PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATIONS
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 before
implementation 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 recategorise the MIV if deemed appropriate.
Product licence holder 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 Hard Copy and Electronic Copy Requirements
PRISM application form
Table of Contents
Declaration of product licence holder for MIV-2
Checklist for MIV(s)
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
Soft Copy
PRISM
PRISM
PRISM
PRISM
PRISM
Hard Copy
N/A
N/A
1 set
N/A
N/A
PRISM
PRISM/CD#
PRISM
1 set+
N/A
N/A
+ Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1
(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, declaration letters,
etc)
# All supporting documents may be submitted via 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 conditions that must be fulfilled in order for the MIV to apply.
 “D” are the relevant documents that are to be submitted for the MIV.
NOTE: When submitting the Checklist, please delete the MIV-2 checklist
category(ies) that do not relate to the MIV application being submitted.
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
Declaration of the product licence holder for MIV-2
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;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
____________________
Name
______________________
Signature
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
_______________
Date
Appendix 16, Part C
C1
Change 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 marketing authorisation holder authorising the
change of product name and committing to inform users of the relevant changes
(where applicable).
4. A declaration from the marketing authorisation holder that there is no other
changes to the product/label except for the drug product name change.
5. Trademark certificate (where applicable).
C2
Change 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) Addition of drug interactions that pose a safety risk to the use of the product (e.g.
increase in drug levels, potentiation of drug action or adverse effects).
e) Tightening of product’s target population.
f) Deletion of indication. (Note: Re-inclusion of the deleted indication in the future should be
submitted as MAV-1 according to the prevailing requirement)
g) Change of distributor’s details.
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. Letter of declaration from the marketing authorisation holder stating that there are
no other changes on the label except for the intended change.
4. Relevant document/reference to support the changes (where applicable).
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Appendix 16, Part C
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.
Note: documents showing the presence of a Qualified Person (QP) on the site can
be submitted in lieu of a GMP certificate or CPP.
3. Official letter from the product owner authorising the company/manufacturer to be
responsible for batch release (where applicable).
C4
Minor 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 marketing authorisation holder 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 marketing authorisation holder 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 marketing authorisation holder 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).
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
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.
C5
Change of Specification of Drug Substance, Drug Product, Process
Intermediate and/or In-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.
3. For (b), applicable to non-compendial method only.
4. 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,
4. Description of any new analytical method and summary of the validation data.
5. 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 marketing authorisation holder that the change does not
interfere with the drug product release and shelf-life specifications test method.
3. A letter of commitment from product owner or marketing authorisation holder 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
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Appendix 16, Part C
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 marketing authorisation holder 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 C24.
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
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
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.
2.
3.
4.
5.
6.
Revised drafts of the package insert incorporating the proposed variation
(where applicable).
Justification for the change in packaging material and appropriate scientific
studies on the new packaging.
Information on construction materials and design features of the proposed
container closure system.
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).
Comparative tabulated format of the currently approved and proposed
specifications of the primary packaging material (where applicable).
A declaration from the marketing authorisation holder 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 marketing authorisation holder stating that there are
no other changes except for the change of outer carton pack sizes for a drug
product.
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Appendix 16, Part C
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 license
application.
D
1. Comparative summary of the current and new working cell/seed bank, 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 bank.
3. A declaration that the release and shelf life specifications of the drug product have
not been changed.
4. A declaration from the marketing authorisation holder 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).
C14 Minor 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 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 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 of two
production batches the drug substance, drug product, excipient, or in-process
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Appendix 16, Part C
control, for all tests in the approved specification.
C15 Change of Compendial Reference Standard
C
1. For a change of compendial reference standard, or, a change from a noncompendial/in house to a compendial reference standard.
2. For a change of non-compendial reference standard, refer to MIV-1 B14.
3. Release and shelf-life specifications of the drug substance/drug product are not
affected.
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.
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):
a. A valid TSE Risk evaluation CEP, OR,
b. 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
C
1. For a change in species of animal-derived material used
a) at any stage in the manufacture of the drug substance and/or drug product
(e.g. from pig to cow);
b) as excipient or active substance (e.g. bovine gelatine to porcine gelatine) of the
drug product; or,
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
c) as an adjuvant.
2. This variation includes all species of animals.
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 for mammalian and avian materials.
4. Identification of new adventitious agents, where applicable.
5. Relevant information to demonstrate that the manufacturing process is capable of
inactivating new adventitious agents, where applicable.
6. For materials derived from TSE-relevant animals (i.e. cattle, sheep, goat, deer,
elk, non-human primates):
a) A valid TSE Risk evaluation CEP, OR,
b) 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
C18 Change in Name and/or Address (for example: postal code, street name)
of Marketing Authorisation Holder
C
1. The name change refers to the renaming of a company or organization.
2. The change does not include transfer of marketing authorisation or product
ownership to another company.
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A letter by the product owner authorising the new name of the marketing
authorisation holder to hold the product license, or, a declaration from the product
owner/marketing authorisation holder that the change does not involve the legal
transfer of ownership to another company.
3. Official document from the relevant authority confirming the change with the new
name and/or address.
C19 Change of Product Owner
C
1. The marketing authorisation holder remains the same.
2. The manufacturing site remains the same.
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A declaration on the transfer of ownership between the old product owner and
new owner.
3. An official letter from the new product owner declaring the change and authorising
the local license holder to be responsible for the product license.
4. 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
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Appendix 16, Part C
drug product on its behalf.
5. If the new product owner is not the manufacturer of the drug product, a letter of
acceptance from the manufacturer that it will be held responsible for
manufacturing and ensuring the efficacy, quality and safety aspect of the drug
product.
C20 Change in Ownership of Manufacturer
C
1. The manufacturing site remains unchanged.
2. No other changes except for the change in ownership of manufacturer.
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A letter of justification on the transfer of ownership, such as a valid GMP
certificate.
3. An official letter stating the transfer of ownership from old manufacturer to the new
manufacturer (where applicable).
4. In case of a contract manufacturer, an official letter from the product owner
declaring the change and authorising the new manufacturer to manufacture the
drug product(s) on its behalf.
5. In case of a contract manufacturer, a letter of acceptance from the new
manufacturer that it will be held responsible for manufacturing and ensuring the
efficacy, quality and safety aspect of the drug product.
C21 Change of Name or Address (for example: postal code, street name) of
Manufacturer of Drug Product
C
1. The manufacturing site remains the same.
2. No other changes except for the change of the name and/or address of a
manufacturer of the drug product.
3. Not applicable to the case in which it involves a change in ownership of the
manufacturer. For a change in ownership of manufacturer, please refer MIV-2
C20.
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A valid GMP certificate, a CPP which covers the GMP certification or an official
document from a relevant authority confirming the new name and/or address.
3. An official letter from the product owner authorising the manufacturer with the new
name/address to manufacture the drug product.
C22 Change of Name or Address (for example: postal code, street name) of
Company or Manufacturer Responsible for Batch Release
C
1. The manufacturer of the drug product remains the same.
2. The batch release site remains the same.
3. Not applicable to the case in which it involves a change in ownership of the
manufacturer. For a change in ownership of manufacturer, please refer MIV-2
C20.
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A valid GMP certificate, a CPP which covers the GMP certification or an official
document from a relevant authority confirming the new name or address (where
applicable).
3. An official letter from the product owner authorising the company/manufacturer
with the new name/address that is responsible for batch release.
4. A declaration from the marketing authorisation holder that the change does not
involve a change of batch release site.
C23 Change of Name and/or Address (for example: postal code, street name)
of Manufacturer of Drug Substance
C
1. The manufacturing site of the drug substance remains unchanged.
2. No other changes except for the change of the name and/or address of a
manufacturer of the drug substance.
D
1. Updated information of the manufacturer of the drug substance.
2. Official document/evidence when required
C24 Withdrawal/Deletion of Alternative Manufacturer(s) for Drug Substance
and/or Drug Product and/or Packager
C
1. An alternative manufacturer is registered.
D
1. Reason for withdrawal/deletion.
C25 Change of Specification of Excipient to Comply with Pharmacopoeia
C
1. Applicable to compendial specifications only.
2. Change is made exclusively to comply with an update of the relevant monograph
of the compendium.
3. Pharmacopoeia recognized by HSA: United States Pharmacopeia, European
Pharmacopoeia, British Pharmacopoeia and Japanese Pharmacopoeia
D
1. Specification of the excipient.
2. Tabulation of the current and revised specification of the excipient(s) with changes
highlighted.
3. Batch analysis of the excipient(s) for all tests in the new specification of at least
two batches.
4. Declaration that the quality of the drug product is not adversely affected.
C26 Deletion of Pack Size for Product
C
1. The remaining pack sizes are adequate to accommodate the dosing regimen as
per the approved product labelling.
2. For addition of pack size for sterile products, please refer to MIV-1 B6. For a
change in the outer carton pack size, please refer to MIV-2 C11.
HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP
Appendix 16, Part C
D
1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. Reason for deletion.
C27 Change of Batch Numbering System
C
1. The manufacturing site remains the same.
D
1. Description of the revised batch numbering system.
2. An official letter stating the commencement date of the change.
C28 Addition or Replacement of Name of Quality Control (QC) Testing
Laboratory
C
1. The testing laboratory remains the same.
2. No other changes except for the change of the name and/or address of the
currently registered laboratory(ies) for stability tests or any quality control tests.
D
1. Updated information of the testing laboratory.
2. An official letter from the product owner authorising the testing laboratory with the
new name/address.
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Appendix 16, Part C