Regulatory Updates for Therapeutic Product Registration

As part of HSA’s ongoing initiative to improve regulatory efficiency and enhance clarity in our regulatory requirements and processes, the Therapeutic Products Branch (TPB), Health Products Regulation Group, is pleased to update on the implementation of the revisions to the Guidance on Therapeutic Product Registration, effective 29 Apr 2022.

1.    Revised checklists for post-approval minor variations (MIV-1 and MIV-2)

The list of changes under post-approval minor variations MIV-2 Do-And-Tell has been expanded, with the re-categorisation of a list of chemistry, manufacturing & controls (CMC) variations from MIV-2 Notification to Do-And-Tell, and the introduction of new Do-And-Tell checklists. The MIV-1 checklists have also been revised to reflect the new changes, as well as to clarify the eligible conditions and documentary requirements.

The expansion of the Do-And-Tell changes aims to reduce regulatory submission burden and enable timely implementation of administrative and minor CMC changes that do not have any impact on the product’s safety, efficacy and quality.

The highlights of the changes to the MIV checklists are as below:

a)    Re-categorisation from MIV-2 Notification to MIV-2 Do-And-Tell

Drug substance

• Change in batch size of drug substance (DS) within 10‐fold of currently approved batch size

• Tightening of DS specification limits or in-process tests of limits (IPC) of DS

• Minor change of test procedure of DS

• Revision of CEP of DS

• Submission of CEP for an approved DS manufacturer

Drug product and excipients

• Minor change in the manufacturing process for drug product (DP)

• Tightening of DP specification limits or IPC of DP

• Minor change of test procedure for excipient

• Change in source of empty hard capsule (non-animal derived material)

• Change of outer carton pack sizes of the DP

b)    New checklists under MIV-2 Do-And-Tell

• Expansion of the “Change of release shelf-life specification to comply with latest compendium” checklist to three separate checklists:

• Change of specification of drug substance to comply with latest compendium

• Change of specification of drug product to comply with latest compendium

• Change of specification of excipient or drug substance starting material to comply with latest compendium

• Change in the specification parameters and/or limits or test procedure of primary packaging material

• Change in name and/or address of product registrant on product labelling

c)    New checklists under MIV-1

• Widening of specification limits of IPC or deletion of test parameters and limits of IPC of DP

• Widening of specification limits and deletion of significant test parameter of excipients

d)    Other changes

• Expansion of scope of product labelling change under Do-And-Tell

• Inclusion of requirements for submission of electronic format of Drug Master File (DMF) prior to the submission of MIV-1 applications supported by DMF (Refer to the B1, B3 checklists of Appendix 13)

• Streamlining of submission requirements

• Clarification of conditions and/or documentation requirements

Please note that the checklist numbering has changed with the above revisions. The online self-guided tool for MIV and Appendices 13 and 14 of the Guidance on Therapeutic Product Registration of Singapore have been updated to reflect these changes.

2.    Extension of verification evaluation route to biological products, including biosimilar products

The verification evaluation route has been extended to biological products, including biosimilar products, to enable greater leveraging of reference agencies’ assessments and minimise duplication of effort. The eligibility criteria for this route has been updated accordingly in main guidance (Sections 14.3, 24.1).

3.    Other updates

a)    Biosimilar product applications

The guidance in Appendix 15 has been incorporated into Chapter E of the main Guide to provide a consolidated guidance document on the registration of biosimilar products. With this, Appendix 15 has been obsoleted.

b)    Minor/ editorial amendments to the following appendices

• Patent declaration forms (Appendix 1)

• Application checklists (Appendices 2A and 3A)

• Sample verification document for translator (Appendix 4)

• Points to consider for Singapore labelling (Appendix 7)

• Product Interchangeability and biowaiver request for Chemical Generic Drug Applications (Appendix 10)

• Guideline on Drug Master File (Appendix 11)

• Guidance on Submission Requirements for Risk Management Plan Documents (Appendix 16)

• Guidelines on PRISM submission (Appendix 17)

• Dossier clarification supplement (Appendix 18A)

c)    Editorial updates to the following guidance documents:

• Change of registrant for registered therapeutic product

• Retention of therapeutic product on the product register

• Application to import a therapeutic product on consignment basis

The updated guidance documents may be accessed on the HSA website.