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 Drug Product................................................................................................................ 9 B13 Change of Product Labelling............................................................................... 9
PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION.................................. 10
C1 Change of Contact Person................................................................................ 10 C2 Change of Product Name.................................................................................. 10 C3 Change of Product Owner................................................................................. 11 C4 Change of Batch Numbering System................................................................ 11 C5 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Substance.......................................................................................................... 11 C6 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Product ........................................................................................................................... 11 C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product, Packager or Batch Releaser) ............................................................................ 12 C8 Deletion of Pack Size for Drug Product............................................................. 12 C9 Minor Change of Manufacturing Process of Drug Substance ........................... 12 C10 Change of Batch Size of Drug Substance......................................................... 13 C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance....... 13 C12 Change of Test Procedure of Drug Substance.................................................. 13 C13 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s) of Drug Substance............................................................................................. 14 C14 Extension of Shelf Life or Retest Period of Drug Substance............................. 14 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 2 of 25
C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing on Capsules Including Addition or Change of Inks Used for Product Marking....... 14 C16 Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without Change in Qualitative and Quantitative Composition and Mean Mass ............. 15 C17 Minor Qualitative Change of Excipient .............................................................. 15 C18 Minor Quantitative Change or Deletion of Existing Excipient............................ 16 C19 Change of Colouring System of Drug Product (Addition, Deletion or Replacement of Colourant(s)) ........................................................................... 17 C20 Change of Flavouring System of Drug Product (Addition, Deletion or Replacement of Flavourant(s)).......................................................................... 17 C21 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell.. 18 C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging.......... 18 C23 Change or Inclusion of Site(s) Responsible for Batch Release......................... 18 C24 Change of Batch Size of Drug Product.............................................................. 19 C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product19 C26 Minor Change of Manufacturing Process of Drug Product................................ 20 C27 Change to Comply with Pharmacopoeia for Excipient ...................................... 20 C28 Change of Test Procedure for Excipient............................................................ 21 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 Test Parameter(s) and Limit(s) of Drug Product........................................................ 22 C32 Minor Change or Inclusion of Container Closure System of Drug Product ....... 22 C33 Change in Shape of Container Closure System................................................ 22 C34 Change or Inclusion of Pack Size for Drug Product.......................................... 23 C35 Addition or Replacement of Measuring Device for Oral Liquid and Other Dosage Forms................................................................................................... 23 C36 Change of Product Labelling due to Safety Updates......................................... 24 C37 Change of Product Labelling Relating to:.......................................................... 24 C38 Change of Product Labelling of Language(s) Other Than English.................... 24
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 3 of 25
PART A: INTRODUCTION
This document describes the requirements of a Minor Variation Application (MIV) submitted for an existing registered chemical drug product in Singapore. Applicants should be familiar with the contents of this document, the Guidance on Medicinal Product Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.
Minor Variation Applications are divided into two sub-categories: MIV-1: A minor variation which requires regulatory approval MIV-2: A minor variation or an administrative change which does not require regulatory approval; i.e., notification.
If an MIV contains multiple proposed variations that belong to both MIV categories, the MIV should be categorized as an MIV-1. If a proposed MIV-2 does not meet its specified conditions, then the MIV must be categorized as an MIV-1 with supporting documents. HSA reserves the right to re-categorise the MIV if deemed appropriate.
Registration Process
A minor variation application (MIV) is submitted via the Amendment to a Licence of Western Drug Product form in PRISM.
Applicants should fully disclose all proposed change(s) in Section 0 Licence Summary under Section 0.4 Amendment Summary, and in the Table of Amendment Details, downloaded via the link indicated in Section 0.5 Amendment Details. Any undisclosed variation(s) embedded in the submitted data, or any follow-on changes not specifically requested by HSA, will not be considered for evaluation.
NOTE: Applicants are encouraged to fax or email the MIV Filing and Submission Inquiry Form in Appendix 13 for any issues regarding MIV filing. 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 4 of 25
Documentary Requirements
The following documents must be submitted with each MIV submission, as given in Table A below:
Hard Copy E-Copy PRISM application form Yes N/A Table of Contents Yes Optional* Checklist for MIV applications Yes Optional* Table of Amendment Details Yes PRISM MIV-specific Supporting documents - Administrative (Module 1/Part 1) - Other supporting documents
Yes Optional
PRISM PRISM/CD Current and proposed product labelling (annotated and pristine copies), where applicable Yes PRISM * E-copies may be submitted via PRISM or CD-ROM.
Table A. MIV Application Hard Copy and Electronic Copy Requirements
The Checklist for Minor Variation Applications for Chemical Drugs is located in Appendix 14A of this guidance document. This Checklist serves as a guide for submitting the required documents relevant to each proposed MIV. When submitting the Checklist, the following should be included: A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be checked to ensure that the required documents are included in the submission; and, The Declaration for the MIV with the submission date and the local applicants name and signature.
The Table of Amendment Details concisely describes the proposed MIV(s). The following information must be stated in the Table: Section of the original dossier affected by the change(s); Current and proposed condition(s); Reason for the change(s); and, Registration status and date of the proposed change(s) in other countries.
The required documents for each proposed MIV-1 or MIV-2 variation are specified in Part B or Part C of this document respectively. For an MIV application with multiple related or unrelated variations, all of the supporting documents for each individual variation should be submitted. If the required documents have not been submitted, justification must be provided.
This document reflects the current thinking of HSA on the minimum data necessary for assessment. Applicants are responsible for ensuring that all necessary validations were conducted to demonstrate that the change does not adversely affect the quality, safety or efficacy of the product concerned. HSA reserves the right to request additional information if deemed appropriate. 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. 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 5 of 25
PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION
B1 Change or Inclusion of Manufacturing Site(s) of Drug Substance
Supporting Documents 1) CTD Section S, European Pharmacopoeia Certificate of Suitability (CEP) for the drug substance, or both the open and closed portions of the Drug Master File; 2) Tabulation of the differences compared with the registered manufacture information (if applicable); 3) Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the drug substance from the current and proposed manufacturers/sites; 4) A letter of commitment to conduct the appropriate stability study for the drug product manufactured with the drug substance from the proposed manufacturer.
B2 Major Change of Manufacturing Process of Drug Substance
For any changes not covered by MIV2 C9 (e.g. alternative synthetic route)
Supporting Documents 1) Relevant CTD section S; 2) Tabulation of the current and proposed process with changes highlighted; 3) Batch analysis data (in a comparative table) of at least two batches (pilot scale or production scale) manufactured according to the currently approved and proposed process; 4) A declaration from the applicant that no new impurities have been introduced at or above the accepted threshold for qualification of impurities or that there is no increase in the level of impurities, which require further safety studies; 5) If any potential new impurities are detectable at an acceptable limit of detection, appropriate evidence must be provided; 6) A declaration from the applicant that the specification of the drug substance has not changed or if there is any change to the specification (i.e. tightening), the texts of the current and proposed specifications should be provided (in a comparative table where possible); 7) Relevant stability studies of the drug substance in accordance with the relevant guidelines should be provided; 8) A letter of commitment to conduct the appropriate stability study for the drug product manufactured with the drug substance from the new manufacturing process, and report if any results fall outside shelf life specification (with proposed action).
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 6 of 25
B3 Change of Specification of Drug Substance or Drug Product
For any changes not covered by MIV2 C13 and C31
Supporting Documents 1) Scientific and/or historical data used to support the change; 2) Currently registered version of the release and/or shelf life specifications with the proposed change(s) clearly highlighted, underscored, or otherwise indicated (in a comparative table); 3) Release and shelf-life specifications; 4) Batch analysis for all tests in the new specification; 5) Description of any new analytical method and summary of the validation data, if applicable; 6) Results of appropriate real time stability studies of at least two production scale batches of the drug product with undertaking to continue the stability studies up till the proposed shelf life and to report if any results fall outside shelf life specification.
B4 Change or Inclusion of Manufacturing Site(s) of Drug Product
Supporting Documents 1) Proof that the proposed site is appropriately authorised for the pharmaceutical form concerned: a GMP certificate; 2) Official letter authorising the proposed site to manufacture the product; 3) Product formula; 4) Specification of drug substance; 5) Release and shelf life specifications of drug product; 6) Batch numbering system; 7) Appropriate stability data of at least 6 months on 2 batches (pilot/production) with undertaking to conduct on-going stability study and report if any results fall outside shelf life specification (with proposed action); 8) Batch analysis data on a minimum two production batches (or one production batch and two pilot batches) simulating the production process and comparative data on the last 3 batches from the current site; batch analysis data on the next 2 full production batches should be available upon request or reported if outside release and shelf life specifications (with proposed action); 9) For sterile or parenteral products, validation data of the manufacturing process and sterilization process at the proposed site for products should be provided. 10) Official letter declaring that the formulation, drug substance source & specification, manufacturing process, analytical test methods, release and shelf life specifications have not changed.
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 7 of 25
B5 Change of Manufacturing Process and/or Test Methods of Drug Product
For any change in the procedure of the current registered manufacturing process at any stage during manufacture drug product not covered by MIV2 C25 or C26.
Supporting Documents 1) Release and shelf life specifications of drug product; 2) Appropriate stability data of at least 6 months on 2 batches (pilot/production) with undertaking to conduct on-going stability study and report if any results fall outside shelf life specification (with proposed action); 3) Batch analysis data of at least two production batches (or one production batch and two pilot batches) manufactured according to currently registered and proposed processes; 4) For solid dosage forms, comparative dissolution profile data of at least one representative pilot/production batch of the drug product of the currently registered and proposed processes; 5) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; 6) Tabulation of the changes and differences; 7) Validation scheme and data on manufacturing process and/or analytical method (where applicable).
B6 Change or Inclusion of Score/Break Line of Tablet
Supporting Documents 1) Detailed drawing or written description of the current and proposed tablet; 2) J ustification to support the change or inclusion of score/break line; 3) Data on uniformity of content of the subdivided parts of the tablets; 4) Official letter of commitment to inform users of the relevant changes, and that the current product stocks will be exhausted before the new product is marketed; 5) Current and proposed release and shelf life specifications.
B7 Change of Batch Size of Drug Product
For any change in the scale of the current registered manufacturing process at any stage during manufacture drug product not covered by MIV2 C24.
Supporting Documents 1) Amended relevant CTD Section P.3; 2) Appropriate stability data of at least 6 months on 2 batches (pilot/production) with undertaking to conduct on-going stability study and report if any results fall outside shelf life specification (with proposed action); 3) Batch analysis data (in a comparative table) of at least two production batches (or one production batch and two pilot batches) manufactured according to currently registered and proposed batch sizes; 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 8 of 25
4) Release and shelf life specifications of the drug product; 5) For solid dosage forms, comparative dissolution profile data of at least one representative pilot/production batch of the drug product of the currently registered and proposed processes; 6) Validation scheme and data on proposed manufacturing process and/or analytical method.
B8 Change or Inclusion of Primary Packaging Site(s)
Supporting Documents 1) Proof that the proposed site is appropriately authorised for the packaging activity concerned: GMP certificate; 2) Official letter authorising the proposed site to package the product and stating the types of activity performed by the packager; 3) Validation data on manufacturing process (for suspensions and emulsions); 4) A declaration from the applicant that the appropriate stability studies have been started on at least two pilot or production scale batches and that the relevant stability studies will be finalised; data should be provided only if outside shelf life specification (with proposed action) or when requested.
B9 Change or Inclusion of Container Closure System of Drug Product
For any changes not covered by MIV2 C32
Supporting Documents 1) Amended section P.7 and technical information; 2) Appropriate stability study of at least 6 months on 2 production batches of the proposed primary packaging material with undertaking to continue the stability studies up till the proposed shelf life and report if any results fall outside shelf life specification (with proposed action) or when requested; 3) A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable; 4) For sterile products, validation data of the relevant manufacturing and sterilization process.
B10 Change of Shelf Life or Storage Condition of Drug Product
Supporting Documents 1) Results of appropriate real time stability studies of at least two production scale batches of the drug product in the authorised packaging material covering the duration of the proposed/approved shelf life; 2) A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable.
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 9 of 25
B11 Change of Shelf Life After Reconstitution or First Opening
Supporting Documents 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 authorised packaging material covering the duration of the proposed shelf life; 2) Results of appropriate microbiological testing if applicable; 3) A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable.
B12 Change of Pack Size (Volume) or Inclusion of New Pack Size for Sterile Drug Product
Supporting Documents 1) J ustification that the proposed pack size is consistent with the dosage regimen and duration of use as is approved in the package insert; 2) Validation data of the manufacturing process, sterilization and container closure system (where applicable); 3) Results of the stability study for at least 6 months on 2 production batches of the proposed pack size with undertaking to continue the stability studies up till the proposed shelf life and to report if any results fall outside shelf life specification (with proposed action); 4) A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable.
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
Supporting Documents 1) J ustification and clinical documents to support proposed changes. 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 10 of 25
PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION
An MIV-2 application is a variation for which only a notification is required to be submitted to HSA. Each MIV-2 notification shall be submitted at least 2 months in advance of the commencement date.
If a proposed MIV-2 does not meet its specified conditions, then the MIV must be submitted as an MIV-1 with supporting documents. HSA reserves the right to re- categorise the MIV if deemed appropriate.
C1 Change of Contact Person
Condition - The product licence holder remains the same.
Supporting Documents 1) Particulars of the contact person updated in the on-line PRISM application.
C2 Change of Product Name
Conditions - There is no change to the product (formulation, release and shelf life specifications, manufacturing source and process) except the product name change; - No confusion with another drug product either when spoken or written; - New name does not imply (a) greater safety or efficacy than supported by clinical data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic use for the product, or (d) the presence of substance(s) not present in the product.
Supporting Documents 1) Official letter authorising the change of product name; 2) A declaration from the applicant that there is no change to the product except name; 3) Official letter of commitment to inform users of the relevant changes, and that the current product stocks will be exhausted before the product labelled with the new name is marketed; 4) CPP.
NOTE: Applicants are encouraged to fax or email the MIV Filing and Submission Inquiry Form in Appendix 13 for any issues regarding MIV filing. 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 11 of 25
C3 Change of Product Owner
Condition - The product licence holder remains the same.
Supporting Documents 1) Official letter from the new product owner declaring the change, and authorising the local licence holder to be responsible for the product licence in Singapore; 2) If the new product owner is not the manufacturer of the drug product, an official letter by the new product owner authorising the manufacturer to manufacture the drug product on its behalf;
C4 Change of Batch Numbering System
Document Required 1) Description of batch number system; 2) Official letter stating the commencement date of the change
C5 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Substance
Condition - The manufacturing site of the drug substance remains at the same physical location.
Supporting Documents 1) Updated information of the manufacturer of the drug substance; 2) A declaration from the applicant that manufacturing site remains the same and that the renaming does not involve changes of the manufacturing process and/or quality of the product.
C6 Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Product
Condition - The manufacturing site remains at the same physical location.
Supporting Documents 1) Official letter authorising the manufacturer with new name/address to manufacture the drug product (not required if the manufacturer is the product owner); 2) GMP certificate with new name or address; 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 12 of 25
3) A declaration from the applicant that the manufacturing site remains the same, and that the renaming does not involve changes of the manufacturing process and/or quality of the product;
C7 Withdrawal/Deletion of Manufacturer (Drug Substance, Drug Product, Packager or Batch Releaser)
Supporting Documents 1) Reason for withdrawal/deletion
C8 Deletion of Pack Size for Drug Product
Supporting Documents 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.
Supporting Documents 1) Relevant CTD section S; 2) Tabulation of the current and proposed process with changes highlighted; 3) Batch analysis data (in a comparative table) of at least two batches (pilot scale or production scale) manufactured according to the currently approved and proposed process; 4) A declaration from the applicant that no new impurities have been introduced at or above the accepted threshold for qualification of impurities or that there is no increase in the level of impurities, which require further safety studies; 5) A declaration from the applicant that the specification of the drug substance has not changed or if there is any change to the specification (i.e. tightening), the texts of the current and proposed specifications should be provided (in a comparative table where possible); 6) A declaration from the applicant that the relevant stability studies of the drug substance in accordance with the relevant guidelines have been started and that the relevant stability studies will be finalised; data should be provided only if outside specification (with proposed action).
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 13 of 25
C10 Change of Batch Size of Drug Substance
Condition - The change does not affect the reproducibility of the process.
Supporting Documents 1) Amended relevant CTD Section S; 2) Batch analysis data (in a comparative table) on a minimum of one production batch manufactured to both the currently approved and the proposed batch sizes. Batch data on the next 2 full production batches should be available on request or reported if outside specification (with proposed action); 3) Specification of the drug substance.
C11 Change to Comply with Accepted Pharmacopoeia(s) for Drug Substance
Pharmacopoeias accepted by HSA are EP, USP, BP, and J P.
Conditions - Change is made exclusively to comply with an update of the relevant monograph of the pharmacopoeia; - Excludes change from one accepted pharmacopoeia to another.
Supporting Documents 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.
Supporting Documents 1) Description of the analytical methodology, a summary of validation data, and comparative analytical results between the current test and the proposed one, if appropriate; 2) Specification of the drug substance; 3) A declaration from the applicant that the specification of the drug substance has not changed.
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 14 of 25
C13 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s) of Drug Substance
Condition - New test method does not concern a novel non-standard technique or a standard technique used in a novel way
Supporting Documents 1) Tabulation of the current and revised specification of drug substance with changes highlighted; 2) Revised specification of drug substance; 3) Batch analysis of the drug substance for all tests in the new specification. 4) Description of any new analytical method and summary of the validation data, if applicable.
C14 Extension of Shelf Life or Retest Period of Drug Substance
Condition - The studies must show compliance with specification
Supporting Documents 1) Stability data of the drug substance should be presented on at least two pilot or production scale batches of the requested shelf life or retest period; 2) Specification of the drug substance.
C15 Change of Imprints, Bossing or Other Markings on Tablet or Printing on Capsules Including Addition or Change of Inks Used for Product Marking
Conditions - New markings do not cause confusion with other tablets or capsules; - The inks have not been rejected for pharmaceutical use; - Release and shelf life specifications of the drug product have not changed (except for appearance). - For changes involving the score/break line, refer to MIV1 B6.
Supporting Documents 1) Details of the proposed new inks (where applicable); 2) Detailed drawing or written description of the current and proposed imprint/bossing/markings/ink; 3) Official letter of commitment to inform users of the relevant changes, and that the current product stocks will be exhausted before the product labelled with the new name is marketed; 4) A declaration from the applicant that the release and shelf life specifications of the product have not changed (except for appearance). 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 15 of 25
C16 Change of Dimensions of Tablet, Capsule, Suppository or Pessary Without Change in Qualitative and Quantitative Composition and Mean Mass C16.1 Conventional dosage form, suppository and pessary C16.2 Critical dosage form and scored tablet
Conditions - No change in dissolution profile; - Release and shelf life specifications of the drug product have not changed (except for dimensions).
Supporting Documents C16.1 Conventional dosage form, suppository and pessary 1) Detailed drawing or written description of the current and proposed appearance; 2) Release and shelf life specifications of the drug product; 3) Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
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 current and proposed dimensions in accordance with HSAs drug registration guidelines; 6) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidelines; 7) Where applicable, data on the test for uniformity of content of the subdivided parts of tablets at release should be submitted and commitment to conduct the test at the end of shelf life, data should be provided only if outside the release and shelf life specifications (with proposed action).
C17 Minor Qualitative Change of Excipient
Conditions - Replacement of an excipient with a comparable excipient; - Same functional characteristics of the excipient; - No change in dissolution profile for solid dosage forms; - The release and shelf life specifications of the drug product have not changed (or have tightened), except for the replacement of the excipients; - For change of preservatives, refer to MIV B3; - For changes affecting release and shelf life specification, refer to MIV1 B3.
Supporting Documents 1) J ustification for the change of excipients must be given by appropriate development pharmaceutics (including stability aspect and antimicrobial preservation where appropriate); 2) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; 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 16 of 25
3) Tabulation of the current and revised product formulation with changes highlighted; 4) Revised product formulation; 5) Release and shelf life specifications and batch analysis of the drug product; 6) Specifications of new excipient; 7) Comparative dissolution profile data of at least one representative pilot/production batch of the drug product in the new and old composition for solid dosage forms in accordance with HSAs drug registration guidelines; 8) A declaration from the applicant that the new excipient does not interfere with the drug product release and shelf life specifications test method; 9) A declaration from the applicant that the release and shelf life specifications of the drug product have not changed; 10) A declaration from the applicant that the relevant stability studies in accordance with the relevant guidelines have been started (on at least two pilot scale or production scale batches) and that the relevant stability studies will be finalised; data should be provided only if outside the shelf life specification (with proposed action) or when requested.
C18 Minor Quantitative Change or Deletion of Existing Excipient
Conditions - Total quantitative change within 5% (w/w), inclusive of the following: Disintegrant: Starch ( 3%), other ( 1%); Binder ( 0.5%); Lubricant: Ca or Mg Stearate ( 0.25%), other ( 1%); Glidant: Talc ( 1%), other ( 0.1%); and/or, Film Coat ( 1%); - No change in the dissolution profile for solid dosage forms; - Release and shelf life specifications of the drug product have not changed. - For changes affecting release and shelf life specification, refer to MIV1 B3.
Supporting Documents 1) J ustification for the change must be given by appropriate development pharmaceutics (including stability aspect and antimicrobial preservation where appropriate); 2) Comparative dissolution profile data of at least one representative pilot/production batch of the drug product in the new and old composition for solid dosage forms in accordance with HSAs drug registration guidelines; 3) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; 4) Tabulation of the current and revised product formulation with changes highlighted; 5) Revised product formulation; 6) Release and shelf life specifications and batch analysis of drug product; 7) A declaration from the applicant that the change of excipient does not interfere with the drug product release and shelf life specifications test method; 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 17 of 25
8) A declaration from the applicant that the appropriate stability studies have been started (on at least two pilot scale or production scale batches) and that the relevant stability studies will be finalised; data should be provided only if outside the shelf life specification (with proposed action) or when requested.
C19 Change of Colouring System of Drug Product (Addition, Deletion or Replacement of Colourant(s))
Conditions - Same functional characteristics, no change in dissolution profile for solid dosage forms; - The colouring system must not have been rejected for pharmaceutical use; - The release and shelf life specifications of the drug product have not changed, except for the change in appearance/colour.
Supporting Documents 1) Qualitative and quantitative information of the colourant; 2) Revised product formulation; 3) Release and shelf life specifications of the drug product; 4) Official letter of commitment to inform users of the relevant changes, and that the current product stocks will be exhausted before the product with the proposed variation is marketed; 5) A declaration from the applicant that the change in the colouring system does not interfere with the drug product release and shelf life specifications test methods; 6) A declaration from the applicant that the release and shelf life specifications have not changed (except for appearance); 7) A declaration from the applicant that the relevant stability studies in accordance with the relevant guidelines have been started (on at least two pilot scale or production scale batches) and that the relevant stability studies will be finalised; data should be provided only if outside the shelf life specification (with proposed action) or when requested.
C20 Change of Flavouring System of Drug Product (Addition, Deletion or Replacement of Flavourant(s))
Conditions - Proposed flavour must not have been rejected for pharmaceutical use; - The release and shelf life specifications of the drug product have not changed, except for the change in flavour.
Supporting Documents 1) Qualitative and quantitative information of the flavouriant; 2) Revised product formulation; 3) Release and shelf life specifications of the drug product; 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 18 of 25
4) Official letter of commitment to inform users of the relevant changes, and that the current product stocks will be exhausted before the product with the proposed variation is marketed; 5) A declaration from the applicant that the change of flavour(s) does not interfere with the drug product release and shelf life specifications test method; 6) A declaration from the applicant that the release and shelf life specifications of the product have not changed (except for flavour); 7) A declaration from the applicant that the relevant stability studies in accordance with the relevant guidelines have been started (on at least two pilot scale or production scale batches) and that the relevant stability studies will be finalised; data should be provided only if outside the shelf life specification (with proposed action) or when requested.
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 respect of weight and dimensions, if applicable.
Supporting Documents 1) Comparative dissolution profile data of at least one pilot/production batch of the drug product in the new and old composition in accordance with HSAs drug registration guidelines (for modified release products, to provide in vitro data which has been correlated with in vivo data); 2) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; 3) Revised release and shelf life specifications of the drug product; 4) A declaration from the applicant that the change does not interfere with the drug product specifications test method; 5) A declaration from the applicant that the release and shelf life specifications of the drug product have not changed (except for average weight).
C22 Change or Inclusion of Manufacturing Site(s) for Secondary Packaging
Supporting Documents 1) Official letter authorising the proposed manufacturer to perform secondary packaging; 2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is appropriately authorised for the packaging activity concerned.
C23 Change or Inclusion of Site(s) Responsible for Batch Release
Condition - The manufacturer of the drug product remains the same; 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 19 of 25
Supporting Documents 1) Official letter authorising the company/manufacturer with new name/address responsible for batch release; 2) GMP certificate with name or address of the new site (where appropriate);
C24 Change of Batch Size of Drug Product
Conditions - The change does not affect consistency of production; - The change only applies to standard immediate release oral dosage forms and to non-sterile liquid forms, refer to MIV1 B9; - Up to a 10-fold change when compared to the batch size currently registered with HSA; - Validation scheme is available or validation of the manufacture has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the relevant guidelines.
Supporting Documents 1) Amended relevant CTD Section P.3; 2) Batch analysis data (in a comparative table) on a minimum of one production batch manufactured to both the currently approved and the proposed batch sizes. Batch data on the next 2 full production batches should be available on request or reported if outside the shelf life specification (with proposed action); 3) Release and shelf life specifications of the drug product; 4) Official letter of commitment to put the product manufactured according to the proposed batch size under stability studies in accordance with relevant stability guidelines.
C25 Change of In-Process Control(s) Applied During Manufacture of Drug Product
Condition - In-process limits are tightened or addition of new tests.
Supporting Documents 1) A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable); 2) Tabulation of the in-process controls and the relevant changes; 3) Batch analysis data of one production batch of the drug product for all tests in the proposed specification (if applicable).
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 20 of 25
C26 Minor Change of Manufacturing Process of Drug Product
Conditions - Release and shelf life specifications of the drug product are not adversely affected; - New process must lead to an identical or better product regarding all aspects of quality, safety and efficacy; - No change in the dissolution profile; - For major changes in the manufacturing process such as from wet granulation to direct compression of dry powder, refer to MIV B5.
Supporting Documents 1) Amended relevant CTD section P; 2) Tabulation of the present process and the new process with changes highlighted; 3) Appropriate justification and validation of the change should be provided where appropriate, especially for sterilisation process; 4) For solid dosage forms, dissolution profile data of one representative production batch in accordance to HSAs drug registration guidelines 5) Release and shelf life specifications of the drug product. If there is any change of the specifications (i.e. tightening), the texts of the current and proposed specifications should be provided (in a comparative table where possible); 6) J ustification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; 7) Batch analysis data (in a comparative table) of at least one batch manufactured according to the currently approved and proposed process; 8) A declaration from the applicant that the appropriate stability studies of the drug product have been started and that the relevant stability studies will be finalised; data should be provided only if outside specification (with proposed action).
C27 Change to Comply with Pharmacopoeia for Excipient
Pharmacopoeias accepted by HSA are EP, USP, BP, and J P.
Conditions - Change is made exclusively to comply with an update of the relevant monograph of the Pharmacopoeia.
Supporting Documents 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.
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 21 of 25
C28 Change of Test Procedure for Excipient
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 a standard technique used in a novel way.
Supporting Documents 1) Description of the analytical methodology, a summary of validation data; 2) Revised specification for impurities (if applicable); 3) Comparative validation results showing that the current test and the proposed one are equivalent.
C29 Tightening of Specification or Addition of New Test Parameter(s) and Limit(s) of Excipient
Condition - New test method does not concern a novel non-standard technique or a standard technique used in a novel way.
Supporting Documents 1) 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, if applicable.
C30 Change of Test Procedure of Drug Product
Condition - Results of method validation show new test procedure to be at least equivalent to the former procedure.
Supporting Documents 1) Description of the analytical methodology, appropriate validation data, and comparative analytical results between the current test and the proposed one; 2) Comparative release and shelf life specifications of the drug product.
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 22 of 25
C31 Tightening of Release and Shelf Life Specifications or Addition of New Test Parameter(s) and Limit(s) of Drug Product
Condition - New test method does not concern a novel non-standard technique or a standard technique used in a novel way.
Supporting Documents 1) Tabulation of the current and revised release and shelf life specifications of the drug 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, if applicable.
C32 Minor Change or Inclusion of Container Closure System of Drug Product
Conditions - The proposed packaging material must be at least equivalent or better than the current approved material in respect of its relevant properties; - The change only concerns the same packaging (for example blister to blister); - For changes related to sterile products, refer to MIV1 B9.
Supporting Documents 1) J ustification for the change in packaging material and appropriate scientific studies on the new packaging; 2) For semisolid and liquid dosage forms, proof must be provided that no interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack); 3) Specifications of the immediate packaging material; 4) A declaration from the applicant that the relevant stability studies in accordance with the relevant guidelines have been started (on at least two pilot scale or production scale batches) and that the relevant stability studies will be finalised; data should be provided only if outside the shelf life specification (with proposed action) or when requested; 5) A declaration from the applicant that the product will meet the release and shelf life specifications.
C33 Change in Shape of Container Closure System
Conditions - No change in the qualitative and quantitative composition of the container and stability of the product in the container; 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 23 of 25
- The change does not concern a fundamental component of the packaging material which affects the delivery or use of the product; - The change does not relate to sterile preparations.
Supporting Documents 1) Details/description of the new container shape; 2) A declaration from the applicant that the specifications of the container (except for shape) have not changed; 3) A declaration from the applicant that the release and shelf life specifications of the drug product have not changed; 4) A declaration from the applicant that the appropriate stability studies have been started with at least two pilot scale batches and that the relevant stability studies will be finalised (for change in the headspace or a change in the surface/volume ratio); data should be provided only if outside the shelf life specification (with proposed action).
C34 Change or Inclusion of Pack Size for Drug Product
Conditions - Does not apply to sterile preparations, unless the change only concerns the number of containers in the outer packaging, otherwise refer to MIV-1 B12; - Release and shelf life specifications of the drug product are not affected; - The new size is consistent with the dosage regimen and duration of use as approved in the PI; - The packaging material remains the same.
Supporting Documents 1) J ustification that the new size is consistent with the dosage regimen and duration of use as is approved in the PI; 2) A declaration from the applicant that the release and shelf life specifications of the drug product are not affected, the container and closure composition is unchanged; 3) A declaration from the applicant that stability studies on at least 2 production batches will be conducted for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
C35 Addition or Replacement of Measuring Device for Oral Liquid and Other Dosage Forms
Conditions - The size and, where applicable, the accuracy of the proposed measuring device must be compatible with the approved posology; - The new device is compatible with the drug product.
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 24 of 25
Supporting Documents 1) Description of the device (including a drawing), where appropriate; 2) The composition of the device material; where applicable, the materials should comply with the Pharmacopoeia; 3) J ustification that size and accuracy of the device are adequate for the posology as is approved in the product labelling;
C36 Change of Product Labelling due to Safety Updates
Conditions - Tightening of the products target-patient population; or, - Add warnings, precautions, contraindications or adverse events/effects to the approved product labelling.
Supporting Documents 1) Official letter outlining: (a) the reasons for the notification, (b) the status of the proposed changes in other countries; 2) A declaration from the applicant that no other changes have been made to the labelling and that the changes are supported by data.
C37 Change of Product Labelling Relating to: Addition/deletion of bar code Replacement of distributor details Layout without altering text or meaning Deletion of indication (Note: Re-inclusion of the deleted indication in the future should be submitted as MAV-1 according to the prevailing requirement.) Addition/deletion/replacement of pictures or diagrams that do not imply an unapproved indication
Conditions - No change to the text or meaning of the wordings; - The change is not an MAV or does not contain promotional information.
Supporting Documents 1) A declaration from the applicant that no other changes have been made to the labelling.
C38 Change of Product Labelling of Language(s) Other Than English
Conditions - No change to the text or meaning of the English wordings; - The change is not an MAV or contains promotional information. 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 25 of 25
Supporting Documents 1) A declaration from the applicant that the information in non-English language(s) provides complete, accurate and unbiased information on the product and is consistent with the English information.