appendix 14_guideline on miv applications for chemical drugs

7/29/2019 Appendix 14_Guideline on MIV Applications for Chemical Drugs

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

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 14 - Page 1 of 25

APPENDIX 14 GUIDELINE ON MINOR VARIATION APPLICATIONS (MIV-1 &MIV-2) FOR CHEMICAL DRUGS

TABLE OF CONTENTS

PART A: INTRODUCTION.............................................................................................. 3

PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION.................................... 5

B1 Change or Inclusion of Manufacturing Site(s) of Drug Substance....................... 5

B2 Major Change of Manufacturing Process of Drug Substance ............................. 5

B3 Change of Specification of Drug Substance or Drug Product ............................. 6

B4 Change or Inclusion of Manufacturing Site(s) of Drug Product ........................... 6

B5 Change of Manufacturing Process and/or Test Methods of Drug Product .......... 7

B6 Change or Inclusion of Score/Break Line of Tablet ............................................. 7

B7 Change of Batch Size of Drug Product................................................................ 7

B8 Change or Inclusion of Primary Packaging Site(s) .............................................. 8

B9 Change or Inclusion of Container Closure System of Drug Product ................... 8

B10 Change of Shelf Life or Storage Condition of Drug Product................................ 8

B11 Change of Shelf Life After Reconstitution or First Opening................................. 9

B12 Change of Pack Size (Volume) or Inclusion of New Pack Size for Sterile DrugProduct ................................................................................................................ 9

B13 Change of Product Labelling ............................................................................... 9

PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION.................................. 10

C1 Change of Contact Person ................................................................................ 10

C2 Change of Product Name.................................................................................. 10

C3 Change of Product Owner ................................................................................. 11

C4 Change of Batch Numbering System ................................................................ 11

C5 Renaming (e.g. street name, postal code) of Manufacturing Site of DrugSubstance.......................................................................................................... 11

C6 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Product

........................................................................................................................... 11C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product,

Packager or Batch Releaser) ............................................................................ 12

C8 Deletion of Pack Size for Drug Product ............................................................. 12

C9 Minor Change of Manufacturing Process of Drug Substance ........................... 12

C10 Change of Batch Size of Drug Substance......................................................... 13

C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance....... 13

C12 Change of Test Procedure of Drug Substance.................................................. 13

C13 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s)of Drug Substance............................................................................................. 14

C14 Extension of Shelf Life or Retest Period of Drug Substance ............................. 14


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C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing onCapsules Including Addition or Change of Inks Used for Product Marking....... 14

C16 Change of Dimensions of Tablet, Capsule, Suppository or Pessary WithoutChange in Qualitative and Quantitative Composition and Mean Mass ............. 15

C17 Minor Qualitative Change of Excipient .............................................................. 15

C18 Minor Quantitative Change or Deletion of Existing Excipient ............................ 16

C19 Change of Colouring System of Drug Product (Addition, Deletion orReplacement of Colourant(s)) ........................................................................... 17

C20 Change of Flavouring System of Drug Product (Addition, Deletion orReplacement of Flavourant(s)).......................................................................... 17

C21 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell .. 18

C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging .......... 18

C23 Change or Inclusion of Site(s) Responsible for Batch Release......................... 18

C24 Change of Batch Size of Drug Product.............................................................. 19

C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product 19

C26 Minor Change of Manufacturing Process of Drug Product ................................ 20

C27 Change to Comply with Pharmacopoeia for Excipient ...................................... 20

C28 Change of Test Procedure for Excipient............................................................ 21

C29 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s)of Excipient........................................................................................................ 21

C30 Change of Test Procedure of Drug Product ...................................................... 21

C31 Tightening of Release and Shelf Life Specifications or Addition of New TestParameter(s) and Limit(s) of Drug Product........................................................ 22

C32 Minor Change or Inclusion of Container Closure System of Drug Product ....... 22

C33 Change in Shape of Container Closure System................................................ 22C34 Change or Inclusion of Pack Size for Drug Product .......................................... 23

C35 Addition or Replacement of Measuring Device for Oral Liquid and OtherDosage Forms................................................................................................... 23

C36 Change of Product Labelling due to Safety Updates......................................... 24

C37 Change of Product Labelling Relating to: .......................................................... 24

C38 Change of Product Labelling of Language(s) Other Than English.................... 24


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PART A: INTRODUCTION

This document describes the requirements of a Minor Variation Application (MIV)submitted for an existing registered chemical drug product in Singapore. Applicantsshould 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 approvalMIV-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, theMIV should be categorized as an MIV-1. If a proposed MIV-2 does not meet itsspecified conditions, then the MIV must be categorized as an MIV-1 with supportingdocuments. 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 ofWestern Drug Product form in PRISM.

Applicants should fully disclose all proposed change(s) in Section 0 Licence Summaryunder Section 0.4 Amendment Summary, and in the Table of Amendment Details,downloaded via the link indicated in Section 0.5 Amendment Details. Any undisclosedvariation(s) embedded in the submitted data, or any follow-on changes not specificallyrequested by HSA, will not be considered for evaluation.

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


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Documentary Requirements

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

Hard Copy E-CopyPRISM application form Yes N/ATable of Contents Yes Optional*

Checklist for MIV applications Yes Optional*Table of Amendment Details Yes PRISMMIV-specific Supporting documents

- Administrative (Module 1/Part 1)

- Other supporting documents

Yes

Optional PRISMPRISM/CDCurrent and proposed product l abelling (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 Checklistfor Minor Variation Applications for Chemical Drugs is located in Appendix14A of this guidance document. This Checklist serves as a guide for submitting therequired documents relevant to each proposed MIV. When submitting the Checklist, thefollowing should be included:

A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should bechecked 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 nameand signature.

The Table of Amendment Details concisely describes the proposed MIV(s). The followinginformation 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 PartB or Part C of this document respectively. For an MIV application with mult iple relatedor unrelated variations, all of the supporting documents for each individualvariation 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 forassessment. Applicants are responsible for ensuring that all necessary validations wereconducted to demonstrate that the change does not adversely affect the quality, safety orefficacy of the product concerned. HSA reserves the right to request additionalinformation if deemed appropriate.

NOTE: For unstable drug substances or critical dosage forms, whenever stability data isrequired, a minimum of three batches (at least two pilot scale or larger) must be submitted.


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PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION

B1 Change or Inclus ion of Manufactur ing Site(s) of Drug Substance

Supporting Documents

1) CTD Section S, European Pharmacopoeia Certificate of Suitability (CEP) for thedrug substance, or both the open and closed portions of the Drug Master File;

2) Tabulation of the differences compared with the registered manufactureinformation (if applicable);

3) Batch analysis data (in a comparative tabular format) for at least two batches(minimum pilot scale) of the drug substance from the current and proposedmanufacturers/sites;

4) A letter of commitment to conduct the appropriate stability study for the drug

product manufactured with the drug substance from the proposed manufacturer.

B2 Major Change of Manufacturing Process of Drug Substance

For any changes not covered by MIV2 C9 (e.g. alternative synthetic route)


1) Relevant CTD section S;

2) Tabulation of the current and proposed process with changes highlighted;

3) Batch analysis data (in a comparative table) of at least two batches (pilot scale orproduction scale) manufactured according to the currently approved and proposedprocess;

4) A declaration from the applicant that no new impurities have been introduced at orabove the accepted threshold for qualification of impurities or that there is noincrease in the level of impurities, which require further safety studies;

5) If any potential new impurities are detectable at an acceptable limit of detection,appropriate evidence must be provided;

6) A declaration from the applicant that the specification of the drug substance hasnot changed or if there is any change to the specification (i.e. tightening), the textsof the current and proposed specifications should be provided (in a comparativetable where possible);

7) Relevant stability studies of the drug substance in accordance with the relevantguidelines should be provided;

8) A letter of commitment to conduct the appropriate stability study for the drugproduct manufactured with the drug substance from the new manufacturingprocess, and report if any results fall outside shelf life specification (with proposedaction).


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B3 Change of Specification of Drug Substance or Drug Product

For any changes not covered by MIV2 C13 and C31

Supporting Documents1) Scientific and/or historical data used to support the change;

2) Currently registered version of the release and/or shelf life specifications with theproposed change(s) clearly highlighted, underscored, or otherwise indicated (in acomparative table);

3) Release and shelf-life specifications;

4) Batch analysis for all tests in the new specification;

5) Description of any new analytical method and summary of the validation data, ifapplicable;

6) Results of appropriate real time stability studies of at least two production scale

batches of the drug product with undertaking to continue the stability studies up tillthe proposed shelf life and to report if any results fall outside shelf lifespecification.

B4 Change or Inclus ion of Manufactur ing Site(s) of Drug Product


1) Proof that the proposed site is appropriately authorised for thepharmaceutical form concerned: a GMP certificate;

2) Official letter authorising the proposed site to manufacture the product;3) Product formula;

4) Specification of drug substance;

5) Release and shelf life specifications of drug product;

6) Batch numbering system;

7) Appropriate stability data of at least 6 months on 2 batches (pilot/production) withundertaking to conduct on-going stability study and report if any results fall outsideshelf life specification (with proposed action);

8) Batch analysis data on a minimum two production batches (or one productionbatch and two pilot batches) simulating the production process and comparativedata on the last 3 batches from the current site; batch analysis data on the next 2full production batches should be available upon request or reported if outsiderelease and shelf lifespecifications (with proposed action);

9) For sterile or parenteral products, validation data of the manufacturing processand sterilization process at the proposed site for products should be provided.

10) Official letter declaring that the formulation, drug substance source & specification,manufacturing process, analytical test methods, release and shelf lifespecifications have not changed.


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B5 Change of Manufacturing Process and/or Test Methods of Drug Product

For any change in the procedure of the current registered manufacturing process atany stage during manufacture drug product not covered by MIV2 C25 or C26.


1) Release and shelf life specifications of drug product;


3) Batch analysis data of at least two production batches (or one production batchand two pilot batches) manufactured according to currently registered andproposed processes;

4) For solid dosage forms, comparative dissolution profile data of at least onerepresentative pilot/production batch of the drug product of the currently registered

and proposed processes;

5) Justification for not submitting a new bioequivalence study according to thecurrent Bioavailability and Bioequivalence guidance;

6) Tabulation of the changes and differences;

7) Validation scheme and data on manufacturing process and/or analytical method(where applicable).

B6 Change or Inclus ion of Score/Break Line of Tablet


1) Detailed drawing or written description of the current and proposed tablet;

2) Justification to support the change or inclusion of score/break line;

3) Data on uniformity of content of the subdivided parts of the tablets;

4) Official letter of commitment to inform users of the relevant changes, and that thecurrent product stocks will be exhausted before the new product is marketed;

5) Current and proposed release and shelf life specifications.

B7 Change of Batch Size of Drug Product

For any change in the scale of the current registered manufacturing process at anystage during manufacture drug product not covered by MIV2 C24.


1) Amended relevant CTD Section P.3;


3) Batch analysis data (in a comparative table) of at least two production batches (orone production batch and two pilot batches) manufactured according to currentlyregistered and proposed batch sizes;


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4) Release and shelf life specifications of the drug product;

5) For solid dosage forms, comparative dissolution profile data of at least onerepresentative pilot/production batch of the drug product of the currently registeredand proposed processes;

6) Validation scheme and data on proposed manufacturing process and/or analytical

method.

B8 Change or Inclusion of Primary Packaging Site(s)


1) Proof that the proposed site is appropriately authorised for the packaging activityconcerned: GMP certificate;

2) Official letter authorising the proposed site to package the product and stating thetypes of activity performed by the packager;

3) Validation data on manufacturing process (for suspensions and emulsions);

4) A declaration from the applicant that the appropriate stability studies have beenstarted on at least two pilot or production scale batches and that the relevantstability studies will be finalised; data should be provided only if outside shelf lifespecification (with proposed action) or when requested.

B9 Change or Inclus ion of Container Closure System of Drug Product

For any changes not covered by MIV2 C32


1) Amended section P.7 and technical information;

2) Appropriate stability study of at least 6 months on 2 production batches of theproposed primary packaging material with undertaking to continue the stabilitystudies up till the proposed shelf life and report if any results fall outside shelf lifespecification (with proposed action) or when requested;

3) A declaration from the applicant that the release and shelf lifespecifications of thedrug product are not affected if applicable;

4) For sterile products, validation data of the relevant manufacturing and sterilizationprocess.

B10 Change of Shelf Life or Storage Condition of Drug Product


1) Results of appropriate real time stability studies of at least two production scalebatches of the drug product in the authorised packaging material covering theduration of the proposed/approved shelf life;

2) A declaration from the applicant that the release and shelf lifespecifications of thedrug product are not affected if applicable.


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B11 Change of Shelf Life After Reconst itut ion or First Opening


1) Results of appropriate real time stability studies of at least two production scale

batches of the product after reconstitution or first opening in the authorisedpackaging material covering the duration of the proposed shelf life;

2) Results of appropriate microbiological testing if applicable;


B12 Change of Pack Size (Volume) or Inclus ion of New Pack Size for Sterile DrugProduct

Supporting Documents1) Justification that the proposed pack size is consistent with the dosage regimen

and duration of use as is approved in the package insert;

2) Validation data of the manufacturing process, sterilization and container closuresystem (where applicable);

3) Results of the stability study for at least 6 months on 2 production batches of theproposed pack size with undertaking to continue the stability studies up till theproposed shelf life and to report if any results fall outside shelf life specification(with proposed action);


B13 Change of Product Labelling

Conditions

- The change is not a major variation (MAV);

- For safety-related changes of product labelling, refer to MIV-2 C36


1) Justification and clinical documents to support proposed changes.


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PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION

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

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

C1 Change of Contact Person

Condition

- The product licence holder remains the same.


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

C2 Change of Product Name

Conditions

- There is no change to the product (formulation, release and shelf lifespecifications,manufacturing source and process) except the product name change;

- No confusion with another drug product either when spoken or written;

- New name does not imply (a) greater safety or efficacy than supported by clinicaldata, (b) superiority over a similar product in Singapore, (c) imply a therapeuticuse for the product, or (d) the presence of substance(s) not present in the product.


1) Official letter authorising the change of product name;

2) A declaration from the applicant that there is no change to the product exceptname;

3) Official letter of commitment to inform users of the relevant changes, and that thecurrent product stocks will be exhausted before the product labelled with the newname is marketed;

4) CPP.

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


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C3 Change of Product Owner

Condition

- The product licence holder remains the same.


1) Official letter from the new product owner declaring the change, and authorisingthe 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 officialletter by the new product owner authorising the manufacturer to manufacture thedrug product on its behalf;

C4 Change of Batch Numbering System

Document Required

1) Description of batch number system;

2) Official letter stating the commencement date of the change

C5 Renaming (e.g. street name, postal code) of Manufactur ing Site of DrugSubstance

Condition- The manufacturing site of the drug substance remains at the same physical

location.


1) Updated information of the manufacturer of the drug substance;

2) A declaration from the applicant that manufacturing site remains the same andthat the renaming does not involve changes of the manufacturing process and/orquality of the product.

C6 Renaming (e.g. street name, postal code) of Manufactur ing Site of DrugProduct

Condition

- The manufacturing site remains at the same physical location.


1) Official letter authorising the manufacturer with new name/address to manufacturethe drug product (not required if the manufacturer is the product owner);

2) GMP certificate with new name or address;


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3) A declaration from the applicant that the manufacturing site remains the same,and that the renaming does not involve changes of the manufacturing processand/or quality of the product;

C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product,Packager or Batch Releaser)


1) Reason for withdrawal/deletion

C8 Deletion of Pack Size for Drug Product


1) Reason for deletion.

C9 Minor Change of Manufacturing Process of Drug Substance

Conditions

- The synthetic route remains the same;

- Specification of the drug substance remains the same;

- No change in the physical properties;- No new impurities or change in level of impurities which would require further

qualifications in safety studies.


1) Relevant CTD section S;

2) Tabulation of the current and proposed process with changes highlighted;

3) Batch analysis data (in a comparative table) of at least two batches (pilot scale orproduction scale) manufactured according to the currently approved and proposedprocess;

4) A declaration from the applicant that no new impurities have been introduced at orabove the accepted threshold for qualification of impurities or that there is noincrease in the level of impurities, which require further safety studies;

5) A declaration from the applicant that the specification of the drug substance hasnot changed or if there is any change to the specification (i.e. tightening), the textsof the current and proposed specifications should be provided (in a comparativetable where possible);

6) A declaration from the applicant that the relevant stability studies of the drugsubstance in accordance with the relevant guidelines have been started and thatthe relevant stability studies will be finalised; data should be provided only ifoutside specification (with proposed action).


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C10 Change of Batch Size of Drug Substance

Condition

- The change does not affect the reproducibility of the process.


1) Amended relevant CTD Section S;

2) Batch analysis data (in a comparative table) on a minimum of one productionbatch manufactured to both the currently approved and the proposed batch sizes.Batch data on the next 2 full production batches should be available on request orreported if outside specification (with proposed action);

3) Specification of the drug substance.

C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance

Pharmacopoeias accepted by HSA are EP, USP, BP, and JP.

Conditions

- Change is made exclusively to comply with an update of the relevant monograph ofthe pharmacopoeia;

- Excludes change from one accepted pharmacopoeia to another.


1) Tabulation of the current and revised specifications with changes highlighted;

2) Revised specification of the drug substance;

3) Batch analysis of the drug substance for all tests in the new specification

C12 Change of Test Procedure of Drug Substance

Condition

- Results of method validation show new test procedure to be at least equivalent to

the former procedure.


1) Description of the analytical methodology, a summary of validation data, andcomparative analytical results between the current test and the proposed one, ifappropriate;

2) Specification of the drug substance;

3) A declaration from the applicant that the specification of the drug substance hasnot changed.


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C13 Tightening of Specification or Addition of New Test Parameter(s) and Limi t(s)of Drug Substance

Condition

- New test method does not concern a novel non-standard technique or a standardtechnique used in a novel way


1) Tabulation of the current and revised specification of drug substance with changeshighlighted;

2) Revised specification of drug substance;

3) Batch analysis of the drug substance for all tests in the new specification.

4) Description of any new analytical method and summary of the validation data, ifapplicable.

C14 Extension of Shelf Life or Retest Period of Drug Substance

Condition

- The studies must show compliance with specification


1) Stability data of the drug substance should be presented on at least two pilot orproduction scale batches of the requested shelf life or retest period;

2) Specification of the drug substance.

C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing onCapsules Including Addi tion or Change of Inks Used for Product Marking

Conditions

- New markings do not cause confusion with other tablets or capsules;

- The inks have not been rejected for pharmaceutical use;

- Release and shelf life specifications of the drug product have not changed (exceptfor appearance).

- For changes involving the score/break line, refer to MIV1 B6.


1) Details of the proposed new inks (where applicable);

2) Detailed drawing or written description of the current and proposedimprint/bossing/markings/ink;

3) Official letter of commitment to inform users of the relevant changes, and that thecurrent product stocks will be exhausted before the product labelled with the newname is marketed;

4) A declaration from the applicant that the release and shelf life specifications of theproduct have not changed (except for appearance).


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C16 Change of Dimensions of Tablet, Capsule, Supposi tory or Pessary WithoutChange in Qualitative and Quantitative Composition and Mean Mass

C16.1 Conventional dosage form, suppository and pessary

C16.2 Criti cal dosage form and scored tablet

Conditions

- No change in dissolution profile;

- Release and shelf life specifications of the drug product have not changed (exceptfor dimensions).


C16.1 Conventional dosage form, suppository and pessary

1) Detailed drawing or written description of the current and proposed appearance;


3) Revised drafts of the package insert and labelling incorporating the proposedvariation (where applicable).

C16.2 Critical dosage form and scored tablet

4) In addition to C16.1 Documents 1 to 3;

5) Comparative dissolution data on at least one pilot/production batch of the currentand proposed dimensions in accordance with HSAs drug registration guidelines;

6) Justification for not submitting a new bioequivalence study according to thecurrent 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 atthe end of shelf life, data should be provided only if outside the release and shelflifespecifications (with proposed action).

C17 Minor Qualitative Change of Excipient

Conditions

- Replacement of an excipient with a comparable excipient;

- Same functional characteristics of the excipient;

- No change in dissolution profile for solid dosage forms;

- The release and shelf life specifications of the drug product have not changed (orhave tightened), except for the replacement of the excipients;

- For change of preservatives, refer to MIV B3;

- For changes affecting release and shelf life specification, refer to MIV1 B3.


1) Justification for the change of excipients must be given by appropriatedevelopment pharmaceutics (including stability aspect and antimicrobialpreservation where appropriate);



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3) Tabulation of the current and revised product formulation with changeshighlighted;

4) Revised product formulation;

5) Release and shelf life specifications and batch analysis of the drug product;

6) Specifications of new excipient;7) Comparative dissolution profile data of at least one representative pilot/production

batch of the drug product in the new and old composition for solid dosage forms inaccordance with HSAs drug registration guidelines;

8) A declaration from the applicant that the new excipient does not interfere with thedrug product release and shelf life specifications test method;

9) A declaration from the applicant that the release and shelf life specifications of thedrug product have not changed;

10) A declaration from the applicant that the relevant stability studies in accordancewith the relevant guidelines have been started (on at least two pilot scale orproduction scale batches) and that the relevant stability studies will be finalised;

data should be provided only if outside the shelf life specification (with proposedaction) or when requested.

C18 Minor Quantitative Change or Deletion of Existing Excipient

Conditions

- Total quantitative change within 5% (w/w), inclusive of the following:

Disintegrant: Starch ( 3%), other ( 1%);

Binder ( 0.5%);

Lubricant: Ca or Mg Stearate ( 0.25%), other ( 1%);

Glidant: Talc ( 1%), other ( 0.1%); and/or,

Film Coat ( 1%);

- No change in the dissolution profile for solid dosage forms;

- Release and shelf life specifications of the drug product have not changed.

- For changes affecting release and shelf life specification, refer to MIV1 B3.


1) Justification for the change must be given by appropriate development

pharmaceutics (including stability aspect and antimicrobial preservation whereappropriate);

2) Comparative dissolution profile data of at least one representative pilot/productionbatch of the drug product in the new and old composition for solid dosage forms inaccordance with HSAs drug registration guidelines;


4) Tabulation of the current and revised product formulation with changeshighlighted;


6) Release and shelf lifespecifications and batch analysis of drug product;

7) A declaration from the applicant that the change of excipient does not interferewith the drug product release and shelf life specifications test method;


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8) A declaration from the applicant that the appropriate stability studies have beenstarted (on at least two pilot scale or production scale batches) and that therelevant stability studies will be finalised; data should be provided only if outsidethe shelf life specification (with proposed action) or when requested.

C19 Change of Colouring System of Drug Product (Addition, Deletion orReplacement of Colourant(s))

Conditions

- Same functional characteristics, no change in dissolution profile for solid dosageforms;

- The colouring system must not have been rejected for pharmaceutical use;

- The release and shelf life specifications of the drug product have not changed,except for the change in appearance/colour.


1) Qualitative and quantitative information of the colourant;



4) Official letter of commitment to inform users of the relevant changes, and that thecurrent product stocks will be exhausted before the product with the proposedvariation is marketed;

5) A declaration from the applicant that the change in the colouring system does notinterfere with the drug product release and shelf lifespecifications test methods;

6) A declaration from the applicant that the release and shelf life specifications havenot changed (except for appearance);

7) A declaration from the applicant that the relevant stability studies in accordancewith the relevant guidelines have been started (on at least two pilot scale orproduction scale batches) and that the relevant stability studies will be finalised;data should be provided only if outside the shelf life specification (with proposedaction) or when requested.

C20 Change of Flavouring System of Drug Product (Addition, Deletion o r

Replacement of Flavourant(s))

Conditions

- Proposed flavour must not have been rejected for pharmaceutical use;

- The release and shelf life specifications of the drug product have not changed,except for the change in flavour.


1) Qualitative and quantitative information of the flavouriant;




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4) Official letter of commitment to inform users of the relevant changes, and that thecurrent product stocks will be exhausted before the product with the proposedvariation is marketed;

5) A declaration from the applicant that the change of flavour(s) does not interferewith the drug product release and shelf lifespecifications test method;

6) A declaration from the applicant that the release and shelf life specifications of theproduct have not changed (except for flavour);

7) A declaration from the applicant that the relevant stability studies in accordancewith the relevant guidelines have been started (on at least two pilot scale orproduction scale batches) and that the relevant stability studies will be finalised;data should be provided only if outside the shelf life specification (with proposedaction) or when requested.

C21 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell

Conditions

- No change in dissolution profile;

- The product release and shelf life specifications have only been updated in respectof weight and dimensions, if applicable.


1) Comparative dissolution profile data of at least one pilot/production batch of thedrug product in the new and old composition in accordance with HSAs drugregistration guidelines (for modified release products, to provide in vitro data

which has been correlated with in vivo data);2) Justification for not submitting a new bioequivalence study according to the

current Bioavailability and Bioequivalence guidance;

3) Revised release and shelf lifespecifications of the drug product;

4) A declaration from the applicant that the change does not interfere with the drugproduct specifications test method;

5) A declaration from the applicant that the release and shelf life specifications of thedrug product have not changed (except for average weight).

C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging


1) Official letter authorising the proposed manufacturer to perform secondarypackaging;

2) Evidence (i.e. GMP certificate) demonstrating that the proposed site isappropriately authorised for the packaging activity concerned.

C23 Change or Inclusion of Site(s) Responsible for Batch Release

Condition

- The manufacturer of the drug product remains the same;


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1) Official letter authorising the company/manufacturer with new name/addressresponsible for batch release;

2) GMP certificate with name or address of the new site (where appropriate);

C24 Change of Batch Size of Drug Product

Conditions

- The change does not affect consistency of production;

- The change only applies to standard immediate release oral dosage forms and tonon-sterile liquid forms, refer to MIV1 B9;

- Up to a 10-fold change when compared to the batch size currently registered with

HSA;- Validation scheme is available or validation of the manufacture has been

successfully carried out according to protocol with at least three batches at theproposed new batch size in accordance with the relevant guidelines.


1) Amended relevant CTD Section P.3;

2) Batch analysis data (in a comparative table) on a minimum of one productionbatch manufactured to both the currently approved and the proposed batch sizes.Batch data on the next 2 full production batches should be available on request orreported if outside the shelf life specification (with proposed action);


4) Official letter of commitment to put the product manufactured according to theproposed batch size under stability studies in accordance with relevant stabilityguidelines.

C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product

Condition

- In-process limits are tightened or addition of new tests.


1) A description of the analytical methodology and summary of validation data mustbe provided for all new analytical methods (where applicable);

2) Tabulation of the in-process controls and the relevant changes;

3) Batch analysis data of one production batch of the drug product for all tests in theproposed specification (if applicable).


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C26 Minor Change of Manufacturing Process of Drug Product

Conditions

- Release and shelf life specifications of the drug product are not adversely affected;

- New process must lead to an identical or better product regarding all aspects ofquality, safety and efficacy;

- No change in the dissolution profile;

- For major changes in the manufacturing process such as from wet granulation todirect compression of dry powder, refer to MIV B5.


1) Amended relevant CTD section P;

2) Tabulation of the present process and the new process with changes highlighted;

3) Appropriate justification and validation of the change should be provided where

appropriate, especially for sterilisation process;4) For solid dosage forms, dissolution profile data of one representative production

batch in accordance to HSAs drug registration guidelines

5) Release and shelf life specifications of the drug product. If there is any change ofthe specifications (i.e. tightening), the texts of the current and proposedspecifications should be provided (in a comparative table where possible);


7) Batch analysis data (in a comparative table) of at least one batch manufacturedaccording to the currently approved and proposed process;

8) A declaration from the applicant that the appropriate stability studies of the drugproduct have been started and that the relevant stability studies will be finalised;data should be provided only if outside specification (with proposed action).

C27 Change to Comply wi th Pharmacopoeia for Excipient

Pharmacopoeias accepted by HSA are EP, USP, BP, and JP.

Conditions

- Change is made exclusively to comply with an update of the relevant monograph ofthe Pharmacopoeia.


1) Tabulation of the current and revised specifications with changes highlighted;

2) Specification of the excipient;

3) Batch analysis of the excipient for all tests in the new specification;

4) Declaration that the quality of the drug product is not adversely affected.


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C28 Change of Test Procedure for Excip ient

Conditions

- Appropriate validation studies have been performed in accordance with the relevant

guidelines;- Results of method validation show new test procedure to be at least equivalent to

the former procedure;

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


1) Description of the analytical methodology, a summary of validation data;

2) Revised specification for impurities (if applicable);

3) Comparative validation results showing that the current test and the proposed one

are equivalent.

C29 Tightening of Specification or Addition of New Test Parameter(s) and Limi t(s)of Excipient

Condition

- New test method does not concern a novel non-standard technique or a standardtechnique used in a novel way.

Supporting Documents1) Tabulation of the current and revised specification of the excipient with changes

highlighted;

2) Revised specification of the excipient;

3) Batch analysis of the excipient for all tests in the new specification;

4) Description of any new analytical method and summary of the validation data, ifapplicable.

C30 Change of Test Procedure of Drug Product

Condition

- Results of method validation show new test procedure to be at least equivalent tothe former procedure.


1) Description of the analytical methodology, appropriate validation data, andcomparative analytical results between the current test and the proposed one;

2) Comparative release and shelf life specifications of the drug product.


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C31 Tightening of Release and Shelf Life Specifications or Addit ion of New TestParameter(s) and Limit (s) of Drug Product

Condition

- New test method does not concern a novel non-standard technique or a standardtechnique used in a novel way.


1) Tabulation of the current and revised release and shelf life specifications of thedrug product with changes highlighted;

2) Revised release and shelf life specifications of the drug product;

3) Batch analysis of the drug product for all tests in the new specification.

4) Details of any new analytical method and summary of validation data, ifapplicable.

C32 Minor Change or Inclusion of Container Closure System of Drug Product

Conditions

- The proposed packaging material must be at least equivalent or better than thecurrent approved material in respect of its relevant properties;

- The change only concerns the same packaging (for example blister to blister);

- For changes related to sterile products, refer to MIV1 B9.


1) Justification for the change in packaging material and appropriate scientificstudies on the new packaging;

2) For semisolid and liquid dosage forms, proof must be provided that no interactionbetween the content and the packaging material occurs (e.g. no migration ofcomponents of the proposed material into the content and no loss of componentsof the product into the pack);

3) Specifications of the immediate packaging material;

4) A declaration from the applicant that the relevant stability studies in accordancewith the relevant guidelines have been started (on at least two pilot scale orproduction scale batches) and that the relevant stability studies will be finalised;data should be provided only if outside the shelf life specification (with proposedaction) or when requested;

5) A declaration from the applicant that the product will meet the release and shelflife specifications.

C33 Change in Shape of Container Closure System

Conditions

- No change in the qualitative and quantitative composition of the container andstability of the product in the container;


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- The change does not concern a fundamental component of the packaging materialwhich affects the delivery or use of the product;

- The change does not relate to sterile preparations.

Supporting Documents1) Details/description of the new container shape;

2) A declaration from the applicant that the specifications of the container (except forshape) have not changed;

3) A declaration from the applicant that the release and shelf life specifications of thedrug product have not changed;

4) A declaration from the applicant that the appropriate stability studies have beenstarted with at least two pilot scale batches and that the relevant stability studieswill be finalised (for change in the headspace or a change in the surface/volumeratio); data should be provided only if outside the shelf life specification (withproposed action).

C34 Change or Inclusion of Pack Size for Drug Product

Conditions

- Does not apply to sterile preparations, unless the change only concerns the numberof containers in the outer packaging, otherwise refer to MIV-1 B12;

- Release and shelf life specifications of the drug product are not affected;

- The new size is consistent with the dosage regimen and duration of use asapproved in the PI;

- The packaging material remains the same.


1) Justification that the new size is consistent with the dosage regimen and durationof use as is approved in the PI;

2) A declaration from the applicant that the release and shelf life specifications of thedrug product are not affected, the container and closure composition isunchanged;

3) A declaration from the applicant that stability studies on at least 2 productionbatches will be conducted for products where stability parameters could be

affected. Data to be reported only if outside specifications (with proposed action).

C35 Addition or Replacement of Measuring Device for Oral Liquid and OtherDosage Forms

Conditions

- The size and, where applicable, the accuracy of the proposed measuring devicemust be compatible with the approved posology;

- The new device is compatible with the drug product.


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1) Description of the device (including a drawing), where appropriate;

2) The composition of the device material; where applicable, the materials shouldcomply with the Pharmacopoeia;

3) Justification that size and accuracy of the device are adequate for the posology asis approved in the product labelling;

C36 Change of Product Labelling due to Safety Updates

Conditions

- Tightening of the products target-patient population; or,

- Add warnings, precautions, contraindications or adverse events/effects to theapproved product labelling.


1) Official letter outlining: (a) the reasons for the notification, (b) the status of theproposed changes in other countries;

2) A declaration from the applicant that no other changes have been made to thelabelling and that the changes are supported by data.

C37 Change of Product Labelling Relating to :

Addi tion/deletion of bar code

Replacement of dis tributor details

Layout without altering text or meaning

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

Addi tion/deletion/replacement of pictures or diagrams that do not imply anunapproved indication

Conditions

- No change to the text or meaning of the wordings;

- The change is not an MAV or does not contain promotional information.


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

C38 Change of Product Labelling of Language(s) Other Than English

Conditions

- No change to the text or meaning of the English wordings;

- The change is not an MAV or contains promotional information.


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1) A declaration from the applicant that the information in non-English language(s)provides complete, accurate and unbiased information on the product and isconsistent with the English information.