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Effective 1 April 2011

GUIDANCE ON MEDICINAL PRODUCT


REGISTRATION IN SINGAPORE

Please visit HSAs website at http://www.hsa.gov.sg for the latest


update

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE

APRIL 2011

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APRIL 2011

TABLE OF CONTENTS

CHAPTER A
GENERAL OVERVIEW ............................................................................... 9 SEPTEMBER
1 FOREWORD .................................................................................................................. 9
1.1
Scope of this guidance document ..................................................................... 9
1.2
Medicinal product registration ..........................................................................10
2 APPLICANT RESPONSIBILITIES .................................................................................11
3 DATA PROTECTION ....................................................................................................12
4 PATENT LINKAGE........................................................................................................13
CHAPTER B
REGISTRATION PROCESS ......................................................................14
5 PRE-SUBMISSION PREPARATION .............................................................................14
5.1
Application types ..............................................................................................14
5.2
Evaluation routes .............................................................................................16
5.3
Pre-Submission consultation ............................................................................16
5.3.1
Pre-submission inquiry ........................................................................16
5.3.2
Pre-submission meeting ......................................................................16
6 APPLICATION SUBMISSION .......................................................................................17
6.1
PRISM application form ...................................................................................17
6.2
Registration dossier .........................................................................................17
6.2.1
Softcopy and Hardcopy requirements ..................................................18
6.2.2
Language ............................................................................................19
6.2.3
Certifying non-original documents........................................................20
7 APPLICATION SCREENING.........................................................................................20
8 APPLICATION EVALUATION .......................................................................................21
9 REGULATORY DECISION ...........................................................................................23
10 POST-APPROVAL CHANGES......................................................................................24
11 FEES............. ................................................................................................................24
11.1
Screening fee...................................................................................................24
11.2
Evaluation fee ..................................................................................................24
11.2.1 Change in evaluation fees ...................................................................25
11.2.1.1 Change of Application within the Same Application Type...... 25
11.2.1.2 Change of Application between Different Application Types . 25
CHAPTER C
NEW DRUG APPLICATION SUBMISSION ...............................................26
12 APPLICATION TYPES ..................................................................................................26
13 EVALUATION ROUTES ................................................................................................26
13.1
Full evaluation route.........................................................................................27
13.2
Abridged evaluation route ................................................................................27
13.2.1 Priority review ......................................................................................27
13.2.2 Applications for non-prescription medicines .........................................27
13.3
Verification evaluation route .............................................................................28
13.3.1 NDA-3 applications ..............................................................................29
14 DOCUMENTARY REQUIREMENTS .............................................................................29
14.1
Administrative documents ................................................................................29
14.2
CTD overview and summaries .........................................................................35
14.3
Quality documents ...........................................................................................36
14.3.1 Body of Data Drug Substance...........................................................36
14.3.2 Body of Data Drug Product ...............................................................39
14.4
Non-clinical documents ....................................................................................41
14.5
Clinical documents ...........................................................................................41
14.6
Specific documentary requirements for each evaluation route .........................42
14.6.1 Full evaluation route ............................................................................42
14.6.2 Abridged evaluation route ....................................................................42
14.6.3 Verification evaluation route.................................................................42

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CHAPTER D GENERIC DRUG APPLICATION SUBMISSION ..........................................45


15 APPLICATION TYPES ..................................................................................................45
15.1
Generic product ...............................................................................................45 SEPTEMBER
15.2
Singapore reference product ............................................................................45
16 EVALUATION ROUTES ................................................................................................46
16.1
Abridged evaluation route ................................................................................46
16.2
Verification evaluation route .............................................................................46
17 DOCUMENTARY REQUIREMENTS .............................................................................47
17.1
Administrative documents ................................................................................47
17.2
CTD overview and summaries .........................................................................52
17.3
Quality documents ...........................................................................................53
17.3.1 Body of Data Drug Substance...........................................................53
17.3.2 Body of Data Drug Product ...............................................................56
17.4
Non-clinical and clinical documents..................................................................59
17.5
Specific documentary requirements for each evaluation route .........................59
17.5.1 Abridged evaluation route ....................................................................59
17.5.2 Verification evaluation route.................................................................59
CHAPTER E
BIOSIMILAR PRODUCT APPLICATION SUBMISSION ...........................62
18 APPLICATION TYPES ..................................................................................................62
18.1
Biosimilar product ............................................................................................62
18.2
Reference product ...........................................................................................63
19 EVALUATION ROUTES ................................................................................................63
20 DOCUMENTARY REQUIREMENTS .............................................................................63
20.1
Administrative documents ................................................................................64
20.2
CTD overviews and summaries .......................................................................64
20.3
Quality documents ...........................................................................................64
20.4
Non-clinical and clinical documents..................................................................64
CHAPTER F
POST-APPROVAL PROCESS ..................................................................65
21 VARIATION APPLICATION PROCESS ........................................................................66
21.1
Pre-Submission preparation .............................................................................66
21.1.1 Pre-submission inquiry ........................................................................67
21.1.2 Pre-submission meeting ......................................................................67
21.2
Application submission.....................................................................................67
21.2.1 PRISM application form .......................................................................67
21.2.2 Variation application dataset ................................................................67
21.2.2.1 Language ............................................................................. 68
21.2.2.2 Certifying non-original documents......................................... 69
21.3
Application screening .......................................................................................69
21.4
Application evaluation and Regulatory decision ...............................................69
21.5
Fees.................................................................................................................70
21.5.1 Screening fee ......................................................................................70
21.5.2 Evaluation fee ......................................................................................70
CHAPTER G MAJOR VARIATION (MAV) SUBMISSION ...............................................72
22 MAV-1 SUBMISSIONS..................................................................................................72
22.1
Evaluation routes .............................................................................................72
22.1.1 Full evaluation route ............................................................................72
22.1.2 Abridged evaluation route ....................................................................72
22.1.2.1 Applications for non-prescription medicines .......................... 73
22.1.3 Verification evaluation route.................................................................73
22.2
Documentary requirements ..............................................................................73
22.2.1 Administrative documents ....................................................................74
22.2.2 CTD overviews and summaries ...........................................................75
22.2.3 Quality documents ...............................................................................75
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22.2.4
22.2.5

Non-clinical and clinical documents .....................................................75


Specific documentary requirements for each evaluation route .............75
22.2.5.1 Full evaluation route ............................................................. 75 SEPTEMBER
22.2.5.2 Abridged evaluation route ..................................................... 75
22.2.5.3 Verification evaluation route.................................................. 75
23 MAV-2 SUBMISSIONS..................................................................................................76
23.1
Eligibility criteria ...............................................................................................76
23.1.1 Me-too reclassification .......................................................................77
23.2
Documentary requirements ..............................................................................77
23.2.1 Me-too reclassification .......................................................................78
CHAPTER H
MINOR VARIATION (MIV) SUBMISSION ..................................................79
24 MIV SUBMISSIONS ......................................................................................................79
CHAPTER J
SUBMISSION OF A PRISM APPLICATION FORM ...................................80
25 SUBMITTING A PRODUCT APPLICATION ..................................................................80
25.1
Sections of a PRISM Application ......................................................................81
25.1.1 Section 1 Company Particulars .........................................................81
25.1.2 Section 2 Applicant Particulars .........................................................81
25.1.3 Section 3 Application Details.............................................................82
25.1.3.1 Section 3.1 Type of Application.......................................... 83
25.1.3.2 Section 3.2 Type of Product ............................................... 83
25.1.3.3 Section 3.3 Reference Product .......................................... 83
25.1.3.4 Section 3.4 Type of Dossier ............................................... 83
25.1.3.5 Section 3.5 Type of Format ................................................ 84
25.1.4 Section 4 Product Information ...........................................................84
25.1.4.1 Section 4.1 Product Name ................................................. 84
25.1.4.2 Section 4.2 Product Formula.............................................. 85
25.1.4.3 Section 4.3 Ingredients Derived From Human Blood/Animal
Sources .............................................................................. 90
25.1.4.4 Section 4.4 Pharmacotherapeutic Group ........................... 91
25.1.4.5 Section 4.5 Dosage Form .................................................. 91
25.1.4.6 Section 4.6 Route of Administration ................................... 92
25.1.4.7 Section 4.7 Packaging, Shelf Life and Storage Conditions . 92
25.1.4.8 Section 4.8 Forensic Classification .................................... 94
25.1.4.9 Section 4.9 Registration Status in Other Countries ............ 94
25.1.4.10 Section 4.10 Product Owner Information ........................... 96
25.1.5 Section 5 Manufacturer Particulars ...................................................96
25.1.5.1 Active Substance Manufacturer ............................................ 97
25.1.5.2 Finished Product Manufacturer ............................................. 98
25.1.6 Section 6 Information on Company Responsible for Batch Release100
25.1.7 Section 7 Supporting Attachments ..................................................102

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APRIL 2011

LIST OF APPENDICES

SEPTEMBER

APPENDIX 1

Target Processing Timelines

APPENDIX 2A

Application Checklist (ICH CTD NDA and GDA)

APPENDIX 2B

Application Checklist (ICH CTD MAV)

APPENDIX 3A

Application Checklist (ASEAN CTD NDA and GDA)

APPENDIX 3B

Application Checklist (ASEAN CTD MAV)

APPENDIX 4

Flowchart for Translation of Non-English Documents

APPENDIX 5

Guideline on Submission for Non-Prescription Medicinal Products

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 on Acceptability of Bioequivalence Study

APPENDIX 13

Guideline on Submission for Indian Generic Products Under the CECA


Scheme

APPENDIX 14

MIV Filing and Submission Inquiry Form

APPENDIX 15

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


Chemical Drugs

APPENDIX 16

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

APPENDIX 17

Guidance on Registration of Similar Biological Products in Singapore

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APRIL 2011

ABBREVIATIONS AND ACRONYMS


ACPM
ACRA
ACTD
ACTR
ALD
ASEAN
ATC
BA
BE
BP
BSE
BWP
CECA
CEP
CHMP
CMC
CMS
COA
COO
CPP
CPMP
CTD
CVMP
DMF
EDQM
EMA
FDA
FTA
GDA
GSL
GMP
HIV
HPRG
HSA
ICH
INN
JP
MAV
MHRA
MIV
NDA
NfG
OTC
P
PD
PDF
Ph. Eur.
PI
PIC/S
PIL
PK

Advisory Committee on Prescription Medicines


Accounting and Corporate Regulatory Authority
ASEAN Common Technical Document
ASEAN Common Technical Requirements
Audit and Licensing Division
Association of Southeast Asian Nations
Anatomical Therapeutic Chemical
Bioavailability
Bioequivalence
British Pharmacopoeia
Bovine Spongiform Encephalopathy
Blood Working Party
Comprehensive Economic Cooperation Agreement
Certificate of Suitability (Ph Eur monograph)
Committee for Medicinal Products for Human Use (formerly Committee for
Proprietary Medicinal Products) (EU)
Chemistry, Manufacturing and Controls
Concerned Member State
Certificate of Analysis
Country of Origin (Finished product manufacturer)
Certificate of Pharmaceutical Product
Committee for Proprietary Medicinal Products
Common Technical Document
Committee for Medicinal Products for Veterinary Use
Drug Master File
European Directorate for the Quality of Medicines
European Medicines Agency (EU)
Food and Drug Administration (US)
Free Trade Agreement
Generic Drug Application
General Sale List medicine
Good Manufacturing Practice
Human Immunodeficiency Virus
Health Products Regulation Group
Health Sciences Authority (Singapore)
International Conference on Harmonisation (of Technical Requirements for
Registration of Pharmaceuticals for Human use)
International Non-proprietary Names
Japanese Pharmacopoeia
Major Variation
Medicines and Healthcare Products Regulatory Agency (UK)
Minor Variation
New Drug Application
Note for Guidance
Over-The-Counter
Pharmacy only medicine
Pharmacodynamics
Portable document format
European Pharmacopoeia
Package Insert (Singapore), Product Information
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme
Patient Information Leaflet
Pharmacokinetics

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PMF
POM
PRISM
QOS
RMS
SPC
SOP
SQOS
TGA
TSE
URL
USP
WHO
WTO

APRIL 2011

Plasma Master File


Prescription Only Medicine
Pharmaceutical Regulatory and Information System
Quality Overall Summary
Reference Member State
Summary of Product Characteristics
Standard Operating Procedure
Singapore Quality Overall Summary
Therapeutic Goods Administration (Australia)
Transmissible Spongiform Encephalopathy
Uniform Resource Location
United States Pharmacopeia
World Health Organisation
World Trade Organisation

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SEPTEMBER

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE

CHAPTER A

APRIL 2011

GENERAL OVERVIEW

SEPTEMBER

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 include 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 that 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 website1 for the latest version of this guidance
document and other related medicinal product registration guidelines.

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

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1.2

APRIL 2011

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.
A Product Licence is required before a medicinal product can be sold or supplied in
Singapore (Medicines Act, section 5), unless otherwise exempted under the law. 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.
Forensic classification
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).
Prescription Only Medicines (POM) control is required in the following situations:
a) The product poses a direct2 or indirect3 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.
The following also needs to be taken into consideration when deciding whether a product
should be classified as a POM:
2

Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or of
high frequency
3
Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart
disease

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i.
ii.
iii.
iv.
v.
vi.

APRIL 2011

Whether the product contains a substance which is listed in either the Narcotic Drug
Convention or the Psychotropic Substances Convention;
Whether the product is likely to lead to medicinal abuse or addiction if used incorrectly
or to be used for illegal purposes;
Whether the product contains a substance which, by reason of its novelty or
properties, has the potential to fall within point (ii) above;
Whether the product, by reason of its pharmaceutical characteristics, is reserved for
treatments which can only be instituted in a hospital;
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,
Whether the product is intended for outpatients but may produce serious side effects,
which would require medical supervision throughout the treatment.

Pharmacy Only Medicines (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.
General Sales List Medicines (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.
As healthcare products are becoming increasingly complex e.g. combinations of a
medicinal product and medical device the regulation of such products will be based on
how they are classified. Thus, if there is doubt about the products classification, it is
recommended
that
the
applicant
seek
clarification
via
email
to
HSA_MedProd_Enquiry@hsa.gov.sg.

APPLICANT RESPONSIBILITIES

Applicants should note that they are responsible for the medicinal products quality,
efficacy and safety throughout its life cycle. What this means is that the applicants
responsibilities start with the registration of the medicinal product and end when the
product licence expires or is cancelled. Since the products quality, efficacy and safety
can change at any time during the course of its life cycle, it is the applicants responsibility
to inform HSA when these changes occur as per the current guidelines.
The applicants responsibilities include:
i.

To ensure that all of the information 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;

ii.

To 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;

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE

iii.

APRIL 2011

To declare at the time of submission to HSA that the application submitted to HSA
has not been rejected, withdrawn, approved via appeal process or pending deferral
by any drug regulatory agency or HSA reference regulatory agencies, with reasons
in each case if applicable;

iv.

To notify HSA of any change in the information 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;

v.

To notify HSA if the application submitted to HSA has been rejected, withdrawn or
deferred by any drug regulatory agency or HSA reference regulatory agencies, with
reasons in each case if applicable, throughout the products life cycle in the
Singapore market;

vi.

To respond to HSAs queries or requests for more data for review, within the
timelines stipulated by HSA;

vii.

To 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;

viii.

To ensure that all post-approval licensing conditions attached to the product licence
and post-approval commitments are fulfilled within the stipulated timelines;

ix.

To notify HSA of any changes to the products quality, efficacy or safety throughout
the products life cycle in the Singapore market;

x.

To notify HSA if the products marketing authorisation is withdrawn by any drug


regulatory agency or the product is no longer registered in any country, with the
reasons in each case, throughout the products life cycle in the Singapore market;
and,

xi.

To 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).

DATA PROTECTION

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 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.

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APRIL 2011

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 any other such time as HSA may require. As a general
guidance, a confirmatory declaration will be requested 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 include a resolution of board of directors, a 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.
If (i) there is a patent in force in respect of the medicinal product to which the application
relates, (ii) the applicant is not the proprietor of the patent, (iii) the proprietor has not
consented to nor acquiesced in the grant of the product licence, and (iv) the applicant is
requesting for grant of product licence after the expiry of the patent (i.e. Category A3
patent declaration), then such an application may not be made earlier than 18 months
before the expiry of the patent.
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 should seek the assistance of their own legal counsel.

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GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE

CHAPTER B

APRIL 2011

REGISTRATION PROCESS

One part of a products 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 seen
in Figure 1 below:
PRE-SUBMISSION
PREPARATION

NON-ACCEPTANCE /
WITHDRAWAL

APPLICATION
SUBMISSION

APPLICATION
SCREENING
ACCEPTANCE

APPLICATION
EVALUATION
NON-APPROVAL /
WITHDRAWAL

REGULATORY
DECISION
APPROVAL

POST-APPROVAL
CHANGES
Figure 1. Registration Process for a Medicinal Product

For information on the registration processing time, refer to Appendix 1 of this guidance
document.
5

PRE-SUBMISSION PREPARATION

The first step in the registration process is one of the most important because it involves
i. Knowing which application to apply for;
ii. Knowing which evaluation route to choose; and,
iii. Arranging for a pre-submission consultation with HSA for advice, if required.
5.1

Application types

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

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NDA New Drug Application


NDA-1: For the first strength of a product containing a new* chemical or biological entity.
NDA-2: i) For the first strength of a new drug product
containing a new* combination of registered chemical or biological entities;
containing registered chemical or biological entity(ies) in a new dosage
form;
containing registered chemical or biological entity(ies) for use by a new
route of administration; or,
containing registered chemical or biological entity(ies) for new indication(s),
dosage recommendation(s) and/or patient population(s).
ii) For new drug products that do not fall under the requirements for NDA-1,
NDA-3 or GDA.
NDA-3: For subsequent strength(s) of a new drug product that has been registered or has
been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical
dosage form, indication, dosing regimen and patient population shall be the
same as that for the NDA-1 or NDA-2.

SEPTEMBER

* Has not been registered before in Singapore


GDA Generic Drug Application
GDA-1: For the first strength of a generic chemical product.
GDA-2: For subsequent strength(s) of the generic chemical 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 generic product is essentially similar to a currently registered product in Singapore
(known as the Singapore reference product) but excludes biologics. Essentially similar4
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,
the concept of essentially similarity also applies to different conventional immediate
release oral dosage forms (i.e. tablets and capsules) which contain the same active
ingredient(s).
A schematic diagram to illustrate the various types of applications is seen in Figure 2
below:
YES
NO

IS PRODUCT
REGISTERED?
YES

Post-Approval
Process, Chapter F

Essentially similar
to a currently
registered product?
YES

NO

NDA 1

Contains new
chemical or
biological entity?
NO

YES

GDA 1

First strength of
product?

GDA 2
NO

Figure 2. Schematic diagram of application routes for drug registration.

Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.

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Evaluation routes

There are three types of evaluation routes for registration of a new product:
Full dossier:
Abridged dossier:
Verification dossier:

SEPTEMBER

Applies to any product that has not been approved by any drug
regulatory agency at the time of submission.
Applies to any product that has been evaluated and approved by
at least one drug regulatory agency.
Applies to any product that has been evaluated and approved by
HSAs reference drug regulatory agencies, which include EMA*,
US FDA, Health Canada, TGA and UK MHRA#.

* For products approved via the Centralised Procedure


#

For products approved via the national procedure or where MHRA acted as the RMS for the MRP or
Decentralised Procedures in Europe

Applicants should be familiar with the eligibility criteria for each evaluation route for the
application type to be submitted because the documentary requirements for the full,
abridged and verification routes for an NDA and GDA are different.
Applicants should refer to Chapters C, D and E for detailed information about the
selection of appropriate evaluation routes for NDA, GDA and biosimilar product
applications, respectively.
NOTE: Refer to Section E for more information on the application types and
evaluation routes available for biosimilar products.

5.3

Pre-submission consultation

Applicants are encouraged to contact HSA prior to submission of an application if


questions arise or clarification is required. There are two methods to contact HSA:
i.
ii.

Pre-submission Inquiry via email


Pre-submission Meeting

Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.
5.3.1

Pre-submission inquiry

The applicant may submit a pre-submission inquiry via e-mail if any clarification on
medicinal product registration is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Presubmission 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.
5.3.2

Pre-submission meeting

For complex issues relating to an impending submission, applicants are advised to


consult with HSA in a pre-submission meeting. The request for a consultation should be

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made in writing, with the purpose, agenda and proposed date & time for the meeting, via
email to HSA_MedProd_Registration@hsa.gov.sg.
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
application dossier.

APPLICATION SUBMISSION

Application submission comprises of two parts: the PRISM application form and the
registration dossier.
6.1

PRISM application form

All applications must be made on-line via PRISM. Refer to Chapter J for guidance notes
for submitting a PRISM application.
6.2

Registration dossier

The registration dossier contains the documents to support the evaluation of the
submitted application.
The complete dossier should be submitted 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.
Registration dossiers should be in a 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 5 or the ASEAN guidelines on the Common Technical
Document for Registration of Pharmaceuticals for Human use: Organisation of the
Dossier6. 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, the dossier will be in one of the two formats, either the ICH CTD or the ACTD
format. According to the chosen format, 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:
Table 1. Format of the ICH CTD and ACTD.
Documents
Administrative Documents and Product
Information
Common Technical Document Overview
and Summaries
Quality documents
Non-clinical documents
Clinical documents

5
6

Location in
ICH CTD
Module 1

ACTD
Part I

Module 2

Incorporated in Parts II, III and


IV
Part II
Part III
Part IV

Module 3
Module 4
Module 5

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

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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.

SEPTEMBER

The CTD format cannot be changed once the application is submitted. Any subsequent
variation applications for the product should follow the same format.
6.2.1

Softcopy and Hardcopy requirements

In moving towards a greener environment, submission of the complete registration


dossier i.e. Modules 1 to 5 of the ICH CTD or Parts I to IV of the ACTD should be in
electronic format. But there is one exception: documents which require proof of
authenticity (e.g. CPPs, approval letters not available online, authorisation letters, GMP
certificate, patent declaration, declaration letters, etc) should be submitted in electronic
and hard copy format.
Applicants should ensure that all soft copies e.g. scanned documents of the dossier
are legible as illegible soft copies will cause unnecessary delays in the registration
process.
Table 2 and 3 outline the softcopy requirements for NDAs and GDAs submitted via the
full, abridged or verification evaluation route in either ICH or ACTD, respectively:
Table 2. Soft and Hard Copy Requirements for ICH CTD dossiers.
#

CTD Requirement
ICH CTD
NDA (F)
NDA (A)
NDA (V)
GDA (A + V)
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
PRISM/CD
PRISM/CD
Module 3
PRISM/CD
PRISM/CD
PRISM/CD
PRISM/CD
N/A
N/A
N/A
N/A
Module 4
N/A
N/A
N/A
Module 5
PRISM/CD
PRISM/CD
PRISM/CD
#

F: full route; A: abridged route; V: verification route; N/A: not applicable


Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1
(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, patent declaration,
declaration letters, etc)
+:

Table 3. Soft and Hard Copy Requirements for ACTD dossiers.


#

ACTD
Part I
Part II
Part III
Part IV

CTD Requirement
NDA (F)
NDA (A)
NDA (V)
GDA (A + V)
Softcopy Hardcopy Softcopy Hardcopy Softcopy
Hardcopy Softcopy Hardcopy
+
+
+
+
PRISM
1 set
PRISM
1 set
PRISM
1 set
PRISM
1 set
PRISM/CD
PRISM/CD
PRISM/CD
Overview
Overview
Only:
Only:
PRISM/CD
N/A
N/A
N/A
N/A
N/A
PRISM/CD
PRISM/CD
PRISM/CD
PRISM/CD
PRISM/CD

F: full route; A: abridged route; V: verification route; N/A: not applicable


Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1
(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, patent declaration,
declaration letters, etc)
+:

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While Module 1/ Part I must be submitted in softcopy, it must also be submitted in


hardcopy, notably for documents that require proof of authenticity, such as Letters of
Authorisation, GMP certificates, CPPs, patent declaration forms and so forth. Official
documents issued by other drug regulatory agencies, declaration letters and patent
declaration form should also be submitted as the original copy; if these documents cannot
be submitted as originals, then refer to section 6.2.3 for more information on certifying
non-original documents. Applicants should also ensure that submitted electronic copies
are identical to the hardcopy documents.
For Modules 2 to 5/Parts II to IV, applicants can opt to attach the documents either in full
into PRISM section 7 (Supporting Attachments) or submit the softcopies (e.g. PDF
format) in a CD/DVD. However, applicants are advised not to combine PRISM
attachments with a CD/DVD submission i.e. all supporting documents must be attached
in PRISM or all supporting documents submitted in a CD/DVD.
In order to ensure that the dossier is complete, application checklists for both ICH CTD
and ACTD dossiers are provided in Appendix 2A and 3A, respectively. Each checklist
states the required documents for each dossier type and application type. Refer to the
specific Appendices for more details.
When submitting a CD/DVD, applicants are encouraged to organise the dossier via the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
6.2.2

Language

Information and documents supporting an application, such as certificates, approval


letters and approved product labels, must be in English and authenticated. If documents
are not originally in English, applicants should refer to Appendix 4 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
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;

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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 origin of a document is 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.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.
Apostille
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 apostille 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 that are submitted to HSA as part of the application dossier.
6.2.3

Certifying non-original documents

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 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 requires certification by the drug regulatory
agency that issued the approval letter, a notary public or the 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 can provide the internet address
(URL) for validation by HSA.
7

APPLICATION SCREENING

After PRISM and dossier submission, the application will be screened to ensure that the
correct application type has been chosen and that there are no deficiencies that would
delay the registration process.
If the application type needs to be re-categorized, for example from NDA-2 to NDA-3 or
GDA-1 to NDA-2, the applicant will be notified and subsequently, the PRISM application
will be amended as described in section 11.2.1.

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If any deficiencies are identified, a screening query letter via Input Request will be issued
to the applicant. The stop-clock starts whenever HSA requests for clarification or
additional information. The stop-clock ends when HSA receives a complete and
satisfactory response to the query.
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, and hence, the registration dossier, is found to
be adequate.
An acceptance notice will be issued to the applicant via email upon acceptance of an
application. The date of acceptance of the application will be considered as the start of
the evaluation timeline.
If the applicant fails to provide the requested information, or the submitted information is
incomplete or contains unsolicited information, the application will not be accepted for
evaluation. 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.
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.
NOTE: The screening process only determines the completeness of the registration
dossier for evaluation. Acceptance of the dossier for evaluation does not constitute
acceptability of the data provided. Acceptability of the data can only be determined
during evaluation of the application.

APPLICATION EVALUATION

Upon acceptance of an application, 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 and ends when HSA receives a
complete and satisfactory response from the applicant.
If the applicant anticipates difficulty in responding in full or within the specified timeframe,
then 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 stopclock 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.

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For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table 4
describes the applicable product applications and the stages to the evaluation process:
Table 4. Product Applications Applicable for Notification of Stages During Evaluation
Stages of Notification to
Applicant
Application
Type

NDA-1
NDA-2
NDA-3

GDA-1
GDA-2

Dossier
type

Full or
Abridged

Abridged or
Verification

st

1 Stage

nd

Stage

rd

3 Stage

th

4 Stage

Evaluation Status
Accepted for
Evaluation

Application is
accepted for
evaluation
This marks the
start of the
evaluation
timeline

Active
Evaluation

When active
evaluation is in
progress for
the application

Midway in
Evaluation

Evaluation
Completed

Application is
approximately
midway through
the evaluation
(provided that
there were no
prior stop-clocks
which may affect
the evaluation
progress)

Evaluation is
completed for the
application

Applicants could
expect to receive
the first set of
queries from HSA
during this stage

Application is now
undergoing the
regulatory decision
phase, after which
a regulatory
decision letter*
would be issued.
Applicants could
still expect further
queries from HSA
during this stage

* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.

Applicants may view the evaluation stage via track@PRISM. Screenshots on viewing the
change in stages of a pending application are as follows:

Choose these options from


the drop-down lists

Enter PRISM application to


view stage of evaluation

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SEPTEMBER

Active Evaluation

The evaluation stage


is seen here.

Applicants would also be notified via system-generated emails whenever an evaluation


stage change occurs.
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. Applicants will be notified by letter of one of the following outcomes:
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.
If an approvable regulatory decision has been reached, the conditions for approval will
be stated in writing and the applicant will be required to fulfill these conditions within the
stipulated timeframe.
If a non-approvable regulatory decision has been reached, the applicant will be informed
of the non-approvable issues in writing. If the applicant wishes to address the nonapprovable 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.
Applicants should note that issuance of a regulatory decision letter signals the end of the
evaluation timeline. Appendix 1 contains information on the application timelines.
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
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application is withdrawn, the applicant may submit a new application according to


prevailing submission requirements.

SEPTEMBER

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 letter of
commitment should be specific, i.e. it addresses the particular issues of concern and
should provide details on how and when the post-approval licensing commitments will be
fulfilled. Failure to comply with these commitments may result in the suspension or
revocation of the Product Licence.
Applicants are expected to view the licensing conditions on-line in order to be reminded of
all post-approval commitments associated with the Product Licence.
10

POST-APPROVAL CHANGES

Upon issuance of a product licence, applicants will be responsible to maintain the


products quality, efficacy and safety to the end of its life cycle. Any aspect of the product
may change throughout its life cycle for example, there can be a change in
manufacturer or manufacturing process, change in indication or dosage regimen or
change in safety profile.
HSA must be notified of any changes to the products quality, efficacy and safety as per
Chapter F in this Guidance.
11

FEES

The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website7.
11.1

Screening fee

The screening fee per application is payable at the time of PRISM submission. The
screening fees are non-refundable once the application has been successfully submitted
via PRISM.
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.
11.2

Evaluation fee

Evaluation fees are payable upon acceptance of the dossier for evaluation. The
evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 April 2009, the progressive payment scheme was implemented to
allow payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to applications types as listed in Table 5 on the next page:
7

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html

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Table 5. Product Applications Applicable for Progressive Payment Scheme

SEPTEMBER

Percentage of Evaluation Fee Payable at Each Stage


Application
Type

Evaluation
Route

NDA-1
NDA-2
NDA-3

Full or
Abridged

GDA-1
GDA-2

Abridged or
Verification*

Accepted for
Evaluation

30%

Evaluation Status
Active
Midway in
Evaluation
Evaluation

40%

20%

Evaluation
Completed

10%

* Progressive payment scheme for the verification evaluation route for GDAs will be in effect from 1 Jan 2011

NOTE: To apply for the progressive payment for applications under the full
evaluation
route,
the
applicant
must
contact
HSA
via
HSA_Medprod_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.

For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.
11.2.1

Change in evaluation fees

Changes in the evaluation fees may occur if there are changes to the application type.
11.2.1.1 Change of Application within the Same Application Type
Re-categorisation of the application within the same application type (e.g. from NDA-2 to
NDA-3, or GDA-1 to GDA-2) would be carried out by the HSA officer during screening
prior to acceptance of the application. As there are differences in evaluation fees for
different application types, the change in application type would be communicated to the
applicant during the screening process. Applicants may opt to withdraw the application if
they do not agree to the change in application type; applicants are to note that in these
instances, the screening fee is non-refundable.
If there are no objections communicated to HSA, the application would be accepted with
the new application type and the new evaluation fee would be charged accordingly.
11.2.1.2 Change of Application between Different Application Types
Re-categorisation of GDA to NDA 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.
NOTE: Non-GIRO paying applicants may need to make an additional payment to
top-up any differences in fees. Similarly, any excess in evaluation fees collected
would be refunded to the applicant upon acceptance.
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CHAPTER C

APRIL 2011

NEW DRUG APPLICATION SUBMISSION

This chapter applies to new drug applications for products containing new chemical and
biological entities. For new drug applications for biosimilar products, please refer to
Chapter E.
12

APPLICATION TYPES

There are 3 application types for a new drug application:


NDA New Drug Application
NDA-1: For the first strength of a product containing a new* chemical or biological entity.
NDA-2: i) For the first strength of a new drug product
containing a new* combination of registered chemical or biological entities;
containing registered chemical or biological entity(ies) in a new dosage
form;
containing registered chemical or biological entity(ies) for use by a new
route of administration; or,
containing registered chemical or biological entity(ies) for new indication(s),
dosage recommendation(s) and/or patient population(s).
ii) For new drug products that do not fall under the requirements for NDA-1,
NDA-3 or GDA.
NDA-3: For subsequent strength(s) of a new drug product that has been registered or has
been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical
dosage form, indication, dosing regimen and patient population shall be the
same as that for the NDA-1 or NDA-2.
* Has not been registered before in Singapore
13

EVALUATION ROUTES

There are three evaluation routes for an NDA: full, abridged and verification evaluation.
The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
Figure 3 below is a schematic diagram to illustrate the evaluation routes for NDAs:
NO

NDA 1
NDA 2
NDA 3

Is the product
registered with
any drug
regulatory
agency?

FULL ROUTE
NO

YES

Approved by
HSAs reference
agencies and
met verification
criteria?

YES

ABRIDGED
ROUTE
VERIFICATION
ROUTE

Figure 3. Schematic diagram of evaluation routes for NDAs.

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Full evaluation route

Full evaluation will apply to a product that has not been approved by any drug regulatory
agency at the time of submission.
13.2

Abridged evaluation route

Abridged evaluation will apply to a product that has been approved by at least one drug
regulatory agency at the time of submission.
13.2.1

Priority review

For NDAs submitted via the abridged evaluation route, the applicant may request for
priority review for a life-saving drug if there are unmet medical needs. The following
states the criteria that will be considered for priority review:
a) 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.
b) Disease conditions that are of local public health concerns will be given primary
consideration for priority review. Currently these include:
cancer; and,
infectious diseases: dengue, tuberculosis, hepatitis and malaria.
The request for priority review should be made at the point of application submission and
accompanied by justification which 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/or 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.
The decision for the granting of priority review would be conveyed to the applicant at the
point of acceptance of the application for evaluation.
13.2.2

Applications for non-prescription medicines

If the NDA is for a non-prescription medicine and is submitted via the abridged evaluation
route, 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 5 Guideline on
Submission Requirements for Non-Prescription Medicines. However, HSA reserves the
right to request for the complete clinical data set if it is deemed appropriate.
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Verification evaluation route

Medicinal products with similar indication(s), dosing regimen(s), patient group(s), and/or
direction(s) for use that have been approved by at least two of the following HSAs
reference drug regulatory agencies may be submitted via the verification evaluation route.
HSAs reference drug regulatory agencies are:

Australia Therapeutic Goods Administration (TGA);


Health Canada (HC);
US Food and Drug Administration (FDA);
the European Medicines Agency (EMA) via the Centralised Procedure;
UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) via
- the national procedure, or,
- as the Reference Member State (RMS) via the Mutual Recognition Procedure or
Decentralised Procedure.

However, approval by these reference regulatory agencies does not obligate HSA to
approve the application. HSA may also re-categorise applications to other evaluation
routes if deemed appropriate.
One of the reference drug regulatory agencies must be declared as the primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be
submitted.
Additional eligibility criteria for the verification route include:
The application must be submitted within three years from the approval date by the
chosen primary reference agency;
All aspects of the drug products quality, including but not limited to the formulation,
manufacturing site(s), release and shelf life specifications and primary packaging,
must be identical as that currently approved by the chosen primary reference
agency;
The product does not need a more stringent assessment as a result of differences
in local disease patterns and/or medical practices (e.g. some anti-infectives).
The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) has not been rejected, withdrawn, approved via appeal process or
pending deferral by a drug regulatory agency for safety and/or efficacy reasons;
and,
The product is not a biological product.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies. In the event that the chosen primary reference agency does not bear the most
stringent indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use, the
clinical assessment report from the other reference agency that met such requirements
should be submitted. The clinical assessment report from the other reference agency to
be submitted may be obtained from the public domain. The proposed PI/PIL should be
identical to that approved by this reference agency (with the exception of country-specific
information).
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 an 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.

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13.3.1

APRIL 2011

NDA-3 applications

For the NDA-3 application type, the verification evaluation route may be applied to the
registration of subsequent strengths of a currently-registered product in Singapore. To
qualify for the verification evaluation route for an NDA-3 application, if the product has
been evaluated and approved
by at least one of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within two years from the date of approval by that reference agency;
OR,
by at least two of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within three years from the date of approval by the chosen primary
reference agency.
All other eligibility criteria for the verification evaluation route as stated above in section
13.1.3 will apply except the following:
The proposed indication(s), dosing regimen(s), patient group(s), and/or direction(s)
for use must be identical to the corresponding approved NDA-1 and/or NDA-2
product(s); and,
The proposed PI/PIL should also be consistent with that currently approved for the
corresponding NDA-1 and/or NDA-2 product(s).
14

DOCUMENTARY REQUIREMENTS

Table 6 outlines the CTD Modules/Parts required for NDAs submitted under each
evaluation route:
Table 6. Dossier Submission Requirements for an NDA.
Documents

Location in
ICH CTD
ACTD

Full
NDA
Yes

Administrative
Documents
Common Technical
Document Overview
and Summaries
Quality documents
Non-clinical
documents

Module 1

Part I

Module 2

Module 3
Module 4

Incorporated
in Parts II, III
and IV
Part II
Part III

Clinical documents

Module 5

Part IV

Yes

Module/Part required for


Abridged NDA
Verification NDA
Yes

Yes

Yes

Yes

Yes

Yes
Yes

Yes
ICH: No
ACTD: Overview
only
Study report(s) of
pivotal studies and
synopses of all
studies (phase I-IV)
relevant to requested
indication, dosing
and/or patient group

Yes
ICH: No
ACTD: Overview
only
Study report (s) of
pivotal studies and
synopses of all
studies (phase I-IV)
relevant to requested
indication, dosing
and/or patient group

Non-clinical overview included in Module 2 of the ICH CTD.

Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
14.1

Administrative documents

The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to all evaluation routes for NDAs. The following sections are to be
submitted:
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Comprehensive Table of Contents (section 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. If a hardcopy registration dossier is submitted, then 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 (section 1.2)
Applicants should give a concise 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 (section 1.3)
A printout of the PRISM application form is to be included in the dossier.
Labelling, Package Insert and Patient Information Leaflet (section 1.4)
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:

Package Insert (PI), also known as prescribing


information, SPC, or product monograph
Patient Information Leaflet (PIL), also known as
consumer medicine information (CMI)

Forensic Classification in Singapore


POM
P
GSL
Required
Optional
Optional
Optional, unless
warranted

Required

Required

All artwork and drafts should be legible. Any handwritten information is not acceptable.
Separate labels 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.
Appendix 6 contains specific details on product labelling requirements for Singapore.
Approved SPC/PI/PIL (section 1.5)
In this section, the applicant shall submit the following:
i. the approved SPC, PI and/or PIL from the drug regulatory agency that issued the
proof of approval; and,
ii. the approved SPC, PI and/or PIL from all of HSAs reference drug regulatory
agencies, where applicable.
Assessment Report from Reference Agencies (section 1.6)
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the primary reference agency
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and inserted into this section must be unredacted and unedited. Applicants should refer to
section 14.6.3 for specific details on the required documents.

SEPTEMBER

Description of Batch Numbering System (section 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. Where
applicable, examples of the batch numbering system should be included to illustrate how
the batch number enables identification.
Proof of Approval (section 1.8, 1.9)
Proof of approval is not required for NDAs undergoing a full evaluation.
For an abridged evaluation of an NDA product, proof of approval by any 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 SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 for more
information.
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.
Approval letters should be either an original copy or a certified true copy and in English.
Applicants should refer to section 6.2.2 and 6.2.3 for more details.
HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
Authorisation Letters (section 1.10)
All submitted authorisation letters 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:
i. 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.
ii. 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, then the applicant may
opt to submit one authorisation letter which clearly states all of the manufacturers
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(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.
iii. from Product Owner to Batch Releaser (1.10.3) this letter authorises the specified
company to batch release the drug product. If there are multiple sites responsible
for batch release of the product, then 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 letters 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, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated 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 (section 1.11)


Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturers, primary packagers and secondary packagers. A CPP
may be submitted in lieu of a GMP certificate provided that the manufacturers name(s)
and address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses of all manufacturers should be consistent throughout the application i.e.
GMP certificate, Letter of Authorisation, CTD section S2.1 and P3.1 and PRISM.
Proof of GMP compliance must not expire within six (6) months from the time of
submission to HSA and must be in hardcopy, in English and either an original or certified
true copy. Applicants should refer to section 6.2.2 and 6.2.3 for more details.
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.
For biologic NDA applications, proof of GMP compliance for the drug substance must be
submitted in addition to the aforementioned GMP requirements.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain such information:
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the last date of audit by US FDA;


the approved dosage forms;
any licensing conditions or restrictions;
the scope of the inspection; and/or,
objective evidence and the date of a satisfactory close-out of the latest inspection
conducted by US FDA.

* any other supporting document which declares GMP compliance of the manufacturing site in the US
and signed by an official of the US FDA.

All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004 and 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 form8
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer9.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
Patent declaration (section 1.12)
The Patent Declaration form is required for each NDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on patent linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
8

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_
manufacturers/conformity_assessment/eServices_Forms.html
9
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

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The authorised person is ordinarily an officer of the company such as Company


Director or Company Secretary as registered with ACRA, or equivalent. Evidence of
such authorisation is to be submitted together with the declaration.
Evidence of authorisation for Section 8 of the form could be in the form of:
An ACRA printout (BizFile) listing the Company Directors/Secretary;
Resolution of board of directors;
Resolution of a general meeting of the company; or,
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.
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorisation is current at the point of
submission.

Declaration on rejection, withdrawal and deferral (section 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 or withdrawn,
has not been approved via an appeal process, or,
is not pending deferral
by any drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
Declaration for NDA verification (section 1.14)
This section applies only to the verification evaluation route.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen primary reference regulatory agency.
Quality aspects include, but are not limited to, formulation, manufacture site(s), release
and shelf life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
Registration status in other countries (section 1.15)
The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 25.1.4.9 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
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submitted in hardcopy in this section of the CTD dossier. The document should be in the
format as seen in Table 7 below:

SEPTEMBER

Table 7. Table of Information on Registration Status in Other Countries for CTD section 1.15.
Country

Application
status

Status Date

Approved application
indication/dosing regimen details*

Country 1

Approved

12 Jan 2005

Country 2

Approved

2 Feb 2006

Country 3

Withdrawn
by applicant

14 Apr 2002

Country 4

Approved

21 Nov 2004

Adjuvant treatment of colorectal cancer


stage III (Dukes C) following complete
resection of primary tumour.
Adjuvant treatment of colorectal cancer
following surgery
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.
Adjuvant treatment of colorectal cancer
stage III (Dukes C) following complete
removal of primary tumour.

Country 5
*

Pending

Submitted:
15 Jun 2005

Notice of Compliance with Conditions


issued on 16 April 2003 based on
promising efficacy results with
condition to furnish confirmatory
efficacy data.
Adjuvant treatment of colorectal cancer
stage III (Dukes C) following surgery.

Approved
forensic

classification
POM

POM
POM

POM

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.

14.2

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 II, III and IV 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 II, 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.

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.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;
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ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The SQOS template for chemical drug products is given in Appendix 8. The SQOS
template for biologic drug products, including biosimilar products, is given in Appendix 9.
14.3

Quality documents

The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
14.3.1

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

All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then 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).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.
Drug Master File (DMF)
A Drug Master File is a reference that provides information about specific processes or
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
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 3.2.S (ICH
CTD) or Part II.C.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.

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


follows:

SEPTEMBER

From the Applicant:


the open part of the DMF, as part of the submitted dossier; and,
a copy of the Letter of Access.
From the Drug Substance Manufacturer (also referred to as DMF Holder):
the complete DMF i.e. both the open and closed parts; and,
the original Letter of Access.
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(s) (product name, dosage form and product strength)
to be registered;
the local applicant (name and address) 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.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) 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 DMF number. If
there are deficiencies within the closed part of the DMF, HSA will raise queries directly
with the DMF holder.
NOTE: Assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.

If a product application makes reference to a currently-registered DMF, the original Letter


of Access specific to the product application is to be provided by the DMF Holder and a
copy of the Letter of Access is to be submitted by the applicant as part of the registration
dossier.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on the
post-approval process.
Plasma Master File (PMF)
A Plasma Master File is required whenever a human plasma-derived product is used
either as a drug substance or as an excipient as the PMF contains information on the
collection and control of source materials. The PMF may be submitted either as a stand-

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alone document or as part of the registration dossier. Appendix 10 describes the PMF
data requirements for submission.
If the PMF is a stand-alone document, then it 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)
A Certificate of Suitability is a document issued by European Directorate for the Quality of
Medicines and Healthcare (EDQM) that certifies the quality of a drug substance in
compliance to the Ph. Eur. A CEP may be submitted in lieu of the CTD S Section or a
DMF.
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S sections:
i.

ii.

batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).
NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is seemed appropriate.

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.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Control of Drug Substance (3.2.S.4)
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.
Stability Data of Drug Substance (3.2.S.7)
At the time of submission, the minimum stability data required are as follows:

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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.
14.3.2

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.
Pharmaceutical Development (3.2.P.2)
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier sections. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimisation of the manufacturing process, with data.
Process Validation (3.2.P.3.5)
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Applicants should refer to the ASEAN Guidelines on Submission of Manufacturing
Process Validation Data for Drug Registration10 and the accompanying Q&A on ASEAN
Guideline on Process Validation for the minimum data requirements on process
validation. Other relevant international guidelines may also be referred to as appropriate.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
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.

10

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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 excipients derived from human plasma, applicants should refer to the Appendix 10 for
more information on the data requirements.
For excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
Control of Drug Product (3.2.P.5)
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be submitted in sections P.5.2 and P.5.3.
Descriptions (including size, origin and use) and test results of all relevant batches (e.g.
pre-clinical, clinical, pilot and production batches) used to establish the specification and
evaluate the consistency in manufacturing should be provided.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Justification of the specifications (section P.5.6) should be based on scientific knowledge
and data collected during product development.
Container Closure System (3.2.P.7)
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
Stability Data of Drug Product (3.2.P.8)
HSA has adopted the ASEAN Guideline on Stability of Drug Product11 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 have been implemented since 1st January 2009.
11

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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 primary
batches of the drug product, as per the ASEAN guideline;
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.
For example, 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.
Blank Production Batch Records
For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
14.4

Non-clinical documents

The non-clinical documents relate to Module 4 of the ICH CTD or Part III of the ACTD.
Applicants should refer to the ICH CTD Guidelines M4S12 (Safety) technical guidelines or
the ACTD Part III: Nonclinical13 guidelines for detailed information on the contents of nonclinical documents for the application dossier.
14.5

Clinical documents

The clinical documents relate to Module 5 of the ICH CTD or Part IV of the ACTD.
Guidance on how to complete this Module/Part is provided in the ICH CTD Guideline
M4E 14 (Efficacy) technical guidelines, in particular the ICH E3 guidance document on
Structure and Contents of Clinical Study Reports, or the ACTD Part IV: Clinical 15
guidelines.
Clinical studies should generally 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.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.

12
13
14
15

http://www.ich.org/cache/compo/276-254-1.html
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
http://www.ich.org/cache/compo/276-254-1.html
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

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14.6

APRIL 2011

Specific documentary requirements for each evaluation route

14.6.1

Full evaluation route

SEPTEMBER

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 quality documents for both drug substance and drug product;
complete pharmaco-toxicological or non-clinical documents; and,
complete clinical documents relevant to requested indication, dosing and/or patient
group; i.e. all study reports from phase I to phase III, including tables and
appendices.
14.6.2

Abridged evaluation 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 drug
regulatory agency that issued the proof of approval.
The technical documents required include:
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 relevant to requested indication, dosing and/or patient
group (the tables and appendices to the pivotal study reports may be submitted
upon request by HSA).
14.6.3

Verification evaluation route

The complete assessment report and other relevant supporting documents from the
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports from the primary reference agency that are obtained from the public domain are
deemed unacceptable.
Primary reference
agency
Health Canada
and MHRA

US FDA

Documentary requirements
Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes
Assessment reports and/or documents pertaining to postapproval variations, if applicable
Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes*
Assessment reports and/or documents pertaining to postapproval variations, if applicable

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Primary reference
agency
EMA

TGA

APRIL 2011

Documentary requirements
Complete CHMP Assessment Report#, including the following:
- Rapporteurs and Co-Rapporteurs Day 80 Assessment
Reports (non-clinical, clinical, quality, overview and List of
Questions)
- CHMP Day 120 List of Questions
- Rapporteurs Day 150 Assessment Report (non-clinical,
clinical, quality and overview)
- Day 180 List of Outstanding Issues
- All other annexes and appendices
Summary of CHMP Opinion
Assessment reports and/or documents pertaining to postapproval variations, if applicable
Complete Clinical Assessment Reports, including assessment on
the Question & Answer documents between the Sponsor &
Agency and all annexes
Complete Chemistry and Quality Control Assessment Report#,
including assessment on the Question & Answer documents
between the Sponsor & Agency and all annexes
Delegates overview
Pre-ACPM response
ACPM minutes
Assessment reports and/or documents pertaining to postapproval variations, if applicable

* If theres difficulty in obtaining the unredacted reports, the FDA Sponsors Authorization signed by the
products Sponsor in the US can be submitted and HSA will help to facilitate the retrieval of the reports.
The time taken for HSA to retrieve the reports will be considered as the applicants stop-clock time. If
HSA is unable to obtained the reports within 3 months, the application will be routed to the abridged
evaluation route.
#
if the drug substance section is submitted to the primary reference agency as a Drug Master File, the
complete assessment report of the DMF, including assessment on the Question & Answer documents
between the DMF Holder & Agency and all annexes should be provided. Assessment reports, approval
letters and/or documents pertaining to post-approval DMF updates should also be submitted, if
applicable.

Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i.
ii.

iii.
iv.

1.9 Official approval letters, or equivalent documents, from the relevant reference
regulatory agencies that certify the registration status of the drug product;
1.13 Official letter declaring that the application 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 process16, or pending deferral17 by
any drug regulatory agency, with reasons in each case if applicable;
1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the primary reference agency, if applicable; and,
1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that 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 and primary packaging.

16

Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
17
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.

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The technical documents required include:


complete quality documents for both drug substance and drug product, which
includes:
i. Module 3 dossier as initially submitted to the chosen primary reference agency;
ii. From Sponsor:
- Question and Answers between the primary reference agency and sponsor
the Answers should include supporting documents used in response to the
Questions;
- All post-approval variations approved by the primary reference agency up to
the time of submission to HSA, including the application letter for the variation,
supporting documents for the variation, questions and answers between the
primary reference agency and sponsor and the approval letter for the variation
from the primary reference agency (if applicable); and,
- Relevant documents required by HSA which have not been submitted to the
primary reference agency, e.g. stability studies in accordance to ASEAN
Stability Guidelines, Singapore Quality Overall Summary, etc;
iii. From DMF Holder, if applicable:
- The initial open and closed parts of the DMF submitted to the primary
reference agency from the DMF Holder should be provided to HSA, together
with an original Letter of Access;
- Question and Answers between the primary reference agency and DMF
Holder the Answers should include supporting documents used in response
to the Questions; and,
- All post-approval DMF updates approved by the primary reference agency up
to the time of submission to HSA, including the application letter for the DMF
update, supporting documents for the DMF update, questions and answers
between the primary reference agency and sponsor and the approval letter for
the DMF update from the primary reference agency;
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 relevant to requested indication, dosing and/or patient
group (the tables and appendices to the pivotal study reports may be submitted
upon request by HSA).
All of the 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.
In the event that the chosen primary reference agency does not bear 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, a supplemental clinical assessment
report from the reference agency that approved the most stringent indication(s), dosing
regimen(s), patient group(s) and/or direction(s) of use is required. Reports from the public
domain are acceptable. The proposed PI/PIL should be identical to that approved by this
reference agency (with the exception of country-specific information).

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CHAPTER D GENERIC DRUG APPLICATION SUBMISSION


This chapter applies to generic drug applications for products containing currently
registered chemical entities.
15

APPLICATION TYPES

There are 2 application types for a generic drug application:


GDA Generic Drug Application
GDA-1: For the first strength of a generic chemical product.
GDA-2: For subsequent strength(s) of the generic chemical 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.
15.1

Generic product

A generic product is essentially similar to a currently registered product in Singapore


(known as the Singapore reference product) but excludes biologics. Essentially similar 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,
the concept of essentially similarity also applies to different conventional immediate
release oral dosage forms (i.e. tablets and capsules) which contain the same active
ingredient(s).
The generic product must fulfil the following criteria:
i. the generic product is the same pharmaceutical dosage form as the Singapore
reference product;
ii. the route of administration of the generic product is the same as the Singapore
reference product;
iii. the conditions of use for the generic product fall within the directions for use
[including indication(s), dosing regimen(s) and patient group(s)] for the Singapore
reference product; and,
iv. the generic product is bioequivalent with the Singapore reference product.
15.2

Singapore reference product

The Singapore reference product must be a currently registered product that has been
granted market authorisation based on the evaluation of the products quality, efficacy
and safety i.e. a dossier with chemical, pharmaceutical, pharmacological-toxicological
and clinical data. If such a reference product is not registered in Singapore, then an
alternate registered comparator product may be used if adequately justified by the
applicant and agreed upon by HSA.
The generic product should contain the same active substance(s) and strength(s) and be
the same pharmaceutical dosage form as the Singapore reference product.
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.

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Applicants are advised to search HSAs online database 18 to identify the Singapore
reference product. Applicants submitting GDAs should also refer to Appendix 12 for
further details on product interchangeability and biowaiver request.
Applicants are 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 scientific justification for HSAs
consideration. However, a generic drug application for a higher strength than the
Singapore reference product will not be accepted.

EVALUATION ROUTES

16

There are two evaluation routes for a GDA: abridged and verification evaluation. The
eligibility criteria are different for each evaluation route. Applicants should be familiar with
the criteria for each evaluation route because each route will have different documentary
requirements.
Figure 4 below is a schematic diagram to illustrate the evaluation routes for GDAs:
NO

GDA 1
GDA 2

Approved by at least
one of HSAs
reference agencies
and met verification
criteria?
YES

ABRIDGED
ROUTE
VERIFICATION
ROUTE

Figure 4. Schematic diagram of evaluation routes for GDAs.

16.1

Abridged evaluation route

Abridged evaluation will apply to a product that has been approved by at least one drug
regulatory agency at the time of submission.
16.2

Verification evaluation route

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

Australia Therapeutic Goods Administration;


Health Canada;
US Food and Drug Administration;
the European Medicines Agency via the Centralised Procedure;
UK Medicines and Healthcare Products Regulatory Agency via
- the national procedure, or,
- as the Reference Member State (RMS) via the Mutual Recognition Procedure or
Decentralised Procedure.

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

18

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Additional eligibility criteria include:


i. The registration dossier must be submitted within two years from the approval date
by a chosen reference agency;
ii. All aspects of the products quality, including but not limited to formulation,
manufacturing site(s), specifications and primary packaging, must be identical as
that currently approved by the chosen reference agency;
iii. The product is not a biologic product;
iv. The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) has not been rejected, withdrawn, approved by appeal or pending
deferral by a drug regulatory agency for efficacy and/or safety reasons; and,
v. The product has not been approved by the chosen reference agency via an
accelerated/fast-track approval, approval under exceptional circumstances or an
equivalent process.
The chosen reference agency is defined as the reference agency for which the qualifying
supporting documents (as outlined in this guidance) will be submitted.
17

DOCUMENTARY REQUIREMENTS

Table 8 outlines the CTD Modules/Parts required for GDAs submitted under each
evaluation route:
Table 8. Dossier Submission Requirements for a GDA.
Documents
Administrative
Documents and
Product Information

Location in
ICH CTD
ACTD
Module 1
Part I

Module/Part required for


Abridged GDA
Verification GDA
Yes
Yes
(Refer to section 17.5.2)
SQOS + QOS

SQOS + QOS

Module 3

Incorporated
into Parts II,
III and IV
Part II

Yes

Module 4

Part III

No

Yes
(Refer to section 17.5.2)
No

Module 5

Part IV

BE studies or biowaiver
justification may be
inserted in this section

Yes
(same dataset as that
submitted to RA)

Common Technical
Document Overview
and Summaries
Quality documents

Module 2

Non-clinical
documents
Clinical documents

Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
17.1

Administrative documents

The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to the evaluation routes for GDAs. The following sections are to be
submitted:
Comprehensive Table of Contents (section 1.1)
The comprehensive table of contents is a complete list of all documents provided in the
application dossier by Module/Part. If a hardcopy registration dossier is submitted, then
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).
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Introduction (section 1.2)


Applicants should give a concise 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 (section 1.3)
A printout of the PRISM application form is to be included in the dossier.
Labelling, Package Insert and Patient Information Leaflet (section 1.4)
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:

Package Insert (PI), also known as prescribing


information, SPC, or product monograph
Patient Information Leaflet (PIL), also known as
consumer medicine information (CMI)

Forensic Classification in Singapore


POM
P
GSL
Required
Optional
Optional
Optional, unless
warranted

Required

Required

All artwork and drafts should be legible. Any handwritten information is not acceptable.
Separate labels 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.
Appendix 6 of this guidance contains specific details on product labelling requirements for
Singapore.
The clinical information in the proposed PI/PIL should be consistent with that currently
approved for the Singapore reference product.
Approved SPC/PI/PIL (section 1.5)
In this section, the applicant shall submit the approved SPC, PI and/or PIL from the drug
regulatory agency that issued the proof of approval.
Assessment Report from Reference Agencies (section 1.6)
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the chosen reference agency
and inserted into this section must be unredacted and unedited. Applicants should refer to
section 17.5.2 for specific details on the required documents.
Description of Batch Numbering System (section 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. Where
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applicable, examples of the batch numbering system should be included to illustrate how
the batch number enables identification.

SEPTEMBER

Proof of Approval (section 1.8, 1.9)


Proof of approval is not required for GDAs undergoing abridged evaluation for finished
products manufactured (up to primary packaging) in Singapore.
For an abridged evaluation of an imported GDA product, proof of approval by any 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 SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 of this
guidance document for more information.
Note that all aspects of the products quality, should be the same as approved by the drug
regulatory agency that issued the approval letter.
Approval letters should be either an original copy or a certified true copy and in English.
Applicants should refer to section 6.2.2 and 6.2.3 for more details.
HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
Authorisation Letters (section 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:
i.

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.

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

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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, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated 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 (section 1.11)


Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturer(s), primary packer(s) and secondary packer(s). A CPP may
be submitted in lieu of a GMP certificate provided that the manufacturers name(s) and
address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses of all manufacturers should be consistent throughout the application i.e.
GMP certificate, Letter of Authorisation, CTD section S2.1 and P3.1 and PRISM.
Proof of GMP compliance must not expire within six (6) months from the time of
submission to HSA and must be in hardcopy, in English and either an original or certified
true copy. Applicants should refer to section 6.2.2 and 6.2.3 for more details.
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.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain:

the last audited date by US FDA;


the approved dosage forms ;
any licensing conditions/restriction;
the scope of inspection; and/or,
objective evidence and the date of a satisfactory close-out of the latest inspection
conducted by US FDA.

* any other supporting document which declares GMP compliance of the manufacturing site in the US
and signed by an official of the US FDA.

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All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004, and 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 19
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer20.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
Patent declaration (1.12)
The Patent Declaration form is required for each GDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on Patent Linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
The authorised person is ordinarily an officer of the company such as Company
Director or Company Secretary as registered with ACRA, or equivalent. Evidence of
such authorisation is to be submitted together with the declaration.
Evidence of authorisation for Section 8 could be in the form of:
An ACRA printout (BizFile) listing the Company Directors/Secretary;
Resolution of board of directors;
Resolution of a general meeting of the company; or,
Extract of the relevant portion of the companys articles of association.

19

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_
manufacturers/conformity_assessment/eServices_Forms.html
20
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

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Declaration forms must bear the original signatures of the authorised person and the
company stamp of the Applicant.
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorization is current at the point of
submission.

Declaration on rejection, withdrawal and deferral (section 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 drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
Declaration for GDA verification (section 1.14)
This section applies only to the verification evaluation route.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen reference regulatory agency. Quality
aspects include, but are not limited to, formulation, manufacture site(s), release and shelf
life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
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 25.1.4.9 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
submitted in hardcopy in section 1.15 of the CTD dossier. The document should be in the
format as seen in Table 7 on page 35 of this guidance document.
17.2

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 II, III and IV of the ACTD.

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A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part II, 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.
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.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;
ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The SQOS template for chemical drug products is given in Appendix 8.
17.3

Quality documents

The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
17.3.1

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.
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.

All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then the dossier should make reference to a
Drug Master File (DMF) or Certificate of Suitability of Monographs of the European
Pharmacopoeia (CEP).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.

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Drug Master File


A Drug Master File is a reference that provides information about specific processes or
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
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 II.C.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 reference to a DMF are as
follows:
From the Applicant:
the open part of the DMF, as part of the submitted dossier; and,
a copy of the Letter of Access.
From the Drug Substance Manufacturer (also referred to as DMF Holder):
the complete DMF i.e. both the open and closed parts; and,
the original Letter of Access.
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.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) 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 DMF number.
Should there be deficiencies within the closed part of the DMF, HSA will raise queries
directly with the DMF holder.
NOTE: assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.
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If a product application makes reference to a currently-registered DMF, the original Letter


of Access specific to the product application is to be provided by the DMF Holder and a
copy of the Letter of Access is to be submitted by the applicant as part of the registration
dossier.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on filing
variations.
Certificates of Suitability
A Certificate of Suitability is a document issued by European Directorate for the Quality of
Medicines and Healthcare (EDQM) that certifies the quality of a drug substance in
compliance to the Ph. Eur. A CEP may be submitted in lieu of the CTD S Section or a
DMF.
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S section:
i.

ii.

batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).

NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is deemed appropriate.

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.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Control of Drug Substance (3.2.S.4)
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.

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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.
17.3.2

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.
Pharmaceutical Development (3.2.P.2)
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier section. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimization of the manufacturing process, with data.
Process Validation (3.2.P.3.5)
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Applicants should refer to the ASEAN Guidelines on Submission of Manufacturing
Process Validation Data for Drug Registration21 and the accompanying Q&A on ASEAN
Guideline on Process Validation for the minimum data requirements on process
validation. Other relevant international guidelines may also be referred to as appropriate.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
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

21

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

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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 excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
Control of Drug Product (3.2.P.5)
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be included in sections P.5.2 and P.5.3.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Justification of the specifications (section P.5.6) should be based on scientific knowledge
and data collected during product development.
Container Closure System (3.2.P.7)
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
Stability Data of Drug Product (3.2.P.8)
HSA has adopted the ASEAN Guideline on Stability of Drug Product22 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 have been implemented since 1st January 2009.
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 primary
batches of the drug product, as per the ASEAN guideline;
22

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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.
For example, 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.
Product Interchangeability (3.2.P.9)
Since 1st April 2004, in vivo BE data is required for Prescription Only Medicines (POM) in
oral solid dosage forms.
GDA-2 applications will also require BE 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 should ensure that the submitted BE study is complete, including all
appendices and data, as per the relevant guidelines. Examples of information to be
included in the report are:
i. Signature of the Principal Investigator to attest the authenticity of the report;
ii. Audit certificate(s), including a BE site inspection report, if available;
iii. Approval letter(s) from the Institutional Review Board/Independent Ethics
Committee and the appropriate drug regulatory agency;
iv. Information about the reference and test products, such as the product name,
strength, dosage form, batch number, manufacturing site, batch size of the test
product, etc.;
v. Certificates of Analysis of the reference and test products used in the BE study,
including the batch size of the test product and manufacturing/expiry date of both
products (where applicable);
vi. Description of the assay methodology and validation; and,
vii. A signed statement confirming that the test product used in the BE study is the
same formulation and is manufactured by the same process as that submitted for
registration.
In instances when the reference product used in the BE study is not the Singapore
reference product, if the criteria listed in section 2 of Appendix 12 are fulfilled, then the
following additional documents must be submitted in support of the application:
i.
A comparative table that lists the qualitative composition of both the BE and
Singapore reference products;
ii.
Certificates of Analysis of both the reference product used in the BE study and
Singapore reference products, analysed under the proposed specifications for the
generic product;
iii.
Comparative dissolution profiles between the BE and Singapore reference
products, as per guideline; and,
iv.
Comparative dissolution profiles between the generic and Singapore reference
products, as per guideline.
In instances when biowaiver of submission of a BE study is justified, then comparative
dissolution profiles between the generic and Singapore reference products, as per
guideline, are required.
Applicants should be familiar with Appendix 12 on Product Interchangeability and
Biowaiver Request.
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HSA reserves the right to request for any additional information required to determine the
product interchangeability of the generic product to the Singapore reference product.

SEPTEMBER

Blank Production Batch Records


For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
17.4

Non-clinical and clinical documents

GDAs generally are not required to include non-clinical (animal) and clinical (human) data
to establish a drug products safety and efficacy. Instead, documents required must
demonstrate product interchangeability with the Singapore reference product e.g. in
vivo BE and comparative dissolution studies.
17.5

Specific documentary requirements for each evaluation route

17.5.1

Abridged evaluation route

All aspects of the products quality which includes, but is not limited to, the formulation,
site(s) of manufacture, release and shelf life specifications and primary packaging should
be the same as that approved by the drug regulatory agency that issued the proof of
approval.
The technical documents required include:
complete quality documents for both drug substance and drug product;
BE studies or justification for biowaiver, where applicable.
17.5.2

Verification evaluation route

The complete assessment report and other relevant supporting documents from the
chosen reference agency must be submitted, as tabulated on the next page. The
assessment reports must be unredacted or unedited. Reports from the chosen reference
agency that are obtained from the public domain are deemed unacceptable.
Primary reference
agency
Health Canada
and MHRA

US FDA

Documentary requirements
Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes
Assessment reports and/or documents pertaining to postapproval variations, if applicable
Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes*
Assessment reports and/or documents pertaining to postapproval variations, if applicable

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Primary reference
agency
EMA

TGA

APRIL 2011

Documentary requirements
Complete CHMP Assessment Report#, including the following:
- Rapporteurs and Co-Rapporteurs Day 80 Assessment
Reports (non-clinical, clinical, quality, overview and List of
Questions)
- CHMP Day 120 List of Questions
- Rapporteurs Day 150 Assessment Report (non-clinical,
clinical, quality and overview)
- Day 180 List of Outstanding Issues
- All other annexes and appendices
Summary of CHMP Opinion
Assessment reports and/or documents pertaining to postapproval variations, if applicable
Complete Clinical Assessment Reports, including assessment on
the Question & Answer documents between the Sponsor &
Agency and all annexes
Complete Chemistry and Quality Control Assessment Report#,
including assessment on the Question & Answer documents
between the Sponsor & Agency and all annexes
Assessment reports and/or documents pertaining to postapproval variations, if applicable

* If theres difficulty in obtaining the unredacted reports, the FDA Sponsors Authorization signed by the
products Sponsor in the US can be submitted and HSA will help to facilitate the retrieval of the reports.
The time taken for HSA to retrieve the reports will be considered as the applicants stop-clock time. If
HSA is unable to obtained the reports within 3 months, the application will be routed to the abridged
evaluation route.
#
if the drug substance section is submitted to the primary reference agency as a Drug Master File, the
complete assessment report of the DMF, including assessment on the Question & Answer documents
between the DMF Holder & Agency and all annexes should be provided. Assessment reports, approval
letters and/or documents pertaining to post-approval DMF updates should also be submitted, if
applicable.

Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i. 1.4.3 the proposed PI or PIL should be aligned to the currently-registered
Singapore reference product PI or PIL;
ii. 1.9 Official approval letter, or an equivalent document, from the chosen reference
regulatory agency that certify the registration status of the drug product;
iii. 1.13 Official letter declaring that the application 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 process23, or pending deferral24 by
any drug regulatory agency, with reasons in each case if applicable;
iv. 1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the chosen reference agency, if applicable; and,
v. 1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that currently approved by the chosen reference
regulatory agency. This includes, but is not limited to, the formulation, site(s) of
manufacture, release and shelf life specifications and primary packaging.
The technical documents required include:
23

Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
24
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.

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complete quality documents for both drug substance and drug product, which
includes:
i. Module 3 dossier as initially submitted to the chosen reference agency;
ii. From Sponsor:
- Question and Answers between the chosen reference agency and sponsor
the Answers should include supporting documents used in response to the
Questions;
- All post-approval variations approved by the chosen reference agency up to
the time of submission to HSA, including the application letter for the variation,
supporting documents for the variation, questions and answers between the
reference agency and sponsor and the approval letter for the variation from
the reference agency, if applicable; and,
- Relevant documents required by HSA which have not been submitted to the
chosen reference agency, e.g. stability studies in accordance to ASEAN
Stability Guidelines, Singapore Quality Overall Summary, comparative
dissolution studies, etc;
iii. From DMF Holder, if applicable:
- The initial open and closed parts of the DMF submitted to the chosen
reference agency from the DMF Holder should be provided to HSA, together
with the original Letter of Access;
- Question and Answers between the chosen reference agency and DMF
Holder the Answers should include supporting documents used in response
to the Questions; and,
- All post-approval DMF updates approved by the chosen reference agency up
to the time of submission to HSA, including the application letter for the DMF
update, supporting documents for the DMF update, questions and answers
between the reference agency and sponsor and the approval letter for the
DMF update from the reference agency;
clinical documents, such as BE studies or justification for biowaiver, as initially
submitted to the chosen reference agency with all questions and answers, including
supporting documents, between the reference agency and sponsor; and,
any additional documents to demonstrate product interchangeability with the
Singapore reference product as described in section 17.3.2, where applicable.
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.
Special Scheme for Registration of Indian Generic Products
Pursuant to Chapter 5 of the India-Singapore Comprehensive Economic Cooperation
Agreement (CECA), a special scheme (hereinafter referred to as CECA scheme) for the
registration of generic products manufactured in India was introduced to facilitate the
market authorization of these products in Singapore.
Registration of Indian generic products may be possible through the CECA scheme
provided that the application meets the eligibility and documentary requirements.
Applicants intending to submit applications via the CECA scheme should refer to
Appendix 13 for more information.

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CHAPTER E BIOSIMILAR PRODUCT APPLICATION


SUBMISSION
This chapter applies to new drug applications for biosimilar products.
Applicants submitting applications to register biosimilar products must be familiar with the
responsibilities of managing these products throughout their life cycle. Thus, it is
recommended to refer to Appendix 17 or HSAs website25 for more information.
This chapter serves to provide additional guidance on submission of biosimilar products.
18

APPLICATION TYPES

The product must have been approved by at least one of the following reference
agencies: EU EMA, Australia TGA, US FDA and Health Canada.
Biosimilar products are eligible for the NDA-2 and NDA-3 application types. When
selecting the Product Type in PRISM section 3.2, select Biological Drug.
NDA New Drug Application
NDA-1: Not applicable to biosimilar products.
NDA-2:
NDA-3:

18.1

For the first strength of a biosimilar product with the same dosage form and route
of administration as the reference biological product.
For subsequent strength(s) of a biosimilar product that has been registered or
has been submitted as an NDA-2. The product name, pharmaceutical dosage
form, indication, dosing regimen and patient population shall be the same as
that for the NDA-2.
Biosimilar product

A biosimilar product is intended to be similar in terms of quality, safety and efficacy to a


registered biological product (reference biological product) for which there is a substantial
evidence of safety and efficacy.
The development of a biosimilar product involves stepwise comparability exercises
starting with comparison of the quality characteristics of the biosimilar product and the
reference product. Demonstration of similarity in terms of quality is a prerequisite for the
reduction of the non-clinical and clinical dataset required for registration. If relevant
differences are found in the quality, non-clinical and/or clinical studies, the product will not
likely qualify as a biosimilar product and a more extensive non-clinical and clinical dataset
will likely be required to support registration.
The standard generic approach of bioequivalence demonstration with reference to a
chemical derived drug product is scientifically not appropriate for biosimilar applications
since biological drugs are much more complex in their structure and inherent properties
as compared to chemically-derived drugs. The biosimilar product approach, based on
comparability (demonstration of similarity), should be followed.

25

Guidance on Registration of Similar Biological Products in Singapore.

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

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18.2

APRIL 2011

Reference product

Considerations for the choice of a biological reference product:


The reference product should be a biological medicinal product registered in
Singapore (hereinafter known as Singapore biological reference product). A
biosimilar product cannot be used as a reference product.
The reference product used in the comparability assessments for quality, safety and
efficacy should be
i. the same product throughout all of the studies;
ii. the same strength as that registered in Singapore; and,
iii. from the same manufacturing site as that registered in Singapore.
The active substance(s) of the biosimilar product and reference product should be
similar in molecular and biological terms;
The pharmaceutical form, strength and route of administration of the biosimilar
product should be the same as the Singapore biological reference product. Any
differences will require additional comparability assessment data and have to be
justified by appropriate studies on case-by-case basis;
The conditions of use for the biosimilar product must fall within the directions for use
including indication(s), dosing regimen(s) and patient group(s) for the Singapore
registered reference product.
A biological product with no suitable Singapore biological reference product will not
qualify for registration as a biosimilar product in Singapore.
19

EVALUATION ROUTES

A biosimilar product is eligible only for the abridged evaluation route.


20

DOCUMENTARY REQUIREMENTS

Table 9 outlines the CTD Modules/Parts required for NDAs submitted for registration of a
biosimilar product:
Table 9. Dossier Submission Requirements for Biosimilar Products.
Documents
Administrative Documents
Common Technical
Document Overview and
Summaries
Quality documents

Location in
ICH CTD
ACTD
Module 1
Part I
Incorporated in
Module 2
Parts II, III and
IV
Module 3
Part II

Non-clinical documents

Module 4

Part III

Clinical documents

Module 5

Part IV

Module/Part required for


Biosimilar product
Yes
Yes

Complete quality module including


comparability studies
Complete non-clinical module
including comparability studies
Complete clinical module including
comparability studies

Non-clinical overview included in Module 2 of the ICH CTD.

Applicants are advised to refer to the Guidance on Registration of Similar Biological


Products in Singapore for detailed information on the complete requirements for
registration of a biosimilar product.

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20.1

APRIL 2011

Administrative documents

The administrative documents of the registration dossier for biosimilar products is the
same as that described in section 14.1 in Chapter C.
20.2

CTD overviews and summaries

The CTD overviews and summaries are the same as that described in section 14.2 in
Chapter C.
20.3

Quality documents

The full quality data (i.e. Module 3 of ICH CTD or Part II of ACTD) should be submitted.
Data submitted should include extensive drug substance and drug product
characterisation and quality comparability data between the biosimilar and the Singapore
biological reference products. The comparability exercise should encompass both drug
substance and drug product and should take into consideration of the following:
the complexity of the molecular structure;
the types of changes introduced in the manufacturing process during development;
and,
the impact on quality, safety and efficacy.
20.4

Non-clinical and clinical documents

Non-clinical and clinical data generated with the biosimilar product is also required.
The amount of non-clinical and clinical data required for submission will depend on:
the product or class of products;
the extent of characterisation possible undertaken using state-of-the-art analytical
methods;
observed or potential differences between the biosimilar product and the reference
product; and,
the clinical experience with the product class.
A case-by-case approach is needed for each class of products.

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CHAPTER F

APRIL 2011

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 5 below is a schematic diagram
of the variation application routes:

IS PRODUCT
REGISTERED?

MAV-1

Efficacy, Safety

MAJOR VARIATION

YES

Change in safety,
efficacy or quality
aspect?

MAV-2
MIV-1
MINOR VARIATION
Quality, Safety

MIV-2
Figure 5. Schematic diagram of variation application routes.

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; recommendation for concomitant administration of
vaccines; additional bacterial strains to expand the indication(s) 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.
HSA reserves the right to re-categorise the application type if appropriate. Applicants are
to note that, in PRISM, the re-categorisation of an application (e.g. MIV to MAV-1, MIV-2
to MIV-1 or vice versa) may require withdrawal of the original application. The applicant
will be notified if it will be required to resubmit the application according to the correct
category.
All applications require HSAs approval before the change(s) can be implemented, with
the exception of MIV-2 applications, where the change(s) can be implemented if there is
no objection from HSA within the notification timeline (refer to Appendix 1 for notification
timeline).

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21

APRIL 2011

VARIATION APPLICATION PROCESS

The steps to submit an MAV or MIV is similar to submitting an NDA or GDA, as seen in
Figure 6 on the next page:

PRE-SUBMISSION
PREPARATION

NON-ACCEPTANCE /
WITHDRAWAL

APPLICATION
SUBMISSION

APPLICATION
SCREENING
ACCEPTANCE

APPLICATION
EVALUATION

NON-APPROVAL /
WITHDRAWAL

REGULATORY
DECISIONb
a
b

An acceptance notice will not be sent for MIV-2 applications.


A regulatory decision letter will not be sent for MIV-2 applications.

Figure 6. 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.
21.1

Pre-submission preparation

Since submission of a variation application is the same as an NDA or GDA, applicants


are advised to ensure that all the requirements for the variation are met before submitting
the application.
Applicants are encouraged to contact HSA prior to submission of a variation application if
there are questions regarding the application. There are two methods to contact HSA:
i.
ii.

Pre-submission Inquiry via email


Pre-submission Consultation

Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.
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21.1.1

APRIL 2011

Pre-submission inquiry

The applicant may submit a Pre-Submission Inquiry via e-mail if any clarification on
submitting an MAV application is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Presubmission inquiry, in order for the e-mail to be sent to the relevant officer.
For issues relating to MIV submissions, the applicant should email a completed MIV Filing
and Submission Inquiry Form (Appendix 14) to HSA_MedProd_Registration@hsa.gov.sg.
Upon receipt of an MIV Inquiry Form, an officer will look into the inquiry and respond back
to the named applicant via email with an Inquiry Reference Number. If the MIV is
submitted, then a copy of the Inquiry Form, with the Inquiry Reference Number, should be
included in the submission. The applicant may also opt to fax the completed form to HSA,
but the use of email is strongly encouraged.
21.1.2

Pre-submission meeting

Applicants may also request for consultation with HSA. The request should be made in
writing, with the purpose, agenda and proposed date & time for the meeting, and emailed
to HSA_MedProd_Registration@hsa.gov.sg. An officer will respond and facilitate the
arrangement of the meeting.
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
application dossier.
21.2

Application submission

A variation application should comprise of both the submission of the PRISM application
form and the variation application dataset.
21.2.1

PRISM application form

Submitting the application through PRISM is similar to that of a NDA or GDA, although
some of the fields in the PRISM application form would not be editable for variation
applications.
Refer to Chapter J for guidance on submitting a PRISM application.
21.2.2

Variation application dataset

The submission of the complete dataset 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 dataset should be using the CTD format that was selected for the original new
product application.
In moving towards a greener environment, submission of the variation application dataset
should be in electronic format. But there is one exception: documents which require proof
of authenticity (e.g. CPPs, approval letters not available online, authorisation letters, GMP
certificate, patent declaration, declaration letters, etc) should be submitted in electronic
and hard copy format.

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Applicants are responsible to ensure that all soft copies e.g. scanned documents of
the dossier are legible.
When submitting a CD/DVD, applicants are encouraged to organise the dossier via the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
21.2.2.1 Language
Information and documents supporting an application, such as certificates, approval
letters and approved product labels, must be in English and authenticated. If documents
are not originally in English, applicants should refer to Appendix 4 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
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.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.

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Apostille
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 apostille 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.
21.2.2.2 Certifying non-original documents
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 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.
21.3

Application screening

The screening process is similar to that for an application for a new medicinal product 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 acceptance notice will be issued to the applicant
for MAV and MIV-1 applications. The date of acceptance of the application will be
considered as the start of the evaluation timeline.
21.4

Application evaluation and Regulatory decision

The evaluation process is similar to that for an application for a new medicinal product.
For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table
10 describes the applicable applications and the stages to the evaluation process for
post-approval changes:

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Table 10. Variation Applications Applicable for Notification of Stages for Post-Approval Changes
Stages of Notification to
Applicant
Application
Type

MAV-1

Dossier
type

Full or
Abridged

st

1 Stage

nd

Stage

rd

3 Stage

th

4 Stage

Evaluation Status
Accepted for
Evaluation

Application is
accepted for
evaluation
This marks the
start of the
evaluation
timeline

Active
Evaluation

When active
evaluation is in
progress for
the application

Midway in
Evaluation

Evaluation
Completed

Application is
approximately
midway through
the evaluation
(provided that
there were no
prior stop-clocks
which may affect
the evaluation
progress)

Evaluation is
completed for the
application

Applicants could
expect to receive
the first set of
queries from HSA
during this stage

Application is now
undergoing the
regulatory decision
phase, after which
a regulatory
decision letter*
would be issued.
Applicants could
still expect further
queries from HSA
during this stage

* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.

Applicants may view the evaluation stage via track@PRISM. Applicants would also be
notified via a system-generated email whenever a status change occurs.
The regulatory decision process is also similar to that for an application for a new
medicinal product. However, a regulatory decision letter will not be issued for MIV-2
applications as these are notifiable changes.
21.5

Fees

The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website26.
21.5.1

Screening fee

The screening fee per application is payable at the time of PRISM submission. It is only
applicable for MAV-1 applications. The screening fees are non-refundable once the
application has been successfully submitted via PRISM.
Applicants are advised to ensure that the dataset 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.
21.5.2

Evaluation fee

There are two different evaluation fees for MAV-1 applications:


i. Evaluation fees for a single strength product or the first product in a series of
products of different strengths; and,
ii. Evaluation fees for each subsequent product in a series of products of different
strengths.

26

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html

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Evaluation fees for MAV-1 applications are payable upon acceptance of the MAV-1 for
evaluation.
Evaluation fees for MIV-1 applications are payable upon submission of the application in
PRISM.
Evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 Apr 2009*, the progressive payment scheme was implemented to
allow the payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to the application type listed in the Table 11:
Table 11. Variation Applications Applicable for Progressive Payment Scheme

Application
Type
MAV-1

Percentage of Evaluation Fee Payable at Each Stage


Evaluation Status
Dossier
Accepted for
Active Evaluation
Midway in
type
Evaluation
Evaluation
Full or
Abridged

30%

40%

20%

Evaluation
Completed

10%

NOTE: To apply for the progressive payment for applications submitted via the full
evaluation
route,
the
applicant
must
contact
HSA
via
HSA_MedProd_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.

For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.

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CHAPTER G

APRIL 2011

MAJOR VARIATION (MAV) SUBMISSION

This chapter applies to major variation applications for currently registered products.

MAV-1 SUBMISSIONS

22

An MAV-1 application applies to any variation to the following:


i. approved indication(s);
ii. approved dosing regimen(s);
iii. approved patient group(s); and/or,
iv. inclusion of clinical information outside the approved usage of the product for
example, clinical trial information related to an unapproved indication, dosing
regimen and/or patient population; recommendation for concomitant administration
of vaccines; and additional bacterial strains to expand the indication(s) for
antimicrobial products.
22.1

Evaluation routes

There are three evaluation routes for an MAV-1:


Full dossier:
Abridged dossier:

Verification dossier:

Applies to any MAV-1 variation that has not been approved by


any drug regulatory agency at the time of submission.
Applies to any MAV-1 variation that has been evaluated and
approved by at least one 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.
Applies to any MAV-1 variation that has been evaluated and
approved by at least two of HSAs reference drug regulatory
agencies, which include EMA*, US FDA, Health Canada, TGA
and UK MHRA#.

* For products approved via the Centralised Procedure


#

For products approved via the national procedure or where MHRA acted as the RMS for the MRP or
Decentralised Procedures in Europe

The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
22.1.1

Full evaluation route

Full evaluation will apply to a major variation that has not been approved by any drug
regulatory agency at the time of submission.
22.1.2

Abridged evaluation route

Abridged evaluation will apply to a major variation that has been evaluated and approved
by at least one 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.

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22.1.2.1 Applications for non-prescription medicines


If the MAV-1 is for a non-prescription medicine and is submitted via the abridged
evaluation route, 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 5 Guideline
on Submission Requirements for Non-Prescription Medicines. However, HSA reserves
the right to request for the complete clinical data set if it is deemed appropriate.
22.1.3

Verification evaluation route

Similar to an NDA, at least two of HSAs reference drug regulatory agencies must have
evaluated and approved the major variation. However, approval by these reference
regulatory agencies does not obligate HSA to approve the application.
One of the reference drug regulatory agencies must be declared as the primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be submitted
and which approved the strictest indication(s), dosing regimen(s), patient groups(s)
and/or direction(s) for use among the two HSA reference drug regulatory agencies which
approved the variation.
Additional eligibility criteria for the verification route include:
The application must be submitted within three years from the approval date by the
chosen primary reference agency;
The product does not need a more stringent assessment as a result of differences
in local disease patterns and/or medical practices (e.g. some anti-infectives); and,
The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) have not been rejected, withdrawn, approved via appeal process or
pending deferral by a drug regulatory agency for safety and/or efficacy reasons.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies.
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 an 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.
22.2

Documentary requirements

Table 12 outlines the CTD Modules/Parts required for MAV-1s submitted under each
evaluation route:

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Table 12. Dossier Submission Requirements for MAV-1.


Location in
ICH CTD
ACTD
Administrative
Documents and
Product Information
Common Technical
Document Overview
and Summaries
Quality documents
Non-clinical
documents
Clinical documents

Full
MAV-1
Yes

Module/Part required for


Abridged
Verification
MAV-1
MAV-1
Yes
Yes

Module 1

Part I

Module 2

Yes

Yes

Yes

Module 3
Module 4

Incorporated
into Parts II,
III and IV
Part II
Part III

No

No

No
#
No

No
#
No

Module 5

Part IV

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.

For MAV-1 applications, in order to ensure that the dossier is complete, application
checklists for both ICH CTD and ACTD dossiers are provided in Appendix 2B and 3B,
respectively. Each checklist states the required documents for each dossier type and
application type. Refer to the specific Appendices for more details.
22.2.1

Administrative documents

The three evaluation routes for an MAV-1 share the same documentary requirements for
CTD Module 1/Part I. The documents required are:
i. 1.1 Comprehensive Table of Contents;
ii. 1.2 Introduction including the Table of Amendment Details of PRISM section
0.5;
iii. 1.3 PRISM application form;
iv. 1.4 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;
v. 1.5 Approved SPC/PI/PIL from the drug regulatory agency that issued the proof of
approval and from each of HSAs reference drug regulatory agencies (where
applicable);
vi. 1.6 Assessment Report from Reference Agencies only for verification route
(see section 22.2.5.3);
vii. 1.8, 1.9 Proof of Approval for an MAV-1, the official approval letter(s) must
contain information on the requested Singapore variation. For the verification
evaluation route, the approval letters issued by the relevant reference agencies
should be submitted;
viii. 1.13 Declaration on rejection, withdrawal and deferral; and,
ix. 1.15 Registration Status in Other Countries.

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22.2.2

APRIL 2011

CTD overviews and summaries

The following documents are to be submitted:


a non-clinical overview, if applicable; and,
a clinical overview and summaries of clinical efficacy and clinical safety
22.2.3

Quality documents

Quality documents (Module 3/Part II) are not required for MAV-1 applications.
22.2.4

Non-clinical and clinical documents

Each evaluation route will have different non-clinical and clinical documentary
requirements. Refer to section 22.2.5 for more information.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.
22.2.5

Specific documentary requirements for each evaluation route

22.2.5.1 Full evaluation route


The technical documents required include:
complete non-clinical documents, if applicable; and,
complete clinical documents; i.e. all study reports from phase I to phase III relevant
to requested indication, dosing and/or patient group, including tables and
appendices.
22.2.5.2 Abridged evaluation route
The technical documents required include:
a non-clinical overview, if applicable; 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 relevant to requested indication, dosing and/or patient
group (the tables and appendices to the pivotal study reports may be submitted
upon request by HSA).
22.2.5.3 Verification evaluation route
The complete assessment report and other relevant supporting documents from the
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports obtained from the public domain are deemed unacceptable.

Primary reference
agency
Health Canada
and MHRA

Documentary requirements
Clinical assessment reports, including assessment on the
Question & Answer documents between the Sponsor & Agency
and all annexes

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Primary reference
agency
US FDA

EMA

TGA

APRIL 2011

Documentary requirements
Clinical assessment reports, including assessment on the
Question & Answer documents between the Sponsor & Agency
and all annexes*
Summary of CHMP Opinion
European Assessment Reports (i.e. Rapporteur, Co-Rapporteur
and Joint Clinical assessment reports), including assessment on
the Question & Answer documents between the Sponsor &
Agency and all annexes
Clinical assessment reports, including assessment on the
Question & Answer documents between the Sponsor & Agency
and all annexes
Delegates overview
Pre-ACPM response
ACPM minutes

* If theres difficulty in obtaining the unredacted reports, the FDA Sponsors Authorization signed by the
products Sponsor in the US can be submitted and HSA will help to facilitate the retrieval of the reports.
The time taken for HSA to retrieve the reports will be considered as the applicants stop-clock time. If
HSA is unable to obtained the reports within 3 months, the application will be routed to the abridged
evaluation route.

The technical documents required include:


a non-clinical overview, if applicable; 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 relevant to requested indication, dosing and/or patient
group (the tables and appendices to the pivotal study reports may be submitted
upon request by HSA).
All of the 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.
23

MAV-2 SUBMISSIONS

An applicant seeking to change the forensic classification of a registered product should


submit an MAV-2 application, otherwise known as reclassification. Examples of
reclassification include from POM to P or from P to GSL. If an MAV-2 application is riding
on a previous reclassification of an analogous product, then the applicant may submit a
me-too reclassification.
Reclassification may also be undertaken when experience gained shows that there is a
need to supervise the use of a product i.e. from GSL to P or POM.
Only the abridged evaluation route applies for such applications.
23.1

Eligibility criteria

A change of forensic classification of a POM or P drug product may be considered if the


following criteria are met:
i. The use of the product has been sufficiently extensive;

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ii.
iii.

APRIL 2011

The product has been marketed for a period of time sufficient to establish a postmarketing adverse event profile; and,
The products 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:
i. The forensic classification and approved indication(s) and dosing regimen(s) of the
product in the UK, US, Canada and Australia;
ii. 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;
iii. The period of actual product sale in Singapore;
iv. The rationale for requesting a change in the forensic classification;
v. 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,
vi. Potential problems and hazards arising from the inappropriate use of the product.
23.1.1

Me-too reclassification

A me-too reclassification will be considered if an analogous product with the same active
ingredient and intended use has been reclassified to the requested forensic classification.
23.2

Documentary requirements

One set of documents, as outlined in the checklists in Appendix 2B or 3B, should be


submitted in softcopy. Applicants should be reminded that all administrative documents in
CTD Module 1/Part I required for the application must be in softcopy and hardcopy refer
to section 21.2.2.
The documentary requirements for an MAV-2 submission include:
i. 1.1 Comprehensive Table of Contents;
ii. 1.2 Introduction including the justification for re-classification, as listed above,
and the Table of Amendment Details of PRISM section 0.5;
iii. 1.3 PRISM Application Form;
iv. 1.4 Product Labels the proposed product labels/PIL should also be submitted, if
applicable;
v. 1.5 Approved SPC/PI/PIL;
vi. 1.8 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;
vii. 1.15 Registration Status in Other Countries; and,
viii. Module 2/Part IV 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, patientyears;
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,

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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.
23.2.1

Me-too reclassification

The documentary requirements for a me-too reclassification application include:


i.
ii.
iii.
iv.
v.

1.1 Comprehensive Table of Contents;


1.2 Introduction including the justification for re-classification , as listed above,
and the Table of Amendment Details of PRISM section 0.5;
1.3 PRISM Application Form;
1.4 Product Labels the proposed product labels/PIL should also be submitted, if
applicable; and,
1.5 Approved SPC/PI/PIL, if applicable.

The Summary of Clinical Safety in Module 2/Part IV is not required.

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CHAPTER H

APRIL 2011

MINOR VARIATION (MIV) SUBMISSION

This chapter applies to minor variation applications for currently registered products.
24

MIV SUBMISSIONS

Applicants should be familiar with the guidelines before submitting minor variation
applications (MIVs). The guidelines and documentary requirements are described in
Appendix 15 (chemical) and 16 (biologics).
A minor variation application (MIV) is submitted via the Amendment to a Licence of
Western Drug Product form in PRISM:

Here are some points to consider when submitting an MIV:


If one MIV contains multiple changes that belong to both MIV-1 and MIV-2
categories, then the MIV should be categorised as an MIV-1; and,
If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
categorised as an MIV-1 with supporting documents.
With effect from 1 July 2011, MIV-1 changes should be grouped together as one
application when these changes are consequential changes. A consequential change is
regarded as a change that is unavoidable and is a direct result of another change, not
simply a change that occurs at the same time. HSA reserves the right to split any MIV-1
application with non-consequential changes into separate MIV applications.
HSA also reserves the right to re-categorise the MIV if deemed appropriate.
NOTE: Applicants are encouraged to fax or email the MIV Filing and Submission
Inquiry Form in Appendix 14 for any issues regarding MIV filing.

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 15 or 16 for information on whether to submit documents in hardcopy or
softcopy.
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.

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CHAPTER J

APRIL 2011

SUBMISSION OF A PRISM APPLICATION FORM

This chapter primarily describes the process for submitting NDA/GDA applications via
PRISM. However, the process for submitting MAV/MIV applications via PRISM is similar
except that some of the fields would not be editable for MAV/MIV applications.
25

SUBMITTING A PRODUCT APPLICATION

HSA only accepts applications on-line via PRISM. Applicants are advised to visit the
prism@hsa27 webpage for further details on PRISM.
NOTE: NEW applicants must have a CRIS account in order to register medicinal
products via PRISM. For information on setting up a CRIS account, refer to the
following weblink:
http://www.hsa.gov.sg/publish/hsaportal/en/services/cris.html

A separate Product Licence, and therefore a separate application, would be required for
each pharmaceutical dosage form and strength of the medicinal product. Separate
application forms are also required for the following (see Example 1):
Powders for injection containing different amounts of drug substance per container;
Concentrates for reconstitution labelled with the actual amount of drug substance
before reconstitution; and,
All single-use pre-filled syringes containing different amount of active ingredient in
each syringe.
Example 1. Injectable products which require separate licences:
Examples
Powder for Solution
for Injection
Solution for Injection

Concentrate

Single-use Pre-filled
Syringe containing
different amount of
active ingredient in
each syringe

Labelled strength before


reconstitution
25mg/vial
50mg/vial
2mg/mL in a vial containing
1 mL of the solution
2mg/mL in a 1 mL pre-filled
syringe
10mg/5mL
20mg/10mL
100 iu/mL

400 iu/4mL

Application type
Submit as 2 separate applications:
One as NDA-1/GDA-1 and the other as
NDA-3/GDA-2
Submit as 2 separate applications:
One as NDA-1/GDA-1 and the other as
NDA-2/GDA-1
Submit as 2 separate applications:
One as NDA-1/GDA-1 and the other as
NDA-3/GDA-2
Submit as 2 separate applications:
One as NDA-1/GDA-1 and the other as
NDA-3/GDA-2

Example 2 on the next page are examples of injectable products which are allowed to be
registered under one product licence (as pack sizes):

27

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

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Example 2. Injectable products which are allowed to be registered under one product
licence (as pack sizes):
Examples
Solution for Injection

Concentrate

Labelled strength before


reconstitution
2mg/mL in a vial containing
1 mL of the solution
2mg/mL in a vial containing
2 mL of the solution
2mg/mL: presented in 5 mL
vial and 10 mL vial

25.1

Sections of a PRISM Application

25.1.1

Section 1 Company Particulars

SEPTEMBER

Application type
Submit as one application with two pack
sizes (i.e., 1 mL and 2 mL)

Submit as one application with two pack


sizes (i.e., 5 mL and 10 mL)

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/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 (UEN) will be automatically populated. 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.
25.1.2

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 (refer to section 14.1
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 screenshot on
the next page:

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Company address
may be entered

Direct telephone and fax numbers


of the company may be entered.
Take note that only company email
addresses should be entered.

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 notify
HSA immediately via amend@PRISM28 (select Amend Applicants Details for licences
and applications) 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.
25.1.3

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. A screenshot
of PRISM section 3 is shown below:

28

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

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25.1.3.1 Section 3.1 Type of Application


Input the type of application to be submitted to HSA.

SEPTEMBER

Note:
After the application has been submitted, if the type of application is selected incorrectly
and it needs to be changed
within the same application type (e.g. from NDA-2 to NDA-3), then HSA will notify
the applicant and change the application form on behalf of the applicant at the point
of acceptance of the application; 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.
25.1.3.2 Section 3.2 Type of Product
Input either Chemical Drug for chemical drug product or Biological Drug for biologic
drug products. Please note that once the product type is set, it cannot be changed
throughout the entire products life cycle.
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;
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 meeting, as stated
in section 5.3, when in doubt on whether the drug product is considered a chemical or
biologic product.
25.1.3.3 Section 3.3 Reference Product
This section applies 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 database29. If a GDA-2
application is not submitted at the same time as a GDA-1 application, specify both the
Singapore Reference Products and the GDA-1 products SIN numbers.
For NDA-3 applications, if the application is not submitted at the same time as an NDA-1
or NDA-2 application, input the SIN number of the Singapore-registered NDA-1 or NDA2.
25.1.3.4 Section 3.4 Type of Dossier
This refers to the three evaluation routes as mentioned in section 5.2 of this guide.
29

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

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Only one option can be selected from the drop-down menu full, abridged or verification.
For applications under the Special Scheme for registration of Indian generic products,
choose the Verification CECA option.
HSA reserves the right to re-categorise the dossier type when appropriate. The applicant
will be informed if re-categorisation is necessary.
25.1.3.5 Section 3.5 Type of Format
Indicate whether the dossier format is ICH CTD or ACTD. Once the format type has been
set in PRISM, it cannot be changed throughout the entire products life cycle.
Applicants are expected to organise the documents into the respective CTD sections
before submitting the dossier to HSA. Explanatory notes on the registration dossier
format can be found in section 6.2.
25.1.4

Section 4 Product Information

25.1.4.1 Section 4.1 Product Name

The Product Name is the products trade name that is shown on the product labelling.
From this point on, any mention of the term product labels or product labelling in this
guidance document will refer to the inner label, outer carton, package insert (PI) and/or
patient information leaflet (PIL) of the product.
Applicants should ensure that the 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, and will be asked to amend it.
The Product Name should be entered in the following format:
Brand Name
ABC

Pharmaceutical
Dosage Form
Solution for Injection

Product Strength
300mg/ml

Product Standard
(optional)

USP

Applicants are advised to use the same format for the product labelling. However, 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 in the PI.
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).

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For products where it would be difficult to include the strength in the product name (e.g.
vaccines, total parental nutrition solution, haemofiltration solution, etc), the product
strength may be omitted from the product name.
For specific pharmaceutical dosage forms, there are additional points to take note of as
seen in the table below:
Product
Fixed-combination
Single-dose preparation,
total use
Multi-dose preparation
Powder for reconstitution,
oral
Powder for reconstitution,
injection or infusion
Transdermal patches

Format
Strength of each active
ingredient separated by a /
State the amount of active
ingredient per unit dose
State the concentration

Example
Multi-Tab Tablet
100mg/25mg
Ingredient 300mg per vial

State the concentration after


reconstitution
State the amount of active
ingredient before reconstitution
or dilution
State the amount of active
ingredient released in 24 hours

Antibiotic 200mg/5mL

per mL, per puff, per drop,


per kg, per m2, etc.

Ingredient 300mg per vial

Trans-Patch 24mg/24 hrs

25.1.4.2 Section 4.2 Product Formula


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, as seen in the
screenshot below:

Choose either Active


Ingredient or Excipient
from the drop-down list

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. The grade for each ingredient should be specified e.g. in-house, BP, USP,
Ph. Eur., etc.
Full compositions of all ingredients (e.g. colourants, flavouring agents, etc.) used in the
product should be stated in the Product Formula, and their uses differentiated as stated
below.

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Differentiating the use of excipients in the product


Ingredients relating to the pharmaceutical dosage form, such as tablet film coating or
capsule shell, should be indicated within parentheses before the ingredient name, as
shown in the following screenshot:

Film coating ingredient

Printing ink

If the product contains proprietary ingredients, relating to the dosage form (such as tablet
film coating or capsule shell), this information should be captured in PRISM as shown in
Example 3.
Example 3. Entry of proprietary ingredients relating to the dosage form for Product XYZ:
Name of Substance

Type of
Substance
Excipient

Grade

Strength

Remarks

USP

Qs

(Film coat, Coat Brand D)


Ingredient E

Excipient

Inhouse

3mg

(Film coat, Coat Brand D)


Ingredient F

Excipient

Inhouse

1mg

(Film coat, Coat Brand D)


Ingredient G

Excipient

Inhouse

1mg

(Film coat) Coat Brand D

Excipient

Inhouse

5mg

Ingredient H is used in the film


coat, but it is not part of the Coat
Brand D
Coat Brand D is a proprietary film
coat composing of 3mg of
Ingredient E
Coat Brand D is a proprietary film
coat composing of 1mg of
Ingredient F
Coat Brand D is a proprietary film
coat composing of 1mg of
Ingredient G
There is no need to state the
total amount of the proprietary
film coat, Coat Brand D.

(Film coat) Ingredient H

The ingredients in the table above should be entered in PRISM as follows:

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Product XYZ

SEPTEMBER

3mg
1mg
1mg

The 3 ingredients in Film


Coat Brand D are entered
as follows.
There is no need to enter
both Film Coat Brand D
and the total composition
of Film Coat Brand D into
PRISM.

If the product contains ingredients relating to a particular portion of the finished drug
product, such as powder (active substance) and solvent (solution for reconstitution) or a
multi-layered tablet, the portion of the drug product should be stated in parentheses
before the ingredient name of the excipients see Examples 4 and 5:
Example 4. A product with powder and solvent:

Excipient in powder

Excipient in solvent

Example 5. A multi-layered tablet:

Do NOT include layer


separation for active
ingredients

Excipients in Y layer

Excipients in Z layer

Entering the strength of ingredients


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

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APRIL 2011

salt, the quantity stated should reflect that stated on the product labelling, and should be
clearly written in the following format (see table below and Examples 6 to 8):
Eg
6

Description
Strength on the label refers
to the base form of the
active substance.
Strength on the label refers
to the salt form of the
active substance.
Strength refers to neither
the base nor salt form of
the active substance.

Product strength stated


on product label
30mg Active Substance

Format of product strength


to be stated in PRISM
Active Substance phosphate
32mg eqv Active Substance

30mg Active
phosphate

Substance

Active Substance 28mg eqv


Active Substance phosphate

30mg Active
sodium

Substance

Active Substance 28mg eqv


Active Substance phosphate
32mg eqv Active Substance
sodium

Example 6. Strength on label refers to base form of active substance:

Enter the strength of


the active substance
base here if the
strength stated on
the product labels
refers to the active
ingredient in its
base form.

Example 7. Strength on label refers to salt form of active substance:

Enter the strength of


the active substance
salt here if the
strength stated on
the product labels
refers to the active
ingredient in its salt
form.

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Example 8. Strength on label refers to neither base or salt form of active substance:

SEPTEMBER
Enter the strength of
the active substance
as described on
the product label
here if the strength
stated on the
product labels refers
to neither the active
ingredient in its
base nor salt form.

Ingredients of residual amounts in the product


Information on substances which were removed during the manufacturing process, such
as water or ethanol which evaporates during drying, should be included in the Product
Formula, but with the strength stated as qs.
Information on residual amounts of materials of allergic potential (e.g. antibiotics and
preservatives) and 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.
Example 9. Screenshot of product containing residual amounts of certain materials:

This strength will


actually be entered here

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25.1.4.3 Section 4.3 Ingredients Derived From Human Blood/Animal Sources

SEPTEMBER

Section 4.3a Ingredients Derived From Human Blood


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 type of product derived from blood and 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 a PRISM section 4.3(a) entry is given:

If constrained by PRISMs text limit, reference to a document uploaded into PRISM


section 7 e.g. Yes see file xyz.pdf attached in PRISM.
NOTE: additional information is required when human plasma-derived products are used.
Refer to Appendix 10 for details on the data requirements for submission.

Section 4.3b Ingredients Derived From Animal Sources


Animal-derived materials used either 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 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.

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A screenshot of a PRISM section 4.3(b) entry is given:

SEPTEMBER

If constrained by PRISMs text limit, reference to a document uploaded into PRISM


section 7 e.g. Yes see file xyz.pdf attached in PRISM.
NOTE: refer to Appendix 11 for details on the data requirements for submission.

25.1.4.4 Section 4.4 Pharmacotherapeutic Group

Indicate the WHO ATC code for each distinct therapeutic indication proposed for a
product, if available. Applicants may refer to the WHO Collaborating Centre for Drug
Statistics Methodology30 for the ATC Code and more information.
25.1.4.5 Section 4.5 Dosage Form
A screenshot of PRISM section 4.5 is seen below:

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.

30

http://www.whocc.no/

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25.1.4.6 Section 4.6 Route of Administration


Screenshots of PRISM section 4.6 is given below:

SEPTEMBER

Choose from the dropdown


list and Save before
adding another option

Include all routes of administration proposed for the product.

25.1.4.7 Section 4.7 Packaging, Shelf Life and Storage Conditions

Section 4.7.1 Container Closure System (CCS)


This section 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,
Type I 1mL amber glass vial and Transparent PVC/PVdC blister with Alu foil should be
entered instead of Amber glass vial and PVC/PVdC blister, respectively.
If a sample pack is to be registered, include (sample) at the end of the CCS description.
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Section 4.7.2 Quantity per CCS


This section 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.
Section 4.7.3 Shelf Life
This section 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.
Section 4.7.4 Storage Condition
This section 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.
Section 4.7.5 CCS per Pack Size
This section refers to the number of container closure systems in each commercial pack
of the product. For example, for a box of 50 tablets packed as 5 blister strips of 10 tablets
in each strip, the Pack Size should be entered as 5.
A screenshot with PRISM section 4.7 entries is shown below:
NOTE: Click
Save after
each complete
CCS entry.
Thereafter, to
enter a new
CCS, click
New first.

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:

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25.1.4.8 Section 4.8 Forensic Classification


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

HSA reserves the right to approve the product under a different forensic classification, as
deemed appropriate.
25.1.4.9 Section 4.9 Registration Status in Other Countries
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:

For each country, the applicant must state the application status, status date and forensic
classification (if applicable). For all HSAs reference agencies, the applicant must state
the application status, status date, application details and forensic classification. This is
described in Table 13 on the next page.

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Table 13. Registration Status of Drug Product in Other Countries.


Country

Application Status

Status Date

For all countries

APPROVAL

State the approval


date
State the date of
rejection/withdrawal
State the date of
deferment

For HSAs
reference
agencies
(if applicable)

REJECTION or
WITHDRAWAL
DEFERRAL
e.g. non-approvable,
approvable,
conditional approval,
conditional marketing
authorization, etc.
PENDING
EVALUATION

Application
#
Details

POM/P/GSL

State the reason(s)

State the reason(s)

POM/P/GSL

State the
submission date

State the expected


POM/P/GSL
regulatory decision
date, if applicable
PENDING

State the expected


POM/P/GSL
submission date or
SUBMISSION
reason(s) for not
registering
#
For approved indication(s) and dosing regimen(s) for an approved application, you can make
reference to the approved PI of the reference agency instead of typing out the information under
Application Details.

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 below displays some entries into PRISM section 4.9:

For applications submitted or approved by:


Individual countries:
i. Select the name of the country under 4.9.1 State Country; and,
ii. For approval in EU Countries via the national procedure, state National
procedure under 4.9.4 Application Details.
European Union:
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i.

ii.

iii.

APRIL 2011

Select European Union under 4.9.1 State Country and specify the type of
application submitted to the agencies (Centralised, Decentralised or Mutual
Recognition Procedure) under 4.9.4 Application Details; and/or,
For applications approved via Decentralised or Mutual Recognition Procedure,
either state All EU countries or list the EU countries which participated in the
procedure under 4.9.4. Application Details; and,
For applications approved via Decentralised or Mutual Recognition Procedure,
state the EU country which acted as the Reference Member State (RMS) and
Concerned Member State (CMS) under 4.9.4 Application Details.

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 1.15 of the CTD Module 1/Part I. The document
should be in the format as seen in Table 7 in this guidance.
25.1.4.10 Section 4.10 Product Owner Information

Input the full name and address of the legally registered owner of the product formulation,
i.e. the drug product.
25.1.5

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.

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SEPTEMBER

All manufacturers of the active substance(s), drug product (inclusive of diluent packed
and sold together with the drug product), and primary/secondary packaging sites must be
declared.
25.1.5.1 Active Substance Manufacturer
When entering the details of the Active Substance Manufacturer, select the active
substance(s) that is manufactured by that particular manufacturer from the drop-down list
in section 5.8 of the PRISM application form. After selecting the Active Substance, click
the Save Substance button; this may be repeated for other substances if the
Manufacturer produces multiple substances for the drug product. Once complete, click
the Save Manufacturer button to save the entire section for that Active Substance
Manufacturer:

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SEPTEMBER

Save Substance button

Save Manufacturer button

25.1.5.2 Finished Product Manufacturer


Entries of finished product manufacturers would include not only manufacturers of the
finished product but also secondary packagers and manufacturers of diluents that are
packed and sold together with the drug product.
After entering the details of the Finished Product Manufacturer, click the Save
Manufacturer button to save the entire section for that Finished Product Manufacturer:

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SEPTEMBER

Save Manufacturer button

Here are some additional points to note:


For products packed and sold together with the diluent that is used to reconstitute
the product, enter (Diluent) after the name of the diluent manufacturer; and,
For secondary packagers, enter (Secondary packager) after the name of the
manufacturer:

NOTE: ALL Manufacturers names and addresses should be consistent throughout all
of the documents submitted in the application, i.e. CPPs, GMP certificates, Letters of
Authorisation, Module 3/Part II of the CTD and so forth.

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25.1.6

APRIL 2011

Section 6 Information on Company Responsible for Batch Release

Enter the name, site/plant address and office address of the company responsible for the
final batch release of the drug product in the exporting country. The Finished Product
Manufacturer(s), which the Batch Releaser is releasing the product from, must also be
specified.
This screenshot is an example of an entry into PRISM section 6.

Save Manufacturer button

Save Batch Releaser button

After selecting the Finished Product Manufacturer that this particular Batch Releaser is
releasing the products from (PRISM section 6.4), click the Save Manufacturer button to
save that manufacturer to that batch releaser.
Click the Save Batch Releaser button to save the entire section for that Batch Releaser.
It is also possible to have one Batch Releaser releasing products from two finished
product manufacturers as well as multiple Batch Releasers see Examples 11 and 12 on
the next page:

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Example 11. One Batch


Manufacturers.

Releaser

responsible for multiple

APRIL 2011

Finished

Product

SEPTEMBER

2 manufacturers with the same


batch releaser

Example 12. Mulitple Batch Releasers responsible for batch release of the final product.

Two batch releasers for this product

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25.1.7

APRIL 2011

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/DVD.

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;
Attaching a file for document 7.1 CD Submission would render the rest of the
online attachments non-mandatory in PRISM system. However, even if the
submission of the dossier set in CD-ROM is selected, the entire Module 1 would still
be required to be attached in PRISM;
During scanning of documents, applicants are advised not to break seals of
authenticated documents as this will render them invalid; and,
When attaching new documents in response to an Input Request, do not delete or
override the existing document in PRISM. Attach it as a new document.

NOTE: Acceptance of the dossier for evaluation does not constitute acceptability
of the data provided in the dossier. Acceptability of the data can only be
determined during evaluation of the application.

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