Appendix 15 - Guideline On MIV Applications For Biologics

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &MIV-2) FOR BIOLOGICS

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 15 - Page 1 of 13

APPENDIX 15 GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &
MIV-2) FOR BIOLOGICS

TABLE OF CONTENTS

PART A: INTRODUCTION.............................................................................................. 2

PART B: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1 ................................... 2

B1 Change of Manufacturing Site............................................................................4
B2 Change of Testing Laboratory............................................................................4
B3 Change of Manufacturing Process .....................................................................4
B4 Change of Test Procedure .................................................................................5
B5 Change of Specifications....................................................................................5
B6 Change of Container Closure System................................................................5
B7 Change of Shelf Life and/or Storage Condition..................................................6
B8 Change of Excipient ...........................................................................................6
B9 Change of Product Label....................................................................................6
B10 Seasonal Variation of Influenza Strains for Vaccine...........................................7

PART C: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-2 .................................... 8

C1 Change of Contact Person.................................................................................8
C2 Change of Product Name...................................................................................8
C3 Change of Product Owner..................................................................................9
C4 Change of Batch Numbering System.................................................................9
C5 Renaming of Manufacturing Site........................................................................9
C6 Change of Batch Release Site ...........................................................................9
C7 Addition or Replacement of Secondary Packaging Site...................................10
C8 Withdrawal of Manufacturer or Manufacturing Site ..........................................10
C9 Deletion of Pack Size for Drug Product............................................................10
C10 Change of Secondary Packaging.....................................................................10
C11 Change of Impirints, Bossing, or Other Markings (except Score/Break Line on
Tablet or Printing on Capsule Including Addition or Change or Inks Used for
Product Marking................................................................................................10
C12 Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without
Change in Qualitative and Quantitative Composition and Mean Mass .............11
C13 Change in Colouring or Flavouring System of Product Including Addition,
Deletion or Replacement of Colourant(s) or Flavourant(s)................................12
C14 Quantitative Change in Coating Weight of Tablet or Weight of Capusle Shell.12
C15 Change of Product Labelling due to Safety Updates........................................12
C16 Change of Product Labelling............................................................................13
C17 Change of Product Labelling of Language(s) Other Than English...................13

PART A: INTRODUCTION

This document describes the requirements of a Minor Variation Application (MIV)
submitted for an existing registered biologic drug product in Singapore. Applicants
should be familiar with the contents of this document, the Guidance on Medicinal Product
Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.

Minor Variation Applications are divided into two sub-categories:
MIV-1: A minor variation which requires regulatory approval
MIV-2: A minor variation or an administrative change which does not require
regulatory approval; i.e., notification.

If an MIV contains multiple proposed variations that belong to both MIV categories, the
MIV should be categorized as an MIV-1. If a proposed MIV-2 does not meet its
specified conditions, then the MIV must be categorized as an MIV-1 with supporting
documents. HSA reserves the right to re-categorise the MIV if deemed appropriate.

Registration Process

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

Applicants should fully disclose all proposed change(s) under Section 0.4 Amendment
Summary in Section 0 Licence Summary, and in the Table of Amendment Details. The
Table template can be downloaded via the link indicated in Section 0.5 Amendment
Details. Any undisclosed variation(s) embedded in the submitted data, or any flow-on
changes not specifically requested by HSA, will not be considered for evaluation.

NOTE: Applicants are encouraged to fax or email the MIV Filing and
Submission Inquiry Form in Appendix 13 for any issues regarding MIV filing.

Documentary Requirements

The following documents must be submitted with each MIV submission, as given in Table
A below:

Hard Copy E-Copy
PRISM application form Yes N/A
Table of Contents Yes Optional*
Checklist for MIV applications Yes Optional*
Table of Amendment Details Yes PRISM
MIV-specific Supporting documents
- Administrative (Module 1/Part 1)
- Other supporting documents

Yes
Optional

PRISM
PRISM/CD
Relevant CTD section(s) of the currently registered
version with the proposed change(s) clearly annotated
Optional PRISM/CD
Current and proposed product labelling (annotated and
pristine copies), where applicable
Yes PRISM
* E-copies may be submitted via PRISM or CD-ROM.

Table A. MIV Application Hard Copy and Electronic Copy Requirements

The Checklist for Minor Variation Applications for Biologic Drugs is located in Appendix
15A and 15B of this guidance document. This Checklist serves as a guide for submitting
the required documents relevant to each proposed MIV. When submitting the Checklist,
the following should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission;
and,
The Declaration for the MIV with the submission date and the local applicants
name and signature.

The Table of Amendment Details concisely describes the proposed MIV(s). The following
information must be stated in the Table:
Section of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason for the change(s); and,
Registration status and date of the proposed change(s) in other countries.

The required documents for each proposed MIV-1 or MIV-2 variation are specified in Part
B or Part C of this document respectively. For an MIV application with multiple related
or unrelated variations, all of the supporting documents for each individual
variation should be submitted. If the required documents have not been submitted,
justification must be provided.

This document reflects the current thinking of HSA on the minimum data necessary for
assessment. Applicants are responsible for ensuring that all necessary validations were
conducted to demonstrate that the change does not adversely affect the quality, safety or
efficacy of the product concerned. HSA reserves the right to request additional
information if deemed appropriate.


PART B: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-1

B1 Change of Manufacturing Site

For any change, including addition to or replacement, of currently registered
manufacturing site(s) of drug substance, drug product, process intermediates, and/or
primary packager. If there are any changes in the manufacturing process, include
documents listed under B3.

Supporting Documents
1) Official letter authorising the proposed site to perform the related activity;
2) GMP certificate;
3) Validation study reports and/or summaries of the manufacturing process at the
proposed manufacturing site;
4) Release and/or shelf life specifications;
5) Batch analysis data (in a comparative tabular format) of at least three batches
manufactured at the currently registered and proposed site;
6) Results of appropriate stability studies of at least three batches produced at the
proposed manufacturing site in accordance with the relevant stability guidelines;
7) Batch numbering system.

B2 Change of Testing Laboratory

For any addition or replacement of the current registered laboratories for stability tests
or any quality control (QC) tests.

1) Official letter authorising the proposed site to perform the related activity;
2) Analytical assays at the proposed site;
3) Validation study reports and/or summaries at the proposed site;
4) Release specification;
5) Batch analysis data (in a comparative tabular format) of at least two batches
tested at the currently registered and proposed site

B3 Change of Manufacturing Process

For any change in the procedure and/or scale of the current registered manufacturing
process at any stage during manufacture of drug substance and/or drug product.

1) Validation study reports and summaries of the proposed manufacturing process;
2) Release and/or shelf life specifications;
manufactured according to the currently registered and proposed process;

4) Results of appropriate stability studies of at least three batches produced with the
proposed manufacturing process in accordance with the relevant stability
guidelines;
5) A declaration from the applicant that no new impurities have been introduced at or
above the accepted threshold for qualification of impurities or that there is no
increase in the level of impurities, which require further safety studies.

B4 Change of Test Procedure

For any change of test procedure of drug substance, drug product, in-process tests,
excipients, product release tests, and/or stability tests.

1) Validation study reports and summaries of the proposed test procedure.

B5 Change of Specifications

For any change of release and/or shelf life specifications of drug substance, drug
product, in-process tests, product release tests, and/or stability tests.

1) Scientific and/or historical data used to support the change;
2) Currently registered version of the release and/or shelf life specifications with the
proposed change(s) clearly highlighted, underscored, or otherwise indicated.

B6 Change of Container Closure System

For any change of the container closure system that is in immediate contact with the
drug substance, drug product, process intermediates, and/or diluent used for
reconstitution.

1) Information on construction materials and design features of the proposed
container closure system;
2) Study reports and/or summaries on compatibility, leaching materials, leak tests,
etc. for demonstrating the suitability of using the proposed container closure
system;
3) Release and shelf life specifications;
4) Results of appropriate stability studies of at least three batches produced with the
proposed container closure system in accordance with the relevant stability
guidelines.


B7 Change of Shelf Life and/or Storage Condition

For any change of shelf life and/or storage condition of drug substance, drug product,
and/or process intermediates after initial opening or after reconstitution.

2) Results of appropriate stability studies of at least three batches covering the
duration of the proposed shelf life under the proposed storage conditions in
accordance with the relevant stability guidelines.

B8 Change of Excipient

For any change of the qualitative or quantitative formulation of excipients of drug
substance and/or drug product.

manufactured according to the currently registered and proposed formulation;
3) Results of appropriate stability studies of at least three batches with the proposed
formulation in accordance with the relevant stability guidelines.

B9 Change of Product Label

For any change of product labelling of the package insert (PI), patient information
leaflet (PIL), unit carton label, inner label, and/or blister strips which cannot be
classified as an MAV or an MIV-2.

1) J ustification for the proposed change(s) and supporting clinical documents, where
applicable;
2) Currently registered product label with the proposed change(s) clearly highlighted,
underscored, or otherwise indicated;
3) Proposed product label with all change(s) incorporated;

B10 Seasonal Variation of Influenza Strains for Vaccine

Change of only influenza strains for the formulation of an influenza vaccine according
to WHO Recommendations for Influenza Vaccine Composition may be expedited.
Additional changes other than strain changes will require additional supporting
documents, and may delay the evaluation timeline.

Document Required In Addition to MIV-1 Compulsory Documents:
1) CTD Module 2 - Section 2.3 Quality Overall Summary;

2) CTD Module 3 - Section 3.2.P.8 Stability (Summary & Conclusion) of at least 6
months of the vaccine from the preceding year or season;
3) Currently registered product label with the proposed change(s) clearly highlighted,
underscored, or otherwise indicated;
4) Proposed product label with all change(s) incorporated;
5) A commitment from the applicant to perform stability studies up to the proposed
shelf-life of the product.


PART C: DOSSIER REQUIREMENTS FOR BIOLOGICS MIV-2

An MIV-2 application is a variation for which only a notification is required to be submitted
to HSA. Each MIV-2 notification shall be submitted at least 2 months in advance of the
commencement date.

If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.

C1 Change of Contact Person

Condition
- The product licence holder remains the same.

1) Particulars of the contact person updated in the on-line PRISM application form.

C2 Change of Product Name

Conditions
- There is no change to the product (formulation, specifications, manufacturing
source and process) except the product name;
- No perceived conflict, confusion, or similarity to name(s) of existing medicinal
products;
- New name does not imply (a) greater safety or efficacy than supported by clinical
data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic
use for the product, or (d) the presence of substance(s) not present in the product.

1) Official letter authorising change of product name;
2) A declaration from the applicant that there is no change to the product except
name;
3) Official letter of commitment to inform users of the relevant changes, and that the
current product stocks will be exhausted before the product labelled with the new
name is marketed;
4) CPP.

NOTE: Applicants are encouraged to fax or email the MIV Filing and
Submission Inquiry Form in Appendix 13 for any issues regarding MIV filing.

C3 Change of Product Owner

Condition
- The product licence holder remains the same.

1) Official letter by the new product owner declaring the change, and authorising the
local licence holder to be responsible for the product licence in Singapore;
2) If the new product owner is not the manufacturer of the drug product, an official
letter by the new product owner authorising the manufacturer to produce the drug
product on its behalf.

C4 Change of Batch Numbering System

1) Official letter stating the commencement date of the change;
2) Description of batch number system.

C5 Renaming (e.g. street name, postal code) of Manufacturing Site

Condition
- The current manufacturing site(s) of drug substance, drug product, process
intermediates, packaging, and/or batch release remains unchanged and at the
same physical location.

1) Official letter authorising the site to perform the related activity (not required if the
manufacturer is the product owner);
2) A declaration from the applicant that the manufacturing site remains the same,
and that the renaming does not involve changes of the manufacturing process
and/or quality of the product;
3) Official letter stating the commencement date of the change;
4) GMP certificate with new name or address.

C6 Change of Batch Release Site

Condition
- Batch release procedure is equivalent between the current and new site.

1) Official letter authorising the site for batch release;
2) GMP certificate of the new site.


C7 Addition or Replacement of Secondary Packaging Site

1) Official letter authorising the proposed manufacturer to perform secondary
packaging;
2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is
appropriately authorised for the packaging activity concerned.

C8 Withdrawal of Manufacturer or Manufacturing Site

1) Official letter stating the withdrawal or deletion of the manufacturer or
manufacturing site to perform the related activity.

C9 Deletion of Pack Size for Drug Product

1) No additional documents required.

C10 Change of Secondary Packaging

Conditions
- Conformance to current drug product release and shelf life specifications;
- The change is consistent with the dosage regimen and duration of use as
approved in the PI.

1) Official letter stating that release and shelf life specifications, the container and
closure system compositions have not been changed;
2) J ustification that the change is consistent with the dosage regimen and duration of
use as approved in the PI.

C11 Change of Imprints, Bossing or Other Markings (except Score/Break Line) on
Tablet or Printing on Capsule Including Addition or Change of Inks Used for
Product Marking

Conditions
- New markings do not cause confusion with other tablets or capsules;
- The inks are acceptable for pharmaceutical use;
- Conformance to current drug product release and shelf life specifications except
for appearance.


1) A declaration from the applicant that that the release and shelf life specifications
(except appearance) of the drug product have not been changed;
current product stocks will be exhausted before the new product is marketed;
3) Detailed drawings and/or written descriptions of the current AND new imprint/
bossing/ markings/ink/etc.;
4) Drug product release and shelf life specifications.

C12 Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without
Change in Qualitative and Quantitative Composition and Mean Mass
C12.1 Conventional Dosage Form, Suppository and Pessary
C12.2 Critical dosage form and scored tablet

Conditions
- No change in dissolution profile;
for dimensions.

C12.1 Conventional dosage form, suppository and pessary
1) Detailed drawing or written description of the current and proposed appearance;
2) Release and shelf life specifications of the drug product;
3) Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).

C12.2 Critical dosage form and scored tablet
4) In addition to C12.1 Documents 1 to 3;
5) Comparative dissolution data on at least one pilot/production batch of the current
and proposed dimensions in accordance with HSAs drug registration guidelines;
6) J ustification for not submitting a new bioequivalence study according to the
current Bioavailability and Bioequivalence guidelines;
7) Where applicable, data on the test for uniformity of content of the subdivided parts
of tablets at release should be submitted and commitment to conduct the test at
the end of shelf life, data should be provided only if outside the release and shelf
life specifications (with proposed action).

C13 Change in Colouring or Flavouring System of Product Including Addition,
Deletion or Replacement of Colourant(s) or Flavourant(s)

Conditions
- Same functional characteristics, no change in dissolution profile for solid dosage
forms;
- The colouring system must not have been rejected for pharmaceutical use;
for colour/flavour.

(except colour and/or flavour) of the drug product have not been changed;
current product stocks will be exhausted before the new product is marketed;
3) Official letter of commitment to conduct the appropriate stability studies of at least
three batches produced with the revised formulation in accordance with the
relevant stability guidelines;
4) Detailed information of the colouring or flavouring agent;
5) Revised product formulation;
6) Drug product release and shelf life specifications.

C14 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell

Conditions
- No change in dissolution profile;
for weight.

(except weight) of the drug product have not been changed;
2) Comparative dissolution data of at least one pilot or production batch of the
current version versus the proposed version in accordance with HSAs drug
registration guidelines; for modified release products, also provide correlative data
comparing in vitro and in vivo data;
3) J ustification for waiving requirements for a new bioequivalence study according to
the relevant guidelines;
4) Drug product release specification.

C15 Change of Product Labelling due to Safety Updates:

Note: Changes to safety information on product labels and package insert may be
allowed without prior approval from HSA provided the changes fulfil the conditions
stipulated below. Companies that need to disseminate safety information urgently
can continue to do so through Dear Healthcare Professionals Letters, in consultation
with HSA. Thereafter, product labelling should be updated in accordance with the
labelling safety-related update notification system.

Conditions
- Addition of warnings, precautions, contraindications or adverse events/effects to
the current product labelling, or
- Tightening of the target-patient population.

1) A declaration from the applicant that no other changes have been made to the

labelling and that the change is supported by data.

C16 Change of Product Labelling Relating to:
Addition/Deletion of Bar Code
Replacement of Distributor Details
Layout without Altering Text or Meaning
Deletion of Indication (Note: Re-inclusion of the deleted indication in the future
should be submitted as MAV-1 according to the prevailing requirement.)
Addition/Deletion/Replacement of Pictures or Diagrams that do not Imply
an Unapproved Indication

Conditions
- No change to the text or meaning of the wordings;
- No unapproved indications, usages, dosage regimens or promotional information.

1) A declaration from the applicant that no other changes have been made to the
labelling.

C17 Change of Product Labelling of Language(s) Other Than English

Conditions
- No change to the text or meaning of the English wordings;
- No unapproved indications, usages, dosage regimens or promotional information.

1) A declaration from the applicant that the information in other language(s) provides
complete, accurate and unbiased information on the product and is consistent
with the English version.

Appendix 15 - Guideline On MIV Applications For Biologics

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GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &MIV-2) FOR BIOLOGICS

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