Guidance on therapeutic Product Registration in SingaporeNOVEMBER 2016

– PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 APPLICATIONS FOR BIOLOGICAL THERAPEUTIC PRODUCTs

APPENDIX 14B PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 APPLICATIONSFOR BIOLOGICal therapeutic products

An MIV-2 application is a variation for which only a notification is required to be submitted to HSA. Each MIV-2 notification shall be submitted at least 40 working days beforeimplementation of the variation.

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

Product registrants should be familiar with the documentary requirements for MIV submissions to facilitate the review process.

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

Table A MIV Application Submission Requirements

Softcopy
PRISM Application Form / PRISM
Table of Contents / PRISM
Cover Letter / PRISM
Checklist for MIV(s) / PRISM
Table of Summary of Changes / PRISM
MIV-specific Supporting Documents
-Administrative (Module 1/Part 1)
-Other supporting documents / PRISM
PRISM/CD#
Current and Proposed Product Labelling (annotated and pristine copies), where applicable / PRISM

# All supporting documents maybe submittedvia PRISM or CD-ROM– do not combine PRISM attachments with a CD submission

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

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

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REVISION HISTORY

Form Version (Publish Date)

TPB-SUB-013-000 (uploaded 31 October 2016)

C1Change of Drug Product Name

C /
  1. There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process) except for the product name change.
  2. No confusion with another drug product either when spoken or written.
  3. The new name does not (i) suggest greater safety or efficacy than supported by clinical data; (ii) imply a therapeutic use; (iii) imply superiority over another similar product; and (iv) imply the presence of substance(s) not present in the product.

D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation.
  2. Updated Certificate of Pharmaceutical Product (CPP) (where applicable).
  3. Official letter from product owner or product registrant authorising the change of product name and committing to inform users of the relevant changes (where applicable).
  4. A declaration from the product registrant that there is no other changes to the product/label except for the drug product name change.

C2Change of Product Labelling

Includes:
a)Change of the layout/artwork without altering meaning.
b)Addition/deletion/replacement of pictures, diagrams, bar code, logos and/or texts that do not imply an unapproved indication.
c)Addition/strengthening of warnings, precautions, contraindications and/or adverse events/effects to the approved product labelling.
Note: Companies that need to disseminate safety information urgently can continue to do so through ‘Dear Healthcare Professional Letters’ in consultation with HSA. Thereafter, product labelling should be updated in accordance with the labelling safety-related update notification system.
d)Tightening of product’s target population.
e)Deletion of indication.(Note: Re-inclusion of the deleted indication in the future should be submitted as MAV-1 according to the prevailing requirements)
f)Change of distributor’s details.
g)Change of product labelling of language(s) other than English
h)Change of product labelling to allow better product differentiation (e.g. addition of colour stickers)
i)Addition of product labelling specific for sample packs
C /
  1. Product labelling refers to Package Insert (PI), Patient Information Leaflet (PIL), unit carton label, inner label and/or blister strips.
  2. The change is not an MIV-1 and does not contain promotional information.

D /
  1. Current approved product labelling.
  2. Proposed product labelling, a clean and annotated version highlighting the changes made.
  3. Relevant document/reference to support the changes (where applicable).
  4. For non-English text, a declaration from the product registrant that the information in the non-English language(s) provides complete, accurate and unbiased information on the product and is consistent with the English information.

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

C /
  1. Only applicable for batch release.
  2. The manufacturer of the drug product remains the same.

D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
  2. Proof that the proposed site is appropriately authorised (accredited by the authority) to be responsible for batch release, such as a valid GMP certificate or CPP which covers the GMP certification, where applicable.
  3. Official letter from the product owner authorising the company/manufacturer to be responsible for batch release (where applicable).

C4Minor Change of Manufacturing Process

C /
  1. For any minor change in the procedure and/or scale of the currently registered manufacturing process at any stage during manufacture of the drug substance and/or drug product.
  2. Relates to a non-critical change in the process, such as change in harvesting and/or pooling procedures without a change in the method of manufacturing, recovery, storage conditions or production scale; duplication of a fermentation train; addition of identical or similar/comparable bioreactors.
  3. No adverse change in qualitative and/or quantitative impurity profile which would require further qualification in safety studies.
  4. The synthetic route remains the same (for example, intermediates remain the same).
  5. Manufacturing process of the drug substance and/or drug product does not use any materials of human/animal origin for which assessment is required for viral safety.
  6. Physicochemical characteristics and other relevant properties of the drug substance and/or drug product remain unchanged.

D /
  1. Amended relevant CTD Sections.
  2. Comparative tabulated format of the currently approved and new processes with changes highlighted (where available).
  3. Technical justification for the change.
  4. A letter of declaration from the product registrant stating that no new impurities have been introduced at or above the accepted threshold for qualification of impurities or that there is no increase in the levels of impurities, which require further safety studies.
  5. A letter of declaration from the product registrant stating that the specifications of the drug substance have not changed or if there is any change to the specification (for example, tightening), the texts of the currently approved and proposed specifications should be provided (in a comparative tabulated format where possible).
  6. A declaration from the product registrant that the relevant stability studies of the drug substance or drug product in accordance with the relevant guideline have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).
  7. Batch analysis data (in a comparative tabulated format) of the drug substance or drug product of at least two batches manufactured according to the currently approved and proposed processes, where appropriate.

C5Change of Specification of Drug Substance, Drug Product, Process Intermediate and/orIn-process Control Tests

a)Specification limits are tightened
b)Addition of new test parameter and limits
C /
  1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
  2. Test procedures remain the same. If there are changes to the test procedures, MIV-1 B12 or MIV-2 C14 is also applicable.
  3. For widening of specification limits and deletion of test parameter and limits, please refer to MIV-1 B3.

D / Specification limits are tightened
  1. Technical justification for the change.
  2. Comparative tabulated format of the currently approved and revised specification with changes highlighted.
  3. Test results of two production scale batches of the drug substance, drug product, process intermediates or in-process controls, for all tests in the revised specification.
Addition of new test parameter and limits
In addition to the above documents,
  1. Description of any new analytical method and summary of the validation data.
  2. Stability data as per the relevant guidelines on the stability study of the drug substance or drug product, and report if any results fall outside of the shelf-life specifications (with proposed action).

C6 Change of Colouring/Flavouring Agent of Product [addition, deletion or replacement of colourant(s)/flavour(s)]

C /
  1. Same functional characteristic, no change in dissolution profile for solid oral dosage forms.
  2. The proposed colouring/flavouring agents must not have been rejected for pharmaceutical use.
  3. The release and shelf-life specifications of the drug product remain unchanged except for the change in colour/flavour.

D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
  2. A declaration from product registrant that the change does not interfere with the drug product release and shelf-life specifications test method.
  3. A letter of commitment from the product owner or product registrant to inform users of the relevant change (where applicable).
  4. Revised product formulation and batch manufacturing formula.
  5. Qualitative and quantitative information of the current and proposed colouring/flavouring agent in a comparative table.
  6. For proposed excipients made of ruminants source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued from the relevant veterinary authority of the issuing country (where applicable).
  7. Revised release and shelf-life specifications of the drug product.
  8. A declaration from the product registrant that the relevant stability studies of the drug substance or drug product in accordance with the relevant guideline have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

C7 Deletion of Solvent/Diluent for Drug Product

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

D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
  2. Justification for the deletion of the solvent/diluent, including a statement regarding alternative means to obtain the solvent/diluent.
  3. Amended relevant CTD Section P (where applicable).

C8 Change of Specification of Excipient

a)Specification limits are tightened
b)Addition of new test parameter and limits
C /
  1. Release and end-of-shelf-life specifications of drug product remain unchanged.
  2. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
  3. Applicable to non compendial excipients. For compendial excipients, please refer to MIV-2 C25.

D /
  1. Description of new method and summary of analytical validation (applicable for addition of new parameter).
  2. Comparative tabulated format of the current and revised specification of the excipient with changes highlighted.
  3. Batch analysis data of the excipient for all tests in the new specification.

C9 Minor Change in Primary Packaging Material for Non-sterile Substance or Product

a)Qualitative and quantitative composition; and/or
b)Type of container; and/or
c)Inclusion of primary packaging material.
C /
  1. For a minor change of the container closure system that is in immediate contact with the drug substance, drug product, process intermediates and/or diluents used for reconstitution.
  2. The proposed packaging material must be at least equivalent to or better than the approved material in respect of its relevant properties.
  3. The change only concerns the same packaging type (for example from blister to blister).
  4. Release and end-of-shelf-life specifications of the drug product remain unchanged.
  5. For a change in the primary packaging material for a sterile drug substance or drug product, please refer to MIV-1 B5.

D /
  1. Revised drafts of the package insert incorporating the proposed variation (where applicable).
  2. Justification for the change in packaging material and appropriate scientific studies on the new packaging.
  3. Information on construction materials and design features of the proposed container closure system.
  4. For semi-solid and liquid dosage forms, proof must be provided that no interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack).
  5. Comparative tabulated format of the currently approved and proposed specifications of the primary packaging material (where applicable).
  6. A declaration from the product registrant that the relevant stability studies of the drug substance or drug product in accordance with the relevant guideline have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

C10 Addition or Replacement of Manufacturer for Secondary Packaging

C / None
D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
  2. Proof that the proposed site is appropriately authorised (accredited by the authority) for the packaging activity concerned, such as a valid GMP certificate and/or CPP which covers the GMP certification.
  3. Official letter from the product owner authorising the new manufacturer or packager to perform secondary packaging (where applicable).

C11 Change of Outer Carton Pack Sizes for Drug Product

C /
  1. Primary packaging materials remain unchanged.
  2. No other changes except for the change of outer carton pack sizes for a drug product.
  3. For any change that only concerns the number of units or containers in a pack; otherwise, refer to MIV-1 B6.
  4. The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved product labelling.

D /
  1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable).
  2. Letter of declaration from the product registrant stating that there are no other changes except for the change of outer carton pack sizes for a drug product.

C12 Change in Any Part of (Primary) Packaging Material Not in Contact with Finished Product Formulation, such as Colour of Flip-off Caps, Colour Code Rings on Ampoules, Change of Needle Shield (different plastic used)

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

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

C13 Replacement or Change of Working Cell/Seed Bank

C /
  1. Establishing a new working cell/seed bank derived from a previously approved master cell/seed bank according to SOPs on file in the approved registrationapplication.

D /
  1. Comparative summary of the current and new working cell/seed banks, e.g. cell number, viability and sterility and functional assay data.
  2. Comparative batch analysis data (in a table) of at least three batches of drug substance derived from the current and new cell/seed banks.
  3. A declaration that the release and shelf life specifications of the drug product have not been changed.
  4. A declaration from the product registrant that the relevant stability studies of the drug substance or drug product in accordance with the relevant guideline have been started and that the relevant stability studies will be finalised; data should be provided only if outside of the specification (with proposed action).

C14Minor Change of Test Procedure

C /
  1. Applicable to update the test procedure to comply with the updated general monograph in official pharmacopoeia, such as Ph. Eur., USP, BP and JP. This includes standard compendial microbiological methods.
  2. Not applicable to a change of test procedure of the drug substance, drug product, excipient, and/or in-process control where the test method is not a biological/ immunological/ immunochemical method, or a method using a biological reagent.
  3. Drug product specifications are not adversely affected unless the specifications are tightened as per the relevant compendial monograph.
  4. Results of method verification/validation show the new test procedure to be at least equivalent to the former procedure.
  5. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.

D /
  1. Justification for the proposed change.
  2. Revised specification of the drug substance/drug product/excipient/ in-process test, if applicable.
  3. Description of the proposed analytical methodology.
  4. Appropriate verification/validation data
  5. Comparative test results between the current and proposed test procedure, or comparative batch analysis,of two production batches of the drug substance, drug product, excipient, or in-process control.

C15 Minor Change of Reference Standard

C /
  1. For a change of in-house/non-compendial reference standard prepared and qualified by an approved preparation and calibration/qualification protocols. If there is a change of the approved protocol, please refer to MIV-1 B14.
  2. For a change of compendial reference standard, or,a change from a non-compendial/in house to a compendial reference standard.

D /
  1. Certificate of analysis of the proposed reference standard.
  2. Batch analysis data (in a comparative tabulated format) of the drug substance or drug product on at least two production batches using the currently registered and proposed reference standard.
  3. Amended relevant CTD Sections.
  4. A declaration that there is no change to the preparation and calibration/qualification protocols, if applicable.

C16 Change in Supplier of Animal-derived Material

C /
  1. For animal-derived material of mammalian or avian origin used as an excipient or active ingredient in the drug product, or as an adjuvant.
  2. There is no change in the animal species from which the animal-derived material is obtained from.
  3. Animal derived material from other species (e.g. insects and fish) is exempted from this variation.

D /
  1. Information on all countries which the animal was sourced from*.
  2. Declaration on the nature of the animal tissue and/or fluid used.
  3. Certificate of analysis for the animal-derived material used, stating the name and address of the supplier.
  4. Relevant information to demonstrate that the manufacturing process is capable of inactivating adventitious agents, where applicable.
  5. For materials derived from TSE-relevant animals (i.e. cattle, sheep, goat, deer, elk, non-human primates):
  6. A valid TSE Risk evaluation CEP; OR
  7. i. Description of the tissue/organ/fluid-collection procedures and measures in place to avoid cross-contamination;
ii. Details of the risk factors associated with the route of administration and maximum therapeutic dosage of the product; and,
iii. Relevant information demonstrating that the manufacturing process is capable of inactivating TSE agents.
* not required for animal derived products from milk and certain milk derivatives such as lactose

C17 Change in Species of Animal-derived Material