appendix 13 guideline on minor variation ... on therapeutic product registration in singapore...

GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE NOVEMBER 2016 – GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP Appendix 13 - of 44

APPENDIX 13 GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS

TABLE OF CONTENTS

PART A: INTRODUCTION ............................................................................................ 4

PART B: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-1 VARIATION ........ 7

B1 Change and/or Addition of Alternative Manufacturer/site of Drug Substance [where

European Pharmacopoeial Certificate of Suitability (CEP) is not available] .............. 7

B2 Change and/or Addition of Alternative Manufacturer/site of Drug Substance [where

European Pharmacopoeial Certificate of Suitability (CEP) is available] .................... 8

B3 Major Change of Manufacturing Process of Drug Substance [where European

Pharmacopoeial Certificate of Suitability (CEP) is not available] ............................... 8


Pharmacopoeial Certificate of Suitability (CEP) is available] .................................... 9

B5 Addition or Replacement of Manufacturing Site of Drug Product .............................. 9

B6 Addition or Replacement of Alternative Site for Primary Packaging (direct contact with

drug product) .......................................................................................................... 10

B7 Change of Specification of Drug Substance [where European Pharmacopoeial

Certificate of Suitability (CEP) is not available] and/or Drug Product ...................... 11


Certificate of Suitability (CEP) is available] ............................................................. 12

B9 Change of Batch Size of Sterile Drug Product ........................................................ 12

B10 Change of Batch Size of Non-sterile Drug Product ................................................. 13

B11 Major Change in Manufacturing Process for Drug Product ..................................... 14

B12 Qualitative or Quantitative Change of Excipient ...................................................... 14

B13 Quantitative Change in Coating Weight of Tablets or Weight and/or Size of Capsule

Shell for Modified Release Oral Dosage Form ........................................................ 15

B14 Change in Primary Packaging Material for Sterile Product ..................................... 16

B15 Change or Addition of Pack Size/Fill Volume and/or Change of Shape or Dimension

of Container or Closure for Sterile Solid and Liquid Drug Product .......................... 17

B16 Inclusion or Replacement of Solvent/Diluent for Drug Product ............................... 17

B17 Change of Shelf-life of Drug Product ...................................................................... 18

B18 Change of Storage Conditions of Drug Product ...................................................... 18

B19 Addition or Change of Score/Break Line of Tablet .................................................. 19

B20 Change of Sterility Testing to Parametric Release .................................................. 19

B21 Implementation of a New Design Space or Extension of an Approved Design Space

for Drug Substance or Drug Product....................................................................... 20

B22 Change of Content of Product Labelling ................................................................. 20



PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 VARIATION ...... 22

C1 Change of Drug Product Name .............................................................................. 22

C2 Change of Product Labelling .................................................................................. 23

C3 Addition or Replacement of Company or Party Responsible for Batch Release ..... 24

C4 Change of Batch Size of Drug Substance [where European Pharmacopoeial

Certificate of Suitability (CEP) is not available] ....................................................... 24

C5 Change of In-process Controls Applied during Manufacture of Drug Substance

[including tightening and addition of new in-process test and where European

Pharmacopoeial Certificate of Suitability (CEP) is not available] ............................. 24

C6 Minor Change of Manufacturing Process of Drug Substance [where European

Pharmacopoeial Certificate of Suitability (CEP) is not available] ............................. 25

C7 Change of Specification of Drug Substance ........................................................... 26

C8 Change of Test Procedure of Non-compendial Drug Substance............................. 26

C9 Change of Shelf-life or Re-test period of Drug Substance ...................................... 26

C10 Change of Storage Conditions of Drug Substance ................................................. 27

C11 Revision of European Pharmacopoeial Certificate of Suitability (CEP) of Drug

Substance .............................................................................................................. 27

C12 Change of Batch Size of Non-sterile Drug Product ................................................. 28

C13 Reduction or Removal of Overage ......................................................................... 28

C14 Qualitative and/or Quantitative Change of Excipient ............................................... 29

C15 Quantitative Change in Coating Weight of Tablets or Weight and/or Size of Capsule

Shell for Immediate Release Oral Solid Dosage Form ............................................ 30

C16 Change of Colouring/Flavouring Agent of Product [addition, deletion or replacement

of colourant(s)/flavour(s)] ........................................................................................ 31

C17 Deletion of Solvent/Diluent for Drug Product .......................................................... 31

C18 Change of In-process Controls Applied during Manufacture of Drug Product (including

tightening and addition of new in-process test) ....................................................... 31

C19 Minor Change of Manufacturing Process for Non-sterile Product ........................... 32

C20 Change of Specification of Excipient ...................................................................... 33

C21 Change of Test Procedure for Excipient, including Replacement of an Approved Test

Procedure by a New Test Procedure ...................................................................... 33

C22 Change in Source of Empty Hard Capsule ............................................................. 34

C23 Change of Release and Shelf-life specification of Drug Product ............................. 34

C24 Change of Imprints, Bossing or Other Markings on Tablets or Printing on Capsules

including Addition or Change of Inks Used for Product Marking ............................. 35

C25 Change of Dimensions and/or Shape of Tablets, Capsules, Suppositories or

Pessaries Without Change in Qualitative and Quantitative Composition and Mean

Mass ...................................................................................................................... 36

C26 Change in Test Procedure of Drug Product (including replacement or addition of a

test procedure) ....................................................................................................... 36



C27 Change in Primary Packaging Material for Non-sterile Substance or Product ......... 37

C28 Addition or Replacement of Manufacturer for Secondary Packaging ...................... 37

C29 Change of Pack Size/Fill Volume and/or Change of Shape or Dimension of Container

or Closure for Non-sterile Product .......................................................................... 38

C30 Change of Outer Carton Pack Sizes for Drug Product ............................................ 38

C31 Change in Any Part of (Primary) Packaging Material Not in Contact with Finished

Product Formulation, such as Colour of Flip-off Caps, Colour Code Rings on

Ampoules, Change of Needle Shield (different plastic used) .................................. 39

C32 Addition or Replacement of Measuring Device for Oral Liquid Dosage Forms and

Other Dosage Forms .............................................................................................. 39

C33 Addition or Replacement of Site Responsible for Quality Control (QC) Testing of Drug

Product ................................................................................................................... 39

C34 Change in Supplier of Animal-derived Material ....................................................... 40

C35 Change in Species of Animal-derived Material ....................................................... 40

C36 Change in Name and/or Address (for example: postal code, street name) of Product

registrant ................................................................................................................ 41

C37 Change of Product Owner ...................................................................................... 41

C38 Change in Ownership of Manufacturer ................................................................... 42

C39 Change of Name or Address (for example: postal code, street name) of Manufacturer

of Drug Product ...................................................................................................... 42

C40 Change of Name or Address (for example: postal code, street name) of Company or

Manufacturer Responsible for Batch Release ......................................................... 42

C41 Change of Name and/or Address (for example: postal code, street name) of

Manufacturer of Drug Substance ............................................................................ 43

C42 Withdrawal/Deletion of Alternative Manufacturer(s) for Drug Substance and/or Drug

Product and/or Packager ........................................................................................ 43

C43 Renewal of European Pharmacopoeial Certificate of Suitability (CEP) ................... 43

C44 Change of Release and Shelf-life specification of Drug Product and/or Drug

Substance and/or Excipient to Comply with Latest Compendium ........................... 44

C45 Deletion of Pack Size for Product ........................................................................... 44

C46 Change of Batch Numbering System...................................................................... 44



PART A: INTRODUCTION

This document describes the requirements of a Minor Variation Application (MIV) submitted for an existing registered chemical drug product in Singapore. Product registrants should be familiar with the contents of this document, Chapters F and H of this guidance 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.

The following points should be considered 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 shall be submitted as an MIV-1 with the relevant supporting documents.

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. In exceptional situations, the evaluation timeline for MIV-1 applications may be extended beyond that published, for example, for extensive grouping of changes. In such cases, the extended timeline will be communicated to the applicant. HSA also reserves the right to re-categorise the MIV if deemed appropriate.

1 REGISTRATION PROCESS

An MIV is submitted via the “Amendment to a Registration of Western Drug Product” form in PRISM. Product registrants should disclose all proposed changes in Section 0 Registration Summary under Section 0.4 MIV Checklist Number (Primary Change) and Section 0.5 MIV Checklist Number (Secondary Change(s)); and in the Table of Amendment Details, which can be downloaded via the link indicated in Section 0.7 Table of Summary of Changes. Any undisclosed variation(s) embedded in the submitted data, or any follow-on changes not specifically requested by HSA, will not be considered for evaluation. Please refer to Section 2 of Appendix 17 for more information on submitting a variation product application.

2 DOCUMENTARY REQUIREMENTS

The following documents listed in Table A must be submitted with each MIV submission:

NOTE: Product registrants are encouraged to email the MIV Filing and Submission

Enquiry Form in Appendix 12 if there are any issues regarding MIV filing, such as the

absence of a relevant checklist for a particular change.



Table A MIV Application Submission Requirements

Softcopy

PRISM Application Form PRISM

Table of Contents PRISM

Cover Letter PRISM

Checklist for MIV(s) PRISM

Table of Summary of Changes PRISM

MIV-specific Supporting Documents

- Administrative (Module 1/Part 1)

- Other supporting documents

PRISM

PRISM/CD#

Current and Proposed Product Labelling (annotated and pristine

copies), where applicable

PRISM

# All supporting documents may be submitted via PRISM or CD-ROM – do not combine PRISM

attachments with a CD submission

The checklists for MIV-1 and MIV-2 applications for chemical drug products are located in

Parts B and C of this Appendix. These checklists serve as guides when 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) – justifications should be provided below the respective document description if there is any omission of documentation; and

The Table of Summary of Changes should concisely describes the proposed MIV(s). The following information must be stated in the Table:

Section(s) of the original dossier affected by the change(s);

Current and proposed condition(s);

Reason(s) for the change(s); and

Registration status and date of the proposed change(s) in other countries/agencies that had approved the variation(s), especially the country of origin and HSA’s reference agencies.

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, justifications must be provided. For MIV applications with labelling changes, annotations should be made on the proposed

labelling materials based on the actual text to be added, and on current approved labelling

materials. Current approved text which is proposed for deletion should be struck through,

whereas new proposed text should be underlined or highlighted. Current approved text that

is not intended to be deleted should not be annotated. However, the translocation of current

approved text from one section to another can be allowed in its entirety.

NOTE: For unstable drug substances or critical dosage forms, whenever stability data

is required, a minimum of three batches (at least two pilot scale or larger) must be

submitted.



This document reflects the current thinking of HSA on the minimum data necessary for

assessment. Product registrants 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 for additional

information if deemed appropriate.

_________________________________________________________________

REVISION HISTORY

Guidance Version (Publish Date)

TPB-GN-014-000 (uploaded 31 October 2016)



PART B: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-1 VARIATION

Product registrants should be familiar with the documentary requirements for MIV submissions to facilitate the review process. The following documents listed in Table A must be submitted with each MIV submission: Table B MIV Application Submission Requirements

Softcopy



Cover Letter PRISM






PRISM

PRISM/CD#



PRISM

# All supporting documents may be submitted via PRISM or CD-ROM – do not combine PRISM attachments with a CD submission

These checklists serve as a guide for submitting the required documents relevant to each proposed MIV. Each checklist will have a “C” and “D” –

“C” are eligibility criteria that must be fulfilled in order for the MIV to apply. “D” are the relevant documents that are to be submitted for the MIV.

B1 Change and/or Addition of Alternative Manufacturer/Site of Drug Substance

[where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

C 1. Specification(s) of drug substance(s) remain unchanged.

2. For a change and/or addition of an alternative manufacturer/site of drug substance where a CEP is available, please refer to MIV-1 B2.

D 1. Complete CTD section S.1-S.7, or both the open and closed parts of the Drug Master File (closed part may be provided directly by manufacturer) with the Letter of Access.

2. Comparative tabulated format of the currently registered and revised drug substance manufacture information (where applicable).

3. Batch analysis data (in a comparative tabulated format) for at least two pilot batches of the drug substance from the current and proposed manufacturing sites.

4. A letter of commitment from the product registrant to conduct real-time and accelerated stability studies for the drug product manufactured with the drug

NOTE: When submitting the Checklist, please delete the MIV-1 checklist

category(ies) that do not relate to the MIV application being submitted.



substance from the proposed manufacturing site(s), and report if any results fall outside of the shelf-life specifications (with proposed action) or when requested.

B2 Change and/or Addition of Alternative Manufacturer/site of Drug Substance

[where European Pharmacopoeial Certificate of Suitability (CEP) is available]

C 1. Specification(s) of drug substance(s) remain unchanged.

2. For a change and/or addition of alternative manufacturer/site of drug substance where a CEP is not available, please refer to MIV-1 B1.

D 1. A valid European Pharmacopoeial Certificate of Suitability (CEP) for the drug substance(s), latest version, with all annexes issued by the European Directorate for the Quality of Medicines (EDQM).

2. A letter of commitment from the product registrant to conduct real time and accelerated stability studies for the drug product manufactured with the drug substance from the proposed manufacturing site(s), and report if any results fall outside of the shelf-life specifications (with proposed action) or when requested.

3. Batch analysis data (in a comparative tabulated format) for at least two pilot batches of the drug substance from the current and proposed manufacturing sites.

4. If the re-test period is not stated in the CEP: real time and accelerated stability data up to the proposed re-test period on two pilot batches of the drug substance manufactured from the proposed manufacturing site(s).


Pharmacopoeial Certificate of Suitability (CEP) is not available]

C 1. Synthetic route is different (for example, new intermediates are formed).

2. For a major change of manufacturing process of the drug substance where a CEP is available, please refer to MIV-1 B4.

D 1. Drug Master File (DMF), or relevant updated drug substance (DS) section(s) or equivalent/audit document.

2. Comparative tabulated format of the currently approved and new processes with changes highlighted (where available).

3. For a sterile drug substance, process validation report (where applicable).

4. A letter of declaration from the product registrant stating 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 levels of impurities, which require further safety studies; or scientific justification for any change in impurity profile.

5. A letter of declaration from the product registrant stating that the specifications of the drug substance have not changed, or, if there is any change to the specification, then the currently approved and proposed specifications should be provided in a comparative tabulated format.

6. Certificates of analysis for two batches of the drug substance.



7. A declaration from the product registrant that the relevant stability studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

8. Batch analysis data (in a comparative tabulated format) of the drug product of at least two batches (pilot/production scale) manufactured with the drug substance according to the currently approved and proposed processes.


Pharmacopoeial Certificate of Suitability (CEP) is available]

C 1. Synthetic route is different (for example, new intermediates are formed).

2. For a major change of the manufacturing process of a drug substance where a CEP is not available, please refer to MIV-1 B3.

D 1. A valid European Pharmacopoeial Certificate of Suitability (CEP) for the drug substance, latest version, with all annexes issued by EDQM.

2. A declaration from the applicant that the relevant stability studies of the drug product in accordance with ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

3. Specification of the drug substance.

4. Results of batch analysis from the drug substance manufacturer* demonstrating compliance with the Ph. Eur monograph and including additional test/limits listed on the CEP.

5. Additional data to address any relevant parameter(s) not addressed in the CEP, such as stability data (S7) if a re-test period is not stated on the CEP and physicochemical characteristics (e.g. particle size, polymorphism etc), if applicable.

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

B5 Addition or Replacement of Manufacturing Site of Drug Product

C 1. Not applicable to changes relating to the manufacturer responsible for batch release or a site where only batch release takes place.

2. For addition or replacement of the company or party responsible for batch release, please refer to MIV-2 C3.

3. If there are changes to the manufacturing process, MIV-1 B11 or MIV-2 C19 is also applicable.

D 1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).

2. Proof that the proposed site is appropriately authorised for the pharmaceutical form concerned, such as a valid Good Manufacturing Practice (GMP) certificate



and/or a Certificate of Pharmaceutical Product (CPP) which covers GMP certification. (Note: GMP Conformity Assessment is required if the proposed site is not currently registered with HSA.)

3. Batch numbering system (where applicable).

4. In case of a contract manufacturer, a letter of appointment for the proposed site to manufacture the product and stating the types of activity to be performed (where applicable).


6. Product formula.

7. Comparative dissolution profile data of at least one representative pilot/production

batch of the drug product manufactured by the currently approved and proposed

manufacturing site(s) as per US FDA SUPAC IR or MR guidelines.

8. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration at the proposed site(s) should be provided upon submission.

9. Holding time studies testing of bulk pack during storage and transportation between the bulk production site and primary packager (where applicable).

10. Release and shelf-life specifications of the drug product.

11. Comparative batch analysis data of the drug product of at least two production batches (or one production batch and two pilot batches) from the proposed site and last three batches from the current site; a letter of commitment to provide batch analysis data on the next two full production batches should be available upon request or reported if outside of the specifications (with proposed action).

12. Stability data as per ASEAN Guideline on Stability Study of Drug Product and report if any results fall outside of the shelf-life specifications (with proposed action).

B6 Addition or Replacement of Alternative Site for Primary Packaging (direct contact

with drug product)

C 1. No other changes except for the addition or replacement of an alternative site(s) for primary packaging (direct contact with drug product).


2. Proof that the proposed site is appropriately authorised for the packaging activity of the pharmaceutical form concerned, such as a valid GMP Certificate and/or a CPP which covers GMP certification. (Note: GMP Conformity Assessment is required if the proposed site is not currently registered with HSA.)

3. In case of a contract primary packager, a letter of appointment for the proposed site to package the product and stating the types of activity to be performed by the packager (where applicable).

4. For a sterile product, validation scheme and/or report on primary packaging processes as per ASEAN Guideline on Submission of Manufacturing Process



Validation Data for Drug Registration at the proposed site(s) should be provided upon submission.

5. Holding time studies testing of bulk pack during storage and transportation between the bulk production site to primary packager (where applicable).



Certificate of Suitability (CEP) is not available] and/or Drug Product

a) Specification limits are widened b) Deletion of test parameter and limits

C 1. Test procedures remain the same, or changes in the test procedure are minor.

2. Not applicable to compendial drug substances/drug products. Refer to MIV-2 C44 for a change in specification due to update of the compendium.

3. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.

4. If the currently approved shelf-life specification is not met, please submit the Product Defect Reporting Form (RR1) found on the HSA website within 24 hours of receiving the product defect information.

5. For change of specification of drug substance where a CEP is available, please refer to MIV-1 B8.

D Specification limits are widened

1. Revised specification of drug substance/drug product.

2. Comparative tabulated format of the currently approved and revised specification of drug substance/drug product with changes highlighted.

3. Batch analysis data of the drug substance/drug product for all tests in the new specification for two pilot or production scale batches.

4. Justification for change substantiated with scientific data to be provided.

5. For change of drug product specification, stability data as per ASEAN Guideline on Stability Study of Drug Product and report if any results fall outside of the shelf-life specifications (with proposed action).

6. For change of drug substance specification on any stability-indicating parameters, (a) Results of at least six months real time stability studies of at least two

production batches of the drug substance; AND

(b) A letter of undertaking to continue the stability studies to the retest period or shelf life, where applicable, and to report to HSA of any out-of-specification result (with proposed action) or when requested; AND

(c) A declaration from the product registrant that the relevant stability studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

Deletion of test parameter and limits

http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/safety_information/files_-_forms.Par.72921.File.dat/FORM_RR1_007_Product%20Defect%20Reporting%20Form.doc



In addition to the above documents except D5 and D6,

7. Certificate of analysis of the drug substance/drug product for all tests with the new specification.


Certificate of Suitability (CEP) is available]

a) Specification limits are widened b) Deletion of test parameter and limits

C 1. Not applicable to compendial drug substances/drug products. Refer to MIV-2 C44 for a change in specification due to update of the compendium.



D

1. A valid European Pharmacopoeial Certificate of Suitability (CEP) for the drug substance, latest version, with all annexes issued by EDQM.

2. A declaration from the applicant that the relevant stability studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).


4. Results of batch analysis from the drug substance manufacturer* demonstrating compliance with the Ph. Eur monograph and including additional test/limits listed on the CEP.


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

B9 Change of Batch Size of Sterile Drug Product

C 1. The change does not affect consistency of production.

2. The product formulation remains unchanged.

3. Release and shelf-life specifications of the drug product remain unchanged.

4. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches appropriate to the proposed batch size in accordance with




the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

D 1. Comparative tabulated format of proposed and currently approved batch manufacturing formula.

2. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration of the proposed batch size should be provided upon submission.


4. Batch analysis data (in a comparative tabulated format) of the drug product of at least two production batches manufactured according to the currently approved and proposed batch sizes.


B10 Change of Batch Size of Non-sterile Drug Product

C 1. The change does not affect consistency of production.


3. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches appropriate to the proposed batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

4. This is applicable to a change of batch size of more than 10-fold compared to the currently registered batch size. For a change of batch size up to 10-fold compared to the currently registered batch size, please refer to MIV-2 C12.

D 1. For oral solid dosage forms, comparative dissolution profile for at least one production batch (where applicable) to both the currently approved and proposed batch sizes as per US FDA SUPAC IR or MR.

2. Comparative tabulated format of proposed and current batch manufacturing formula.

3. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration of the proposed batch size should be provided upon submission.


5. Batch analysis data (in a comparative tabulated format) of the drug product on a minimum of one production batch manufactured according to the currently approved and proposed batch sizes and a letter of undertaking to submit batch data on the next one full production batch.




B11 Major Change in Manufacturing Process for Drug Product

C 1. The change does not cause a negative impact on the quality, safety and efficacy of the drug product.

2. The same currently approved manufacturing site. If there is a change in manufacturing site, MIV-1 B5 is also applicable.

3. For a minor change of the manufacturing process for a non-sterile product, please refer to MIV-2 C19.

D 1. Description of the new manufacturing process and technical justification for the change.


batch of the drug product manufactured using the currently approved and proposed

manufacturing process as per US FDA SUPAC IR or MR guidelines.

3. Validation scheme and/or report of the proposed manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration should be provided upon submission.

4. Copy of currently approved release and shelf-life specifications. Alternatively, a copy of the proposed release and shelf-life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.

5. Comparative batch analysis data of the drug product for a minimum of one production batch manufactured according to the currently registered and proposed processes.


7. Justification for not submitting a new bioequivalence study according to the ASEAN Guideline for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).

B12 Qualitative or Quantitative Change of Excipient

a) For immediate release oral dosage forms (as per Level 2 and 3, Part III Components and Composition, SUPAC guideline)

b) For modified release oral dosage forms

c) For other critical dosage forms such as sterile preparations.

C 1. Change will need to comply with the finished product specifications, for example release and shelf-life specifications of the drug product remain the same, excluding product description.

2. Replacement of an excipient with a comparable excipient of the same functional characteristics.

3. The dissolution profile of the proposed product is comparable to that of the current approved product.



4. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed new product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

5. For other qualitative or quantitative changes of excipient for immediate release oral dosage forms and other non-critical dosage forms, please refer to MIV-2 C14.

6. HSA reserves the right to re-categorise the application to NDA or GDA, if deemed appropriate.


2. Justification for the change must be given by appropriate development of pharmaceutics.

3. Comparative tabulated format of the current and revised product formulation with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).

4. Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation (where applicable) as per US FDA SUPAC IR or MR guidelines.

5. Revised batch manufacturing formula. 6. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in the product formula should be provided upon submission.

7. Revised CTD Section P3.1 to P3.4 (where applicable). 8. Specification of the proposed excipient(s). 9. For proposed excipients made from a ruminant source, Transmitting Animal

Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from the relevant veterinary authority of the issuing country (where applicable).

10. Release and shelf-life specifications of the drug product. 11. Batch analysis data (in a comparative tabulated format) of the drug product on at

least two production (or one production batch and two pilot batches) according to currently approved and proposed product formula.


13. Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).

B13 Quantitative Change in Coating Weight of Tablets or Weight and/or Size of

Capsule Shell for Modified Release Oral Dosage Form

C 1. The dissolution profile of the proposed product is comparable to that of the currently approved product.

2. The release and shelf-life specifications of the drug product remain unchanged except for the weight and/or size (where applicable).



3. For quantitative change in coating weight of tablets or weight and/or size of capsule shell for immediate release oral solid dosage forms, please refer to MIV-2 C15.

D 1. Revised draft of the product label incorporating the proposed change (where applicable).

2. A declaration that the change does not interfere with the drug product release and shelf-life specifications test method.


batch of the drug product between the currently approved and proposed solid

dosage forms formulation (where applicable) as per US FDA SUPAC IR or MR

guidelines.

4. Current and proposed product and batch manufacturing formula.

5. Revised release and shelf-life specifications of the drug product.



B14 Change in Primary Packaging Material for Sterile Product

a) Qualitative and quantitative composition, and/or b) Type of container, and/or, c) Inclusion of primary packaging material

C 1. Release and shelf-life specifications of the drug product remain unchanged.

2. For a change in the primary packaging material for a non-sterile drug product, please refer to MIV-2 C27.


2. Appropriate scientific data on the new packaging (comparative data on permeability, e.g. moisture, O2, CO2).

3. Proof must be provided that no interaction between the content and the packaging material occurs (where applicable).

4. Validation scheme and/or report of the manufacturing and sterilization process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in primary packaging material should be provided upon submission.

5. Comparative tabulated format of the specifications of the proposed and current primary packaging material.

6. Revised CTD Sections P3 and/or P7 (where applicable).




B15 Change or Addition of Pack Size/Fill Volume and/or Change of Shape or

Dimension of Container or Closure for Sterile Solid and Liquid Drug Product

C 1. The proposed pack size is consistent with the dosage regimen and duration of use as approved in the package insert.

2. The packaging material remains the same.

3. Release and shelf-life specifications of the drug product are not affected, except pack size/fill volume specification.

4. Change or addition of pack size/fill volume and/or change of shape or dimension of container or closure for a non-sterile drug product, please refer to MIV-2 C29.


2. Justification that the proposed pack size is consistent with the dosage regimen and duration of use as approved in the package insert.

3. Validation data of the manufacturing process, sterilization and container closure system (where applicable).


B16 Inclusion or Replacement of Solvent/Diluent for Drug Product

C 1. The proposed change does not result in any change in the dosage form, regimen, indication or method of administration of the product.

2. For deletion of the solvent/diluent, please refer to MIV-2 C17.

3. For change of shelf-life and/or storage condition of the drug product after first opening and/or after dilution/reconstitution, please also refer to MIV-1 B17 or B18.

D 1. Revised drafts of the package insert and labelling incorporating the proposed variation.

2. Documentary evidence to certify that the manufacturing site of the diluent/solvent complies with current applicable GMP standards (where applicable). (Note: GMP Conformity Assessment is required if the proposed site is not currently registered with HSA.)

3. Batch numbering system (where applicable).

4. A letter of authorisation from the product owner to authorise the manufacturing site to manufacture and package the solvent/diluent (where applicable).

5. A declaration from the product registrant that the release and shelf-life specifications of the drug product are not affected.

6. In addition to section P for the solvent/diluent and reconstitution stability data, section S is also required (where applicable).



B17 Change of Shelf-life of Drug Product

a) As a package for sale; and/or b) After first opening; and/or c) After dilution/reconstitution

C 1. For (a) & (b), the studies must show conformance to the currently approved shelf-life specification.

2. For (c), the studies must show conformance to the currently approved shelf-life specification for the reconstituted product.



2. Justification for the change of shelf-life of the drug product (where applicable).

3. A letter of commitment from the product owner or product registrant to inform users of the relevant change (where applicable).

4. Results of appropriate real time stability studies covering the duration of the proposed shelf-life of at least two pilot/production scale batches of the product in the authorised packaging material a) as a package for sale; and/or

b) after first opening; and/or

c) after the dilution/reconstitution

in accordance with the ASEAN Guidelines on Stability Study of Drug Product; results of appropriate microbiological testing should be included (where appropriate).

B18 Change of Storage Conditions of Drug Product

a) As a package for sale; and/or

b) After first opening; and/or

c) After dilution/reconstitution

C 1. For (a) & (b), the studies must show conformance to the currently approved shelf-

life specification.

2. For (c), the studies must show conformance to the currently approved shelf-life specification for the reconstituted product.

3. If currently approved shelf-life specification is not met, please submit the Product Defect Reporting Form (RR1) found on the HSA website within 24 hours of receiving the product defect information.


2. Technical justification for the change.






3. Results of appropriate real time stability studies covering the duration of the currently approved shelf-life (at the proposed storage condition) of at least two pilot/production scale batches of the product and in the authorised packaging material in accordance with the ASEAN Guidelines on Stability Study of Drug Product.

B19 Addition or Change of Score/Break Line of Tablet

C 1. New markings do not cause confusion with other registered products.

2. Release and shelf-life specifications of the drug product remain unchanged except for appearance.

3. Score/break-line is not meant for cosmetic purpose.



3. Detailed drawing or written description of the current and proposed imprint/bossing/markings.

4. Release and shelf-life specifications of the drug product with the new product description.

5. Justification for the change (i.e. change in dosing regimen).

6. Data on test of content uniformity of the subdivided parts of the tablets at release should be submitted.

7. Certificates of analysis of two production/pilot scale batches.

B20 Change of Sterility Testing to Parametric Release

C 1. Consult HSA prior to submission.

2. Only a manufacturing site located in a PIC/S participating country with parametric release being approved by the local authority is eligible to apply.

3. HSA reserves the right to request for more supporting documents if deemed necessary.

D 1. Risk assessment: prior knowledge, consistency of performance of steriliser, historical batch analysis data, risk of loading pattern/container/contamination from the environment to product sterility, re-processing plan, etc.

2. Process validation of steriliser: type/design/cycle parameter, container closure system integrity, heat distribution study for 3 consecutive runs, heat penetration studies for 3 consecutive runs for each loading pattern and container size, effectiveness of the load monitor used for each routine run, bioburden, sterility assurance level of 10-6 or better should be demonstrated, re-processing (if applicable), etc.



3. Control Strategy: Tabulation of all validated critical process parameter and loading pattern, describes the process and requirement for releasing/rejection of a batch, bioburden monitoring and control program, segregation of sterile from non-sterile product, routine maintenance/re-validation program for steriliser, etc.

4. Approval letter or recent documentary evidence of approval status (i.e. GMP) for parametric release issued by a local authority (PIC/s). The manufacturing site and product name must be clearly stated. (Note: GMP Conformity Assessment is required if proposed site is not currently registered with HSA for parametric release.)

5. Release and shelf life specifications of the drug product. Revision of the certificates of analysis that parametric release is now the method used to provide assurance of the requirement of sterility.

6. Stability data as per ASEAN Guideline on Stability Study of Drug Product and a letter of commitment to submit the data to HSA upon completion (includes sterility test).

B21 Implementation of a New Design Space or Extension of an Approved Design

Space for Drug Substance or Drug Product

C 1. Applies to a design space with multidimensional combination and interaction of input variables and process parameters.

2. For changes to proven acceptable ranges (i.e. loosening), refer to checklist MIV-1 B3 or MIV-1 B11.

3. HSA reserves the right to request for more supporting documents if deemed

necessary

D 1. Amended relevant CTD sections

2. A comparative table of the current and proposed design space, including the variables (material attributes and/or process parameters).

3. Justification for the proposed change.

4. Results from product, process and analytical development studies (e.g. interaction studies of the different parameters forming the design space, including risk assessment and multivariate studies, where appropriate) to support the proposed design space in production scale manufacturing.


B22 Change of Content of Product Labelling

C 1. Product labelling refers to Package Insert (PI), Patient Information Leaflet (PIL),

unit carton label, inner label and/or blister strips.

2. The change is not an MIV-2 and not within the scope of MAV-1.

D 1. Currently approved product labelling.



2. Proposed product labelling, a clean and annotated version highlighting the changes made.

3. Approved PI/SmPC/PIL from an approved reference regulatory agency or the country of origin containing the proposed changes (where applicable).

4. Justification for the changes proposed and supporting clinical documents where applicable.

5. For non-English text, a declaration from the product registrant that the information in the non-English language(s) provides complete, accurate and unbiased information on the product and is consistent with the English information.



PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 VARIATION

An MIV-2 application is a variation for which only a notification is required to be submitted to HSA. Each MIV-2 notification shall be submitted at least 40 working days before implementation of the variation. 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. Product registrants should be familiar with the documentary requirements for MIV submissions to facilitate the review process. The following documents listed in Table A must be submitted with each MIV submission:

Table C MIV Application Submission Requirements

Softcopy



Cover Letter PRISM






PRISM

PRISM/CD#



PRISM

# All supporting documents may be submitted via PRISM or CD-ROM – do not combine PRISM attachments with a CD submission

These checklists serve as a guide for submitting the required documents relevant to each proposed MIV. Each checklist will have a “C” and “D” –

“C” are eligibility criteria that must be fulfilled in order for the MIV to apply.

“D” are the relevant documents that are to be submitted for the MIV.

C1 Change of Drug Product Name

C 1. There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process) except for the product name change.

2. No confusion with another drug product either when spoken or written.

3. The new name does not (i) suggest greater safety or efficacy than supported by clinical data; (ii) imply a therapeutic use; (iii) imply superiority over another similar product; and (iv) imply the presence of substance(s) not present in the product.

NOTE: When submitting the Checklist, please delete the MIV-2 checklist

category(ies) that do not relate to the MIV application being submitted.



D 1. Revised drafts of the package insert and labelling incorporating the proposed variation.

2. Updated Certificate of Pharmaceutical Product (CPP) (where applicable).

3. Official letter from the product owner or product registrant authorising the change of the product name and committing to inform users of the relevant changes (where applicable).

4. A declaration from the product registrant that there is no other changes to the product/label except for the drug product name change.

C2 Change of Product Labelling

Includes:

a) Change of the layout/artwork without altering the meaning.

b) Addition/deletion/replacement of pictures, diagrams, bar code, logos and/or text that do not imply an unapproved indication.

c) Addition/strengthening of warnings, precautions, contraindications and/or adverse events/effects to the approved product labelling.

Note: Companies that need to disseminate safety information urgently can continue to do so through ‘Dear Healthcare Professional Letters’ in consultation with HSA. Thereafter, product labelling should be updated in accordance with the labelling safety-related update notification system.

d) Tightening of product’s target population.

e) Deletion of indication. (Note: Re-inclusion of the deleted indication in the future should be submitted as MAV-1 according to the prevailing requirement)

f) Change of the distributor’s details.

g) Change of product labelling of language(s) other than English

h) Change of product labelling to allow better product differentiation (e.g. addition of colour stickers)

i) Addition of product labelling specific for sample packs

C 1. Product labelling refers to Package Insert (PI), Patient Information Leaflet (PIL), unit carton label, inner label and/or blister strips.

2. The change is not an MIV-1 and does not contain promotional information.

D 1. Current approved product labelling.

2. Proposed product labelling, a clean and annotated version highlighting the changes made.

3. Relevant document/reference to support the changes (where applicable).

4. For non-English text, a declaration from the product registrant that the information in the non-English language(s) provides complete, accurate and unbiased information on the product and is consistent with the English information.



C3 Addition or Replacement of Company or Party Responsible for Batch Release

C 1. Only applicable for batch release.

2. The manufacturer of the drug product remains the same.


2. Proof that the proposed site is appropriately authorised (accredited by the authority) to be responsible for batch release, such as a valid GMP certificate or CPP which covers the GMP certification, where applicable.

3. Official letter from the product owner authorising the company/manufacturer to be responsible for batch release (where applicable).

C4 Change of Batch Size of Drug Substance [where European Pharmacopoeial

Certificate of Suitability (CEP) is not available]

C 1. The change does not affect the reproducibility of the process.

2. Specifications of the drug substance remain unchanged.

3. Refer to MIV-2 C11 if this change resulted in a revision of a CEP.

D 1. A letter of declaration from the product registrant that the specifications of the drug substance have not changed and the reproducibility of the process has not been affected.

2. Comparative batch analysis data with the specification and results (in a comparative tabulated format) on a minimum of one production or pilot batch manufactured to both the currently approved and proposed batch sizes. A letter of commitment to provide batch data on the next two full production batches should be available on request or reported if outside specification (with proposed action).

3. Amended relevant CTD Section S (where applicable).

C5 Change of In-process Controls Applied during Manufacture of Drug Substance

[including tightening and addition of new in-process test and where European


C 1. In-process limits are tightened or new tests are added.

2. The change is not a consequence of any commitment from previous assessments to review the specification limits.

3. The change does not result from unexpected events arising during manufacture, e.g. new unqualified impurity or change in total impurity limits.

4. Any new test method that does not concern a novel non-standard technique or a standard technique used in a novel way.




D 1. A description of the analytical method and summary of validation data must be provided for all new analytical methods (where applicable).

2. Comparative tabulated format of the proposed and current in-process controls and the relevant changes.

3. Comparative batch analysis data of two production batches of the drug substance for all tests in the proposed specification (where applicable).

C6 Minor Change of Manufacturing Process of Drug Substance [where European


C 1. No adverse change in the qualitative and/or quantitative impurity profile which would require further qualification in safety studies.

2. The synthetic route remains the same (for example, intermediates remain the same).

3. Manufacturing process of the drug substance does not use any materials of human/animal origin for which assessment is required for viral safety.

4. Physicochemical characteristics and other relevant properties of the drug substance remain unchanged.

5. Specifications and stability performance of the drug substance remain unchanged.


D 1. Drug Master File (DMF), or relevant updated drug substance (DS) section(s) or equivalent/audit document.

2. Comparative tabulated format of the currently approved and new processes with changes highlighted (where available).

3. For a sterile drug substance, process validation report (where applicable).

4. A letter of declaration from the product registrant stating 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 levels of impurities, which require further safety studies.

5. A letter of declaration from the product registrant stating that the specifications of the drug substance have not changed, or, if there is any change to the specification (for example, tightening), then the texts of the currently approved and proposed specifications should be provided (in a comparative tabulated format where possible).

6. Certificates of analysis for two batches of the drug substance.


8. Batch analysis data (in a comparative tabulated format) of the drug product of at least two batches (pilot/production scale) manufactured with the drug substance according to the currently approved and proposed processes.



C7 Change of Specification of Drug Substance

a) Specification limits are tightened

b) Addition of new test parameter and limits

C 1. This is only applicable for drug substances which are non-compendial and generic drug substances without a European Pharmacopoeial Certificate of Suitability (CEP).


3. Test procedures remain the same or changes in the test procedure are minor.

4. For (b), applicable to non-compendial method only.


6. For widening of specification limits and deletion of test parameter and limits of the drug substance, please refer to MIV-1 B7.

D Specification limits are tightened

1. Technical justification for the change.

2. Comparative tabulated format of the currently approved and revised specification of the drug substance with changes highlighted.

3. Comparative batch analysis data of the drug substance for all tests in the new specification for two pilot or production scale batches.

Addition of new test parameter and limits

In addition to the above documents,

4. Description of any new analytical method and a summary of the validation data.

C8 Change of Test Procedure of Non-compendial Drug Substance

C 1. Results of method validation show that the new test procedure is at least equivalent to the former procedure.


D 1. Description of the analytical methodology, a summary of validation data, and comparative analytical results between the currently approved and proposed test (where applicable).


C9 Change of Shelf-life or Re-test period of Drug Substance

C 1. The stability studies must show compliance with the specification.



2. There is no change in the storage condition.


D 1. Specification of the drug substance.

2. Stability data of the drug substance should be provided on at least two pilot or production scale batches at the requested shelf-life or retest period.

C10 Change of Storage Conditions of Drug Substance

C 1. The stability studies must show compliance with the specification.

2. There is no change in the shelf-life or retest period.


D 1. Specification of the drug substance.

2. Stability data of the drug substance should be provided on at least two pilot or production scale batches at the requested storage condition.

C11 Revision of European Pharmacopoeial Certificate of Suitability (CEP) of Drug

Substance

C 1. Refer to MIV-1 B4 if this change is due to a major change of the manufacturing process of the drug substance.

2. Refer to MIV-1 B8 if this change is due to a widening of the specification limits or deletion of test parameters.


2. If this change is due to a drug substance specification change, a declaration from the applicant that the relevant stability studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

3. Specification of the drug substance (where applicable).

4. Results of batch analysis from the drug substance manufacturer* demonstrating compliance with the Ph. Eur monograph and including additional test/limits listed on the CEP (where applicable).


* If the drug substance manufacturer is CEP-certified and the drug product manufacturer claims

otherwise (USP, JP, In-house etc), data covering S4.1 to S4.5 from the drug product

manufacturer should be submitted.



C12 Change of Batch Size of Non-sterile Drug Product

C 1. The change does not affect the consistency of production.

2. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

3. Release and end-of-shelf-life specifications of the drug product remain unchanged.

4. This is applicable to a change of batch size up to 10-fold compared to the currently registered batch size.

5. For a change of batch size for sterile products, please refer to MIV-1 B9 and for a change of batch size more than 10-fold compared to the currently registered batch size, please refer MIV-1 B10.

D 1. Comparative tabulated format of proposed and current batch manufacturing formula.

2. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed batch size should be provided upon submission.

3. Revised CTD Section P3.1-3.4 (where applicable).


5. Batch analysis data (in a comparative table) of drug product on a minimum of one production batch according to the currently approved and proposed batch sizes and a letter of undertaking to submit batch data on the next full production batch.

6. Stability data as per ASEAN Guideline on Stability Study Of Drug Product and report if any results fall outside of the shelf-life specifications (with proposed action).

C13 Reduction or Removal of Overage

C 1. Changes of previously approved manufacturing overages of the drug substance only.


D 1. Justification for the change.

2. Comparative tabulated format of currently approved and proposed batch manufacturing formula.

3. Certificates of analysis for two batches of the finished product.




C14 Qualitative and/or Quantitative Change of Excipient

a) For immediate release oral dosage forms (as per Level 1, Part III Components and Composition, SUPAC guideline)

b) For other non-critical dosage forms, e.g. oral liquid, external preparation.

C 1. Replacement of an excipient with a comparable excipient of the same functional characteristic (where applicable).

2. The dissolution profile of the proposed product is comparable to that of the currently approved product.

3. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.


5. For a qualitative or quantitative changes of excipient for immediate release (Level 2 and 3 change as per US FDA SUPAC) and modified release oral dosage forms and other critical dosage forms, please refer to MIV-1 B12.


2. A declaration that the new excipient does not interfere with the drug product release and shelf-life specifications test method (where applicable).

3. Justification for the change must be given by appropriate development of pharmaceutics.

4. Comparative tabulated format of the current and revised product formulation with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).

5. Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation as per US FDA SUPAC IR or MR guidelines.

6. Revised batch manufacturing formula.

7. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in product formula should be provided upon submission (where applicable).

8. Revised CTD Section P.3.1-3.4 (where applicable).

9. Specification of the proposed excipient(s).

10. For proposed excipients made from a ruminant source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued from the relevant veterinary authority of the issuing country (where applicable).

11. Release and shelf-life specifications.



12. Batch analysis data (in a comparative tabulated format) of the drug product on at least two production (or one production batch and two pilot) batches according to the currently approved and proposed product formula.


14. Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies.

C15 Quantitative Change in Coating Weight of Tablets or Weight and/or Size of

Capsule Shell for Immediate Release Oral Solid Dosage Form

C 1. The dissolution profile of the proposed product is comparable to that of the current approved product.

2. The product release and end-of-shelf-life specifications of the drug product remain unchanged except for the weight and/or size.

3. For a quantitative change in coating weight of tablets or weight and/or size of capsule shell for modified release oral solid dosage forms please refer to MIV-1 B13.

D 1. Revised drafts of the product label incorporating the proposed change (where applicable).

2. A declaration from the product registrant that the change does not interfere with the drug product release and shelf-life specifications test method.

3. Comparative tabulated format of the current and proposed product and batch manufacturing formula.

4. Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation as per US FDA SUPAC IR or MR guidelines.


6. Stability data as per ASEAN Guideline on Stability Study of Drug Product and report if any results fall outside of the shelf-life specifications (with proposed action). Except for the change in weight and/or size of capsule shell, a letter of declaration from the applicant that the relevant stability studies of the drug product in accordance with ASEAN Guideline on Stability Study of Drug Product have been started will suffice.




C16 Change of Colouring/Flavouring Agent of Product [addition, deletion or

replacement of colourant(s)/flavour(s)]

C 1. Same functional characteristics, no change in dissolution profile for solid oral dosage forms.

2. The proposed colouring/flavouring agents must not have been rejected for pharmaceutical use.

3. The release and shelf-life specifications of the drug product remain unchanged except for the change in colour/flavour.


2. A declaration from the product registrant that the change does not interfere with the drug product release and shelf-life specifications test method.


4. Revised product formulation and batch manufacturing formula.

5. Qualitative and quantitative information of the current and proposed colouring/flavouring agent in a comparative table.

6. For proposed excipients made from a ruminant source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued from the relevant veterinary authority of the issuing country (where applicable).



C17 Deletion of Solvent/Diluent for Drug Product

C 1. The proposed change does not result in any change in the dosage form, regimen, indication or method of administration of the product.


2. Justification for the deletion of the solvent/diluent, including a statement regarding alternative means to obtain the solvent/diluent.

3. Amended relevant CTD Section P (where applicable).

C18 Change of In-process Controls Applied during Manufacture of Drug Product

(including tightening and addition of new in-process test)

C 1. Release and shelf-life specifications of the drug product remain unchanged.



2. The change is not a consequence of any commitment from previous assessments to review the specification limits.

3. The change does not result from unexpected events arising during manufacture, e.g. new unqualified impurity or change in total impurity limits.

4. Any new test method that does not concern a novel non-standard technique or a standard technique used in a novel way.

D 1. Comparative tabulated format of currently approved and proposed in-process controls.

2. A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable).

3. Revised in-process specifications together with justification and relevant process validation data.

4. Comparative batch analysis data of the drug product of at least two production/pilot batches.

C19 Minor Change of Manufacturing Process for Non-sterile Product

C 1. The same currently approved manufacturing site.

2. The overall manufacturing principle remains the same.

3. The change does not cause negative impact on the quality, safety and efficacy of the drug product.

4. The dissolution profile of the proposed product is comparable to that of the currently approved product.


6. For major change in the manufacturing process for the drug product, please refer to MIV-1 B11.

D 1. For solid oral dosage forms, comparative dissolution profile data of at least one representative production batch of the drug product between the currently approved and proposed solid oral dosage forms formulation as per US FDA SUPAC IR or MR guidelines.

2. Description of the new manufacturing process and technical justification for the change.

3. Comparative tabulated format of present and proposed process with changes highlighted.

4. For semi solid and suspension products, validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration should be provided upon submission.

5. Copy of currently approved release and shelf-life specifications. Or alternatively, a copy of the revised release and shelf-life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.



6. Batch analysis data (in a comparative tabulated format) of the drug product on a minimum of one batch manufactured to both the currently approved and the proposed process; batch data on the next two full production batches should be made available upon request.



C20 Change of Specification of Excipient



C 1. Release and end-of-shelf-life specifications of the drug product remain unchanged.


3. Applicable to non-compendial excipients. For compendial excipients, please refer to MIV-2 C44.

D 1. Description of new method and summary of analytical validation (applicable for addition of new parameter).

2. Comparative tabulated format of the current and revised specification of the excipient with changes highlighted.

3. Batch analysis data of the excipient for all tests in the new specification.

C21 Change of Test Procedure for Excipient, including Replacement of an Approved

Test Procedure by a New Test Procedure

C 1. Appropriate method validation studies have been performed in accordance with the ASEAN Guidelines for Validation of Analytical Procedures.

2. Results of method validation show new test procedure to be at least equivalent to the former procedure.

3. There have been no changes of the total impurity limits.

4. Only applicable to the currently approved test parameters.

5. No new unqualified impurities are detected.

6. This applies to a non-compendial excipient.

D 1. Description of the analytical methodology with a comparative tabulation of the changes.



2. For quantitative test change, comparative analytical validation results showing that the current and proposed tests are equivalent.

C22 Change in Source of Empty Hard Capsule

C 1. From TSE-risk material to vegetable-sourced or synthetic empty hard capsules or vice versa.

2. No change in the formulation and manufacturing process of the drug product.

3. Not applicable to a change from a hard capsule to a soft gel.

4. Excipient and finished product release and end of shelf-life specifications remain unchanged.

D 1. A letter of declaration from the manufacturer or the product registrant of the material that it is purely of vegetable, animal or synthetic origin.

2. Technical specifications and composition of the empty hard capsule of the new source.

3. For empty hard capsule made from a ruminant source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued by a competent authority of the issuing country.

4. Comparative dissolution profile data of one batch representative of pilot/production batch of the drug product using the hard capsule between the two sources (where applicable) as per US FDA SUPAC IR or MR guidelines.

5. Certificates of analysis of the empty hard capsule of the proposed new source.


C23 Change of Release and Shelf-life specification of Drug Product



C 1. Applicable to non-compendial method.


3. The test methods remain the same or changes in the test methods are minor.

4. If there are changes to the test procedure, MIV-2 C26 is also applicable.

5. For widening of specification limits and/or deletion of test parameter and limits of the drug product, please refer to MIV-1 B7.

D Specification limits are tightened 1. Technical justification for the change.



2. Comparative tabulated format of the current and revised release and shelf-life specifications of the drug product with changes highlighted.

3. Comparative batch analysis of the drug product for all tests in the new specification of at least two batches.

Addition of new test parameter and limits

In addition to the above documents:

4. Description of any new method and summary of analytical validation data for the non-compendial method.

5. Stability data as per ASEAN Guideline on Stability Study of Drug Product and report if any results fall outside of the shelf-life specifications (with proposed action). (where applicable).

C24 Change of Imprints, Bossing or Other Markings on Tablets or Printing on

Capsules including Addition or Change of Inks Used for Product Marking

C 1. New markings do not cause confusion with other registered products.

2. Any ink proposed must comply to relevant pharmaceutical legislation or of food grade and not a listed banned substance.

3. Release and shelf-life specifications of the drug product remain unchanged except for appearance.

4. Refer to MIV-1 B19 for addition or removal of score/break-line.



3. Details and specifications of the proposed new ink (where applicable).

4. Detailed drawing or written description of the current and proposed imprint/bossing/markings.

5. Certificate of analysis of the ink/printing material (pharmaceutical grade and of food grade) (where applicable).

6. Release and shelf-life specifications of the drug product with the new product description.



C25 Change of Dimensions and/or Shape of Tablets, Capsules, Suppositories or

Pessaries Without Change in Qualitative and Quantitative Composition and Mean

Mass

a) Immediate release oral solid dosage form, suppositories and pessaries

b) Other than immediate release oral solid dosage forms, suppositories and pessaries.

C 1. If appropriate, the dissolution profile of the proposed product is comparable to that of the currently approved product.

2. Release and shelf-life specifications of the drug product remain unchanged except for dimension and/or shape.

D Immediate release oral solid dosage form, suppositories and pessaries 1. Revised drafts of the package insert and labelling incorporating the proposed

variation (where applicable).

2. Detailed drawing or written description of the current and proposed appearance.

3. Comparative dissolution data on at least one pilot/production batch of the currently approved and proposed dimensions.

4. Data on test of content uniformity of the subdivided parts of tablets at release as conformed to compendial requirement should be submitted (only applicable for drug product with score/break-line).


Other than immediate release oral solid dosage forms, suppositories and

pessaries

In addition to the above condition,


C26 Change in Test Procedure of Drug Product (including replacement or addition of

a test procedure)

C 1. Drug product specifications are not adversely affected unless the specifications are tightened.

2. Results of method verification/validation show the new test procedure to be at least equivalent to the former procedure.


D 1. Justification for the proposed change.

2. Comparative tabulated format of the currently approved and proposed release and shelf-life specifications of the drug product.

3. Description of the analytical methodology.



4. Appropriate verification/validation data and comparative analytical results between the currently approved and proposed test.

5. Certificate of analysis of the finished product of two production batches.

C27 Change in Primary Packaging Material for Non-sterile Substance or Product

a) Qualitative and quantitative composition; and/or

b) Type of container; and/or

c) Inclusion of primary packaging material

C 1. The proposed packaging material must be at least equivalent to or better than the approved material in respect of its relevant properties.

2. The change only concerns the same packaging type (for example from blister to blister).

3. For any change of the container closure system that is in immediate contact with

the drug substance and product.

4. Release and end-of-shelf-life specifications of the drug substance or product remain unchanged.

5. For a change in the primary packaging material for a sterile drug substance or product, please refer to MIV-1 B14.

D 1. Revised drafts of the package insert incorporating the proposed variation (where applicable).

2. Justification for the change in packaging material and appropriate scientific studies on the new packaging.

3. For semi-solid and liquid dosage forms, proof must be provided that no interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack).

4. Comparative tabulated format of the currently approved and proposed specifications of the primary packaging material (where applicable).


C28 Addition or Replacement of Manufacturer for Secondary Packaging

C None


2. Proof that the proposed site is appropriately authorised (accredited by the authority) for the packaging activity concerned, such as a valid GMP certificate and/or a CPP



which covers the GMP certification. (Note: GMP Conformity Assessment is required if the proposed site is not currently registered with HSA.)

3. Official letter from the product owner authorising the new manufacturer or packager to perform secondary packaging (where applicable).

C29 Change of Pack Size/Fill Volume and/or Change of Shape or Dimension of

Container or Closure for Non-sterile Product

C 1. The change only concerns the same packaging type and material.

2. The new size is consistent with the dosage regimen and duration of use as approved in the package insert.

3. Change in the dimension of the primary packaging material (where applicable).


5. For change of pack size/fill volume and/or change of shape or dimension of container or closure for a sterile solid and liquid drug product, please refer to MIV-1 B15.


2. Justification for the proposed pack size.


C30 Change of Outer Carton Pack Sizes for Drug Product

C 1. Primary packaging materials remain unchanged.

2. No other changes except for the change of outer carton pack sizes for a drug product.

3. The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved product labelling.


2. A letter of declaration from the product registrant stating that there are no other changes except for the change of outer carton pack sizes for a drug product.



C31 Change in Any Part of (Primary) Packaging Material Not in Contact with Finished

Product Formulation, such as Colour of Flip-off Caps, Colour Code Rings on

Ampoules, Change of Needle Shield (different plastic used)

C 1. The change does not concern a part of the packaging material which affects the delivery, use, safety or stability of the finished product.

D 1. Amendment of the relevant section(s) of the dossier (presented in the CTD format), including revised product labelling as appropriate.

C32 Addition or Replacement of Measuring Device for Oral Liquid Dosage Forms and

Other Dosage Forms

C 1. The size and, where applicable, the accuracy of the proposed measuring device must be compatible with the approved posology.

2. The new device is compatible with the drug product.


2. Description of the device (including a drawing; where applicable).

3. The composition of the device material. Where applicable, the materials should comply with the pharmacopoeia.

4. Justification that the size and accuracy of the device are adequate for the posology as approved in the product labelling.

C33 Addition or Replacement of Site Responsible for Quality Control (QC) Testing of

Drug Product

C 1. The manufacturer and primary packager of the drug product remains the same.

2. Method transfer from the currently approved to the proposed site or test laboratory has been successfully completed.

D 1. Declaration from the drug product manufacturer / product owner on the following:

a) The change does not affect the release and shelf life specifications of the drug product.

b) The tests used by the proposed QC testing site are equivalent to the registered methods.

c) List of tests used by the proposed QC testing site with indication if the method suitability / transfer / validation has been completed for each test.



C34 Change in Supplier of Animal-derived Material

C 1. For animal-derived material of mammalian or avian origin used as an excipient or active ingredient in the drug product, or as an adjuvant.

2. There is no change in the animal species from which the animal-derived material is obtained from.

3. Animal-derived materials from other species (e.g. insects and fish) are exempted from this variation.

4. For change in source of empty hard capsule, refer to MIV-2 C22.

D 1. Information on all countries which the animal was sourced from*.

2. Declaration on the nature of the animal tissue and/or fluid used.

3. Certificate of analysis for the animal-derived material used, stating the name and address of the supplier.

4. Relevant information to demonstrate that the manufacturing process is capable of inactivating adventitious agents, where applicable.

5. For materials derived from TSE-relevant animals (i.e. cattle, sheep, goat, deer, elk, non-human primates): a) A valid TSE Risk evaluation CEP, OR

b) i. Description of the tissue/organ/fluid-collection procedures and measures in place to avoid cross-contamination;

ii. Details of the risk factors associated with the route of administration and maximum therapeutic dosage of the product; and,

iii. Relevant information demonstrating that the manufacturing process is capable of inactivating TSE agents.

* not required for animal derived products from milk and certain milk derivatives such as lactose

C35 Change in Species of Animal-derived Material

C 1. For a change in species of animal-derived material used a) at any stage in the manufacture of the drug substance and/or drug product (e.g.

from pig to cow);

b) as an excipient or active substance (e.g. bovine gelatine to porcine gelatine) of the drug product; or

c) as an adjuvant.

2. This variation includes ALL species of animals.

D 1. Information on all countries which the animal was sourced from*.

2. Declaration on the nature of the animal tissue and/or fluid used.

3. Certificate of analysis for the animal-derived material used, stating the name and

address of the supplier for mammalian and avian materials.



4. Identification of new adventitious agents, where applicable.

5. Relevant information to demonstrate that the manufacturing process is capable of

inactivating new adventitious agents, where applicable

6. For materials derived from TSE-relevant animals (i.e. cattle, sheep, goat, deer, elk,

non-human primates):

a) A valid TSE Risk evaluation CEP, OR

b) i. Description of the tissue/organ/fluid-collection procedures and measures in place to avoid cross-contamination.

ii. Details of the risk factors associated with the route of administration and

maximum therapeutic dosage of the product; and,

iii. Relevant information demonstrating that the manufacturing process is

capable of inactivating TSE agents.

* not required for animal derived products from milk and certain milk derivatives such as lactose

C36 Change in Name and/or Address (for example: postal code, street name) of

Product registrant

C 1. The name change refers to the renaming of a company or organization.

2. The change does not include transfer of marketing authorisation or product ownership to another company.


2. A letter by the product owner authorising the new name of the product registrant to hold the product registration, OR, a declaration from the product owner/product registrant that the change does not involve the legal transfer of ownership to another company.

3. Official document from the relevant authority confirming the change with the new name and/or address.

C37 Change of Product Owner

C 1. The product registrant remains the same.

2. The manufacturing site remains the same.


2. A declaration on the transfer of ownership between the old product owner and new owner.

3. An official letter from the new product owner declaring the change and authorising the local registrant to be responsible for the product registration.



4. If the new product owner is not the manufacturer of the drug product, an official letter by the new product owner authorising the manufacturer to manufacture the drug product on its behalf.

C38 Change in Ownership of Manufacturer

C 1. The manufacturing site remains unchanged.

2. No other changes except for the change in ownership of the manufacturer.


2. A letter of justification on the transfer of ownership, such as a valid GMP certificate.

3. An official letter stating the transfer of ownership from the old manufacturer to the new manufacturer (where applicable).

4. In case of a contract manufacturer, an official letter from the product owner declaring the change and authorising the new manufacturer to manufacture the drug product(s) on its behalf.

C39 Change of Name or Address (for example: postal code, street name) of

Manufacturer of Drug Product

C 1. The manufacturing site remains the same.

2. No other changes except for the change of the name and/or address of a manufacturer of the drug product.

3. Not applicable to the case in which it involves a change in ownership of the manufacturer. For a change in ownership of manufacturer, please refer to MIV-2 C38.


2. A valid GMP certificate, a CPP which covers the GMP certification or an official document from a relevant authority confirming the new name and/or address.

3. An official letter from product owner authorising the manufacturer with the new name/address to manufacture the drug product.

C40 Change of Name or Address (for example: postal code, street name) of Company

or Manufacturer Responsible for Batch Release

C 1. The manufacturer of the drug product remains the same.

2. The batch release site remains the same.



3. Not applicable to the case in which it involves a change in ownership of the manufacturer. For a change in ownership of manufacturer, please refer to MIV-2 C38.


2. A valid GMP certificate, a CPP which covers the GMP certification or an official document from a relevant authority confirming the new name and/or address (where applicable).

3. An official letter from the product owner authorising the company/manufacturer with the new name/address that is responsible for batch release.

4. A declaration from the product registrant that the change does not involve a change of batch release site.

C41 Change of Name and/or Address (for example: postal code, street name) of

Manufacturer of Drug Substance

C 1. The manufacturing site of the drug substance remains unchanged.

2. No other changes except for the change of the name and/or address of a manufacturer of the drug substance.

D 1. Updated information of the manufacturer of the drug substance.

2. An official document/evidence when required.

C42 Withdrawal/Deletion of Alternative Manufacturer(s) for Drug Substance and/or

Drug Product and/or Packager

C 1. An alternative manufacturer is registered.

D 2. Reason for withdrawal/deletion.

C43 Renewal of European Pharmacopoeial Certificate of Suitability (CEP)

C 1. Only applicable if the renewal of a CEP does not involve any variation.




C44 Change of Release and Shelf-life specification of Drug Product and/or Drug

Substance and/or Excipient to Comply with Latest Compendium

C 1. Applicable to compendial specifications only.

2. Change is made to comply with an update of the relevant monograph of the compendium or from one recognised pharmacopoeia to another.

3. Pharmacopoeia recognised by HSA: United States Pharmacopeia, European Pharmacopoeia, British Pharmacopoeia and Japanese Pharmacopoeia.

D 1. Revised release and shelf-life specifications.

2. Tabulation of the current and revised release and shelf-life specifications of the drug product and/or drug substance and/or excipient with changes highlighted.

3. Batch analysis of the drug product and/or drug substance and/or excipient for all tests in the new specification of at least two batches.

4. For changes in excipients and drug substances, a declaration that the change has no impact on the manufacturing process and quality of the drug product.

C45 Deletion of Pack Size for Product

C 1. The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved product labelling.

2. For addition of pack size for sterile and non-sterile products, please refer to MIV-1 B15 and MIV-2 C29 respectively. For change in the outer carton pack size, please refer to MIV-2 C30.


2. Reason for the deletion.

C46 Change of Batch Numbering System

C 1. The manufacturing site remains the same.

D 1. Description of the revised batch numbering system.

2. An official letter stating the commencement date of the change.