer or Manufacturing Site

1)
Official letter stating the withdrawal or deletion of the manufacturer or
manufacturing site to perform the related activity.


1) No additional documents required.


C10 Change of Secondary Packaging
Conditions
- Conformance to current drug product release and shelf life specifications;
-
The change is consistent with the dosage regimen and duration of use as
approved in the PI.

1)
Official letter stating that release and shelf life specifications, the container and
closure system compositions have not been changed;

2)
J ustification that the change is consistent with the dosage regimen and duration
of use as approved in the PI.

C11
Change of Imprints, Bossing or Other Markings (except Score/Break Line) on
Tablet or Printing on Capsule Including Addition or Change of Inks Used for
Product Marking

Conditions
- The inks are acceptable for pharmaceutical use;
-
Conformance to current drug product release and shelf life specifications
except for appearance.

1)
A declaration from the applicant that that the release and shelf life
specifications (except appearance) of the drug product have not been changed;

2)
the current product stocks will be exhausted before the new product is
marketed;

3)
Detailed drawings and/or written descriptions of the current AND new imprint/
bossing/ markings/ink/etc;


C12
Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without

Conditions
-
(except for dimensions).

1)
appearance;

3)
Revised drafts of the package insert and labelling incorporating the proposed


5)
Comparative dissolution data on at least one pilot/production batch of the
current and proposed dimensions in accordance with HSAs drug registration
guidelines;


6)

7)
Where applicable, data on the test for uniformity of content of the subdivided
parts of tablets at release should be submitted and commitment to conduct the
test at the end of shelf life, data should be provided only if outside the release
and shelf life specifications (with proposed action).

C13
Change in the Colouring or Flavouring System of the Product Including
Addition, Deletion or Replacement of Colourant(s) or Flavourant(s)

Conditions
-
Same functional characteristics, no change in dissolution profile for solid
dosage forms;

-
except for colour/flavour.

1)
specifications (except colour and/or flavour) of the drug product have not been
changed;

2)
the current product stocks will be exhausted before the new product is
marketed;

3)
Official letter of commitment to conduct the appropriate stability studies of at
least three batches produced with the revised formulation in accordance with
the relevant stability guidelines;

4) Detailed information of the colouring or flavouring agent;


Conditions
-
except for weight.

1)
specifications (except weight) of the drug product have not been changed;

2)
Comparative dissolution data of at least one pilot or production batch of the
current version versus the proposed version in accordance with HSAs drug
registration guidelines; for modified release products, also provide correlative
data comparing in vitro and in vivo data;

3)
J ustification for waiving requirements for a new bioequivalence study according
to the relevant guidelines;

4) Drug product release specification.

C15 Change of Product Labelling due to Safety Updates:

Note: Changes to safety information on product labels and package insert may be
allowed without prior approval from HSA provided the changes fulfil the conditions
stipulated below. Companies that need to disseminate safety information urgently
can continue to do so through Dear Healthcare Professionals Letters, in consultation
with HSA. Thereafter, product labelling should be updated in accordance with the
labelling safety-related update notification system.


Conditions
-
Addition of warnings, precautions, contraindications or adverse events/effects
to the current product labelling, or

- Tightening of the target-patient population.
1)
A declaration from the applicant that no other changes have been made to the
labelling and that the change is supported by data.

C16
Change of Product Labelling Relating to:
Addition/Deletion of Bar Code
Replacement of Distributor Details
Layout without Altering Text or Meaning
Deletion of Indication (Note: Re-inclusion of the deleted indication in the
future should be submitted as MAV-1 according to the prevailing
requirement.)
Addition/Deletion/Replacement of Pictures or Diagrams that do not
Imply an Unapproved Indication

Conditions
-
No unapproved indications, usages, dosage regimens or promotional
information.

1)
A declaration from the applicant that no other changes have been made to the
labelling.

C17 Change of Product Labelling of Language(s) other than English
Conditions
-
No unapproved indications, usages, dosage regimens or promotional
information.

1)
A declaration from the applicant that the information in other language(s)
provides complete, accurate and unbiased information on the product and is
consistent with the English version.



Contact Officer:

Ms Yusyanti Mat Tahir
Senior Regulatory Specialist

Ms Evelyn Lee
Senior Regulatory Specialist

Pharmaceuticals & Biologics Branch
Therapeutics Products Division
Health Products Regulation Group
Health Sciences Authority
11 Biopolis Way, #11-03 Helios
Singapore 138667
www.hsa.gov.sg
T: 68663426/ 68663425
F: 64789031

Guidance On Medicinal Product Registration in Singapore 2009 - Complete With Appendices

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GUIDANCE ON MEDICINAL PRODUCT

has not been registered for medicinal use in Singapore

Applicable to information on reference agencies and Country of Origin.

Non-clinical overview included in Module 2 of the ICH CTD.

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