GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

APPENDIX 14A CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS
Applicants should be familiar with the documentary requirements for MIV submissions refer to Table A in Appendix 14 for the list.
NOTE: When submitting the Checklist, please delete the MIV-1 checklist category(ies) that do not relate to the MIV application.

The following documents must be submitted with each MIV submission, as given below:
Hard Copy PRISM application form Table of Contents Checklist for MIV applications Table of Amendment Details MIV-specific Supporting documents Administrative (Module 1/Part 1) Other supporting documents Current and proposed product labelling (annotated and pristine copies), where applicable * E-copies may be submitted via PRISM or CD-ROM. Yes Yes Yes Yes Yes Optional Yes E-Copy N/A Optional* Optional* PRISM PRISM PRISM/CD PRISM

When submitting the Checklist for Minor Variation Applications (MIV-1) for Chemical Drugs, applicants must make the following declaration: Declaration of the applicant for MIV-1 I hereby submit an application for the concerned product to be varied in accordance with the proposals given above. I declare that There are no other changes than those identified in Section 0.4 Amendment Summary; All Conditions for the change(s) concerned are fulfilled; and, The required documents as specified for the change(s) have been submitted.

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 1 of 6

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

DOSSIER REQUIREMENTS FOR MIV-1 VARIATION Declaration of the applicant for MIV-1 I hereby submit an application for the concerned product to be varied in accordance with the proposals given above. I declare that (please tick the appropriate declarations) There are no other changes than those identified in Section 0.4 Amendment Summary; All Conditions for the change(s) concerned are fulfilled; and, The required documents as specified for the change(s) have been submitted.

____________________ Applicants Name

______________________ Applicants Signature

_______________ Date

B1

Change or Inclusion of Manufacturing Site(s) of Drug Substance Supporting Documents CTD Section S, European Pharmacopoeia Certificate of Suitability (CEP) for 1) the drug substance or both the open and closed portions of the Drug Master File; Tabulation of the differences compared with the registered manufacture 2) information (if applicable); Batch analysis data (in a comparative tabular format) for at least two batches 3) (minimum pilot scale) of the drug substance from the current and proposed manufacturers/sites; A letter of commitment to conduct the appropriate stability study for the drug 4) 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) 2) 3) Relevant CTD section S; Tabulation of the current and proposed process with changes highlighted; Batch analysis data (in a comparative tabulation form) of at least two batches (pilot scale or production scale) manufactured according to the currently approved and proposed process. 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; If any potential new impurities are detectable at an acceptable limit of detection, appropriate evidence must be provided; 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 tabulation form where possible);

4) 5) 6)

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 2 of 6

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

7)

Relevant stability studies of the drug substance in accordance with the relevant guidelines should be provided; 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).

8)

B3

Change of Specification of Drug Substance or Drug Product For any changes not covered by MIV2 C13 and C31 Supporting Documents 1) 2) 3) 4) 5) Scientific and/or historical data used to support the change; 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 tabulation form); Release and shelf-life specifications; Batch analysis for all tests in the new specification; Description of any new analytical method and summary of the validation data, if applicable; 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.

6)

B4

Change or Inclusion of Manufacturing Site(s) of Drug Product Supporting Documents Proof that the proposed site is appropriately 1) pharmaceutical form concerned: a GMP certificate; 2) 3) 4) 5) 6) 7) Product formula; Specification of drug substance; Release and shelf life specifications of drug product; Batch numbering system; 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); 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); For sterile or parenteral products, validation data of the manufacturing process and sterilization process at the proposed site for products should be provided. Official letter declaring that the formulation, drug substance source & specification, manufacturing process, analytical test methods, release and shelf life specifications have not changed. authorised for the

Official letter authorising the proposed site to manufacture the product;

8)

9)

10)

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 3 of 6

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

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 manufacturing drug product not covered by MIV2 C25 or C26 Supporting Documents 1) 2) Release and shelf life specifications of drug product; 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); Batch analysis data of a least two production batches (or one production batch and two pilot batches) manufactured according to currently registered and proposed processes; 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; Justification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance; Tabulation of the changes and differences; Validation scheme and data on manufacturing process and/or analytical method (where applicable).

3)

4) 5) 6) 7) B6

Change or Inclusion of Score/Break Line of Tablet Supporting Documents 1) 2) 3) 4) 5) Detailed drawing or written description of the current and proposed tablet; Justification to support the change or inclusion of score/break line; Data on uniformity of content of the subdivided parts of the tablets; 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; 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) 2) Amended relevant CTD Section P.3; 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); Batch analysis data (in a comparative tabulated format) of at least two production batches (or one production batch and two pilot batches) manufactured according to currently registered and proposed batch sizes; Release and shelf life specifications of the drug product; 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; Validation scheme and data on proposed manufacturing process and/or analytical method.

3) 4) 5) 6)

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 4 of 6

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

B8

Change or Inclusion of Primary Packaging Site(s) Supporting Documents 1) 2) 3) 4) Proof that the proposed site is appropriately authorised for the packaging activity concerned: GMP certificate; Official letter authorising the proposed site to package the product and stating the types of activity performed by the packager; Validation data on manufacturing process (for suspensions and emulsions); 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) 2) Amended section P.7 and technical information; 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; A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable; For sterile products, validation data of the relevant manufacturing and sterilization process.

3) 4) B10

Change of Shelf Life or Storage Condition of Drug Product Supporting Documents 1) 2) 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; A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable.

B11

Change of Shelf Life After Reconstitution or First Opening Supporting Documents 1) 2) 3) 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; Results of appropriate microbiological testing if applicable; 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) Justification that the proposed pack size is consistent with the dosage regimen and duration of use as is approved in the package insert;

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 5 of 6

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE CHECKLIST FOR MINOR VARIATION APPLICATIONS (MIV-1) FOR CHEMICAL DRUGS

JANUARY 2009

2)

Validation data of the manufacturing process, sterilization and container closure system (where applicable); 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); A declaration from the applicant that the release and shelf life specifications of the drug product are not affected if applicable.

3)

4) B13

Change of Product Labelling Condition 1) The change is not a major variation (MAV); For safety-related changes of product labelling, refer to MIV-2 C36 Justification and clinical documents to support proposed changes.

Supporting Documents

HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP

Appendix 14A - Page 6 of 6