AUGUST 2024

GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE

– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

Table of Contents

PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL)

VARIATION

D1 Change in Packaging Material Not in Contact with Drug Product...................3

D2 Addition or Replacement of Site Responsible for Quality Control (QC)
Testing of Drug Product......................................................................................3
D3 Change of Product Owner or Change in Name and/or Address (for example:
postal code, street name) of Product Owner.....................................................4
D4 Change in Ownership of Manufacturer..............................................................4
D5 Change of Name or Address (for example: postal code, street name) of
Manufacturer of Drug Product............................................................................4
D6 Change of Name or Address (for example: postal code, street name) of
Company or Manufacturer Responsible for Batch Release.............................5
D7 Change of Name or Address (for example: postal code, street name) of
Manufacturer of Drug Substance........................................................................5
D8 Withdrawal/Deletion of Alternative Manufacturer(s) for Drug Substance,
Drug Substance Intermediate and/or Drug Product and/or Packager and/or
batch releaser and/or QC Testing Laboratory of Drug Product.......................6
D9 Obsolete................................................................................................................6
D10 Deletion of Pack Size for Drug Product..............................................................6
D11 Change of Batch Numbering System.................................................................6
D12 Update of Product Labelling................................................................................6
D13 Change of Batch Size of Drug Substance..........................................................7
D14 Change of In-process Tests or Limits Applied during Manufacture of Drug
Substance.............................................................................................................7
D15 Change of Specification of Drug Substance......................................................8
D16 Change of Specification of Drug Substance to comply with latest
compendium.........................................................................................................8
D17 Change of Test Procedure of Drug Substance..................................................9
D18 Revision of CEP....................................................................................................9
D19 Submission of CEP for an Approved Drug Substance Manufacturer...........10
D20 Change of In-process Controls Applied during Manufacture of Drug Product
..............................................................................................................................10
D21 Minor Change in the Manufacturing Process for Drug Product....................11
D22 Change of Release and/or Shelf-life Specifications of Drug Product...........12
D23 Change of specification of Drug Product to Comply with Latest
Compendium.......................................................................................................12
D24 Minor change of Test Procedure for Excipient................................................13

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP Appendix 13C - Page 1 of 16
 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION
D25 Change of specification of Excipient or Drug Substance Starting Material to
Comply with Latest Compendium.....................................................................13
D26 Change in Source of Empty Hard Capsule......................................................14
D27 Change or Addition of Pack Size for Drug Product........................................14
D28 Change in the Specification Parameters and/or Limits or Test Procedure of
Primary Packaging Material...............................................................................15
D29 Obsolete.................................................................................................................15
D30 Update of Anatomical Therapeutic Chemical (ATC) code................................15

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

Declaration of the product registrant for MIV-2 Do-and-Tell

I hereby declare that:

 All changes submitted are categorised as MIV-2 Do-and-Tell, and no other changes
have been included in this application.
 The change(s) will not adversely affect the quality, efficacy and safety of the therapeutic
product concerned.
 All information provided by me in this MIV-2 Do-and-Tell is true and accurate.

__________________________ _______________________ _________________

Name Signature Date

D1 Change in Packaging Material Not in Contact with Drug Product

C 1. For change of packaging material not in contact with drug product, such as colour of
flip-off caps, colour code rings on ampoules, change of needle shield.
2. The change does not concern a part of the packaging material which affects the
delivery, use, safety or stability of the drug product.

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

D2 Addition or Replacement of Site Responsible for Quality Control (QC) Testing of

Drug Product

C 1. The manufacturer and primary packager of the drug product remains unchanged.
2. Method transfer from the approved to the proposed site or test laboratory has been
successfully completed.

D 1. Declaration from the drug product manufacturer / product owner on the following:
a) The change does not affect the release and shelf life specifications of the drug
product.
b) The tests used by the proposed QC testing site are equivalent to the registered
methods.
c) List of tests used by the proposed QC testing site with indication if the method
suitability / transfer / validation has been completed for each test.

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

D3 Change of Product Owner or Change in Name and/or Address (for example:

postal code, street name) of Product Owner

C 1. The product registrant remains unchanged.

2. The manufacturing site remains unchanged.

D For change of product owner:

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 from the new product owner.
3. An official letter from the new product owner declaring the change and authorising
the local registrant to be responsible for the product registration.
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 drug
product on its behalf.
For change of name and/or address of product owner:
5. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
6. An official letter from the product owner declaring the change and authorising the
local registrant to be responsible for the product registration.

D4 Change in Ownership of Manufacturer

C 1. The drug substance / drug product manufacturing site remains unchanged.

2. No other changes except for the change in ownership of the drug substance / drug
product 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 the 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
substance(s) or drug product(s) on its behalf.

D5 Change of Name or Address (for example: postal code, street name) of

Manufacturer of Drug Product

C 1. Applicable to all sites involved in the drug product manufacturing process, e.g.,
intermediate, bulk production, primary packaging, secondary packaging, quality
control sites.

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

2. The manufacturing site remains unchanged.

3. No other changes except for the change of the name and/or address of a
manufacturer of the drug product.
4. For a change in ownership of manufacturer, refer to MIV-2 D4.

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 product owner authorising the manufacturer with the new
name/address to manufacture the drug product.

D6 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 unchanged.

2. The batch release site remains unchanged.
3. For a change in ownership of manufacturer, refer to MIV-2 D4.

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 (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 product registrant that the change does not involve a change
of batch release site.

D7 Change of Name or Address (for example: postal code, street name) of

Manufacturer of Drug Substance

C 1. Applicable to all sites involved in the drug substance manufacturing process, e.g.,
intermediate, drug substance, milling/micronisation, quality control sites.
2. The manufacturing site remains unchanged.
3. No other changes except for the change of the name and/or address of a
manufacturer of the drug substance.
4. For a change in ownership of manufacturer, refer to MIV-2 D4.

D 1. Updated information of the manufacturer of the drug substance.

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.

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

D8 Withdrawal/Deletion of Alternative Manufacturer(s) for Drug Substance, Drug

Substance Intermediate and/or Drug Product and/or Packager and/or batch
releaser and/or QC Testing Laboratory of Drug Product

C 1. An alternative manufacturer is registered.

D 2. Reason for withdrawal/deletion.

D9 Obsolete

D10 Deletion of Pack Size for Drug Product

C 1. 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. Reason for the deletion.

D11 Change of Batch Numbering System

C 1. The manufacturing site remains unchanged.

D 1. Description of the revised batch numbering system.

2. An official letter stating the commencement date of the change.

D12 Update of Product Labelling

For Administrative changes as listed below:
• Rearrangement / re-formatting of text without any change in information in PI/PIL
• Changes to non-English text (e.g., Chinese) in PI/PIL as long as the information is
consistent with the approved English text
• Addition / deletion / change of artwork (e.g., pantone colour), images and logos.
• Amendment of typographical errors.
• Change of product registrant information to align with submission via
Transfer@PRISM

C 1. Applicable only to changes listed above.

2. The change does not have any impact on the product’s safety, efficacy and quality.

D 1. Approved product labelling.

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

2. Proposed product labelling: a pristine and annotated version highlighting the

changes made.
3. Relevant document/reference or justification to support the changes (where
applicable).

D13 Change of Batch Size of Drug Substance

C 1. This is only applicable for change of batch size of non-sterile drug substance up to
10-fold compared to the approved batch size. Refer to MIV-2 C4 for change of batch
size of non-sterile drug substance by more than 10-fold.
2. The change does not affect the reproducibility of the process. Any changes to the
manufacturing process is only those necessitated by scale-up or downscaling, e.g.,
use of different-sized equipment.
3. Specifications of the drug substance remain unchanged.
4. The change should not be the result of unexpected events arising during
manufacture or because of stability concerns.

D 1. A letter of declaration from the product registrant that the specifications of the drug
substance have not changed, and the reproducibility of the process has not been
affected and that the change is not the result of unexpected events arising during
manufacture or because of stability concerns.
2. Amended relevant CTD Section S (where applicable).
3. Certificate of analysis or batch analysis data (in a comparative tabulated format) for
at least two batches of the drug substance for all tests in the approved specification
from the approved and proposed batch sizes.

D14 Change of In-process Tests or Limits Applied during Manufacture of Drug

Substance

C 1. Tightening of in-process limits. The test procedure remains the same, or changes in
the test procedures are minor.
2. Addition of in-process tests and limits. The new test method that does not concern a
novel non-standard technique or a standard technique used in a novel way.
3. Deletion of a non-significant in-process test. The specification parameter does not
concern a critical parameter, e.g., assay, impurities, or any critical physical
characteristics.
4. For widening of in-process test limits or deletion of a significant in-process test, refer
to MIV-1 B3 or B4.
5. The change is not a consequence of any commitment from previous assessments to
review the specification limits.
6. The change does not result from unexpected events arising during manufacture,
e.g., new unqualified impurity or change in total impurity limits.

D 1. A description of the analytical method and summary of validation data must be

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

provided for all new analytical methods (where applicable).

2. Comparative tabulated format of the approved and proposed in-process controls
and the relevant changes.
3. Certificate of analysis or batch analysis data (in a comparative tabulated format) for
at least two production batches of the drug substance for all tests in the approved
and proposed specification (where applicable).
4. (For deletion of non-significant in-process test) Justification/risk assessment, as
appropriate, that the in-process tests are non-significant, or that the in-process tests
are obsolete.

D15 Change of Specification of Drug Substance

a) Specification limits are tightened.
b) Deletion of non-significant parameter (e.g., obsolete parameter)

C 1. For widening of specification limits and deletion of significant test parameter and
limits of the drug substance, refer to MIV-1 B5. For addition or replacement of a
specification parameter and limit, refer to MIV-1 C6.
2. Test procedures remain the same or changes in the test procedure are minor.

D Specification limits are tightened

1. Technical justification for the change.
2. Comparative tabulated format of the approved and proposed specification of the
drug substance with changes highlighted.
3. Certificate of analysis or batch analysis data (in a comparative tabulated format) for
at least two pilot batches of the drug substance for all tests in the approved and
proposed specification.
Deletion of non-significant parameter
In addition to documents (1) and (2),
4. Justification/risk assessment showing that the parameter is non-significant or that it
is obsolete.

D16 Change of Specification of Drug Substance to comply with latest compendium

C 1. Applicable to compendial specifications only. All the tests in the specification need
to correspond to the pharmacopoeia standard after the change, except any
additional supplementary tests.
2. Change is made to comply with an update of the relevant monograph of the
compendium or from one recognised pharmacopoeia to another.
3. Pharmacopoeia recognised by HSA: United States Pharmacopeia, European
Pharmacopoeia, British Pharmacopoeia and Japanese Pharmacopoeia.
4. No significant changes in qualitative and quantitative impurities profile unless the
specifications are tightened.

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

D 1. Tabulation of the approved and proposed release and/or shelf-life specifications of

the drug substance with changes highlighted.
2. Certificate of analysis or batch analysis of at least two batches of drug substance for
all tests in the proposed specification.

D17 Change of Test Procedure of Drug Substance

C 1. Minor change to an approved test procedure.

2. Deletion of a test procedure, if an alternative test procedure is already included in
the approved drug substance specification.
3. Appropriate validation studies have been performed and show that the updated test
procedure is at least equivalent to the former procedure.
4. There have been no changes of the total impurity limits, and no new unqualified
impurities are detected.

D 1. Description of the test procedure, and a summary of validation data (where

applicable).
2. Specification of the drug substance.
3. Comparative analytical results between the approved and proposed test (where
applicable).

D18 Revision of CEP

C 1. For submission of a revision of CEP for an approved manufacturer only.

2. For minor change to the drug substance, includes change of manufacturing process,
change of batch size, in-process controls, specification (tightening or addition of test
parameters), test procedure, shelf life/re-test period, and/or storage condition, that
are covered by a valid CEP.
3. Refer to MIV-1 B4 if this change is due to a major change of the manufacturing
process of the drug substance.
4. Refer to MIV-1 B6 if this change is due to a widening of the specification limits or
deletion of test parameters.

D 1. A copy of the valid CEP, including all annexes as issued by the EDQM, and a copy
of the Letter of Access from the CEP holder to authorise the applicant to refer to the
CEP in support of their application.
2. Specification of the drug substance (where applicable).
3. Results of batch analysis from the drug substance manufacturer* demonstrating
compliance with the Ph. Eur. monograph and including additional test/limits listed on
the CEP (where applicable).
* If the drug substance manufacturer is CEP-certified and the drug product
manufacturer claims otherwise (USP, JP, In-house etc.), data covering S4.1 to
S4.5 from the drug product manufacturer should be submitted.
4. Additional data to address any relevant parameter(s) not addressed in the CEP,

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

such as stability data (S7) if a re-test period is not stated on the CEP and
physicochemical characteristics (e.g., particle size, polymorphism etc.), where
applicable.
5. If this change is due to a drug substance specification change, a commitment letter
to conduct relevant stability studies of the drug product in accordance with the
ASEAN Guideline on Stability Study of Drug Product to support the approved shelf
life. The product registrant shall report to the Health Sciences Authority of any out-
of-specification result (with proposed action). Submission of the data in the form of a
finalised report is not required but the data shall be provided to the Health Sciences
Authority.

D19 Submission of CEP for an Approved Drug Substance Manufacturer

C 1. Submission of CEP for an approved drug substance manufacturer that is currently

supported by Drug Master File (DMF) / ICH Common Technical Document (CTD) /
ASEAN CTD (ACTD) dossier.
2. If there are other changes to the drug substance, the relevant MIV checklists will
apply.

D 1. Specify the registered DMF number to be replaced.

2. A copy of the valid CEP, including all annexes as issued by the EDQM and a copy
of the Letter of Access from the CEP holder to authorise the applicant to refer to the
CEP in support of their application.
3. A letter of declaration from the product registrant that there are no other changes
except for the change from DMF / ICH CTD / ACTD to CEP.

D20 Change of In-process Controls Applied during Manufacture of Drug Product

C 1. Tightening of in-process limits. The test procedure remains the same, or changes in
the test procedures are minor.
2. Deletion of a non-significant in-process test. The specification parameter does not
concern a critical parameter, e.g., assay, impurities, or any critical physical
characteristics.
3. For widening of specification limits of IPC or deletion of test parameters and limits of
IPC, refer to MIV-1 B24. For addition or replacement of new IPC, refer to MIV-2
C16.
4. Release and shelf-life specifications of the drug product remain unchanged.
5. The change is not a consequence of any commitment from previous assessments
to review the specification limits.
6. The change does not result from unexpected events arising during manufacture,
e.g., new unqualified impurity or change in total impurity limits.

D 1. A description of the analytical methodology and summary of validation data must be

provided for all new analytical methods (where applicable).
2. Comparative tabulated format of currently approved and proposed in-process

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

controls.
3. Proposed in-process specifications together with justification and relevant process
validation data.
4. Certificate of analysis or comparative batch analysis data of the drug product of at
least two production batches.
5. (For deletion of non-significant in-process test) Justification/risk assessment , as
appropriate, that the in-process tests are non-significant, or that the in-process tests
are obsolete.

D21 Minor Change in the Manufacturing Process for Drug Product

C 1. The change, as per Level 1, Part VI Manufacturing, SUPAC Guideline.

2. No change in qualitative and quantitative impurity profile or in physico-chemical
properties.
3. The manufacturing principle including the single manufacturing steps remain
unchanged, e.g., processing intermediates and there are no changes to any
manufacturing solvent used in the process.
4. The approved process has to be controlled by relevant in-process controls and no
changes (widening or deletion of limits) are required to these controls.
5. The specifications of the finished product or intermediates are unchanged.
6. The proposed process must lead to an identical product regarding all aspects of
quality, safety and efficacy.
7. Relevant stability studies in accordance with the relevant guidelines have been
started with at least one pilot scale or production scale batch and at least three
months stability data are at the disposal of the applicant. Assurance is given that
these studies will be finalized and that the data will be provided immediately to the
competent authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life (with proposed action).

D 1. Amendment of the relevant section(s) of the dossier, as appropriate, including a

direct comparison of the approved process and the proposed process.
2. For semi-solid and liquid products in which the active substance is present in non-
dissolved form: appropriate validation of the change including microscopic imaging
of particles to check for visible changes in morphology; comparative size distribution
data by an appropriate method.
3. For solid dosage forms: dissolution profile data of one representative production
batch and comparative data of the last three batches from the previous process;
data on the next two full production batches should be available on request or
reported if outside specification (with proposed action).
4. Justification for not submitting a new bioequivalence study) according to the ASEAN
Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where
applicable).
5. Copy of approved release and shelf life specifications.
6. Certificate of analysis and/or batch analysis data (in a comparative tabulated format)
on a minimum of one batch manufactured to both the approved and the proposed

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

process. Batch analysis data on the next two full production batches should be
made available upon request and reported by the product registrant if outside
specification (with proposed action).
7. A commitment letter to conduct relevant stability studies of the drug product in
accordance with the ASEAN Guideline on Stability Study of Drug Product to support
the approved shelf life. The product registrant shall report to the Health Sciences
Authority of any out-of-specification result (with proposed action). Submission of the
data in the form of a finalised report is not required but the data shall be provided to
the Health Sciences Authority upon request.

D22 Change of Release and/or Shelf-life Specifications of Drug Product

a) Specification limits are tightened.
b) Deletion of non-significant parameter (e.g., obsolete parameter)

C 1. The variation should not be submitted as a result of unexpected events that may
lead to product defects. Variation is only to be submitted after concerns have been
addressed and CAPAs concurred. Refer to the Product Defect Reporting and
Recall Procedures on the HSA website for product defect reporting.
2. Test procedures remain unchanged, or changes in the test procedures are minor
(MIV-2 C24 is also applicable if there is change in test methods).
3. For widening of specification limits and/or deletion of test parameter and limits of the
drug product, refer to MIV-1 B9. For addition of new test parameters and limits, refer
to MIV-2 C21.
4. For a change in specification due to update of the compendium for compendial drug
product, refer to MIV-2 D23.

D 1. Technical justification for the change.

2. Comparative tabulated format of the approved and proposed release and shelf-life
specifications of the drug product with changes highlighted.
3. Certificate of analysis or batch analysis data of the drug product on at least two
batches (preferably production scale) for all tests in the proposed specification.
Deletion of non-significant parameter
In addition to documents (1) and (2),
4. Justification/risk assessment showing that the parameter is non-significant or that it
is obsolete.

D23 Change of specification of Drug Product to Comply with Latest Compendium

C 1. The variation should not be submitted as a result of unexpected events that may
lead to product defects. Variation is only to be submitted after concerns have been
addressed and CAPAs concurred. Refer to the Product Defect Reporting and
Recall Procedures on the HSA website for product defect reporting
2. Applicable to the test parameters and limits described in the compendial only.

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

3. Change is made to comply with an update of the relevant monograph of the

compendium or from one recognised pharmacopoeia to another.
4. Pharmacopoeia recognised by HSA: United States Pharmacopeia, European
Pharmacopoeia, British Pharmacopoeia and Japanese Pharmacopoeia.
5. Any change should be within the range of currently approved limits.
6. The test procedure remains the same, or changes in the test procedures are minor.
7. The change does not concern any impurities (including genotoxic) or dissolution.

D 1. Updated release and/or shelf-life specifications.

2. Tabulation of the approved and proposed release and/or shelf-life specifications of
the drug product with changes highlighted.
3. Certificate of analysis or batch analysis of at least two batches of drug product for all
tests in the proposed specification.

D24 Minor change of Test Procedure for Excipient

C 1. For minor change of a test procedure for excipient. For replacement or addition of a
test procedure for excipients, refer to MIV-2 C19.
2. The method of analysis should remain the same (e.g., change in column height or
temperature, but not a different type of column or method).
3. The specification of the excipient remains unchanged, and there is no change of the
total impurities and no new impurities detected.

D 1. Description of the analytical methodology with a comparative tabulation of the

changes.
2. Results of appropriate method validation to show proposed test procedure to be at
least equivalent to the approved procedure, if applicable.
3. For quantitative test change, comparative analytical validation results showing that
the approved and proposed tests are equivalent.

D25 Change of specification of Excipient or Drug Substance Starting Material to

Comply with Latest Compendium

C 1. Applicable to compendial specifications only. All the tests in the specification need
to correspond to the pharmacopoeia standard after the change, except any
additional supplementary tests.
2. Change is made to comply with an update of the relevant monograph of the
compendium or from one recognised pharmacopoeia to another.
3. Pharmacopoeia recognised by HSA: United States Pharmacopeia, European
Pharmacopoeia, British Pharmacopoeia and Japanese Pharmacopoeia.

D 1. Revised specification of the excipient or drug substance starting material.

2. Comparative tabulated format of the approved and proposed specification of

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

excipient or drug substance starting material with changes highlighted.

3. Certificate of analysis or batch analysis of the excipient or starting material for all
tests in the new specification of at least two batches.
4. A declaration that the change has no impact on the manufacturing process and
quality of the drug product or drug substance.

D26 Change in Source of Empty Hard Capsule

C 1. From TSE-risk material to vegetable-sourced or synthetic capsule. For change of

vegetable-sourced or synthetic to TSE-risk material capsule, please refer to MIV-2
C20.
2. Not applicable to a change from a hard capsule to a soft gel.
3. The formulation and manufacturing process of the drug product remain unchanged.
4. The specifications of excipients and specifications of the release and shelf-life of
drug product remain unchanged.

D 1. A letter of declaration from the manufacturer or the product registrant of the material
that it is purely of vegetable or synthetic origin.
2. Technical specifications and composition of the empty hard capsule of the proposed
source.
3. Certificates of analysis of the empty hard capsule of the proposed source.
4. Comparative dissolution profile data of one batch representative of pilot/production
batch of the drug product using the hard capsule between the two sources (where
applicable) as per US FDA SUPAC IR or MR guidelines.
5. A commitment letter to conduct relevant stability studies of the drug product in
accordance with the ASEAN Guideline on Stability Study of Drug Product to support
the approved shelf life. The product registrant shall report to the Health Sciences
Authority of any out-of-specification result (with proposed action). Submission of the
data in the form of a finalised report is not required but the data shall be provided to
the Health Sciences Authority upon request.

D27 Change or Addition of Pack Size for Drug Product

C 1. For change or addition of pack size involving the following:

 Number of blister strips in a pack, where the number of tablets/capsules per
blister strip remains unchanged
 Number of containers in a pack (e.g., vials, ampoules) where the content per
container (e.g., fill volume/weight) remains unchanged
Otherwise, refer to MIV-1 B16 or MIV-2 C28.
2. The type and specification of the primary packaging material remain unchanged.
3. The product presentation(s) must be adequate for the dosing regimen and duration
of use as per the approved product labelling.

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GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION

D 1. Revised drafts of the package insert and labelling incorporating the proposed
variation (where applicable).
2. A letter of declaration from the product registrant stating that there are no other
changes except for the change of pack sizes for a drug product.
3. A commitment letter to conduct relevant stability studies of the drug product in
accordance with the ASEAN Guideline on Stability Study of Drug Product to
support the approved shelf life (where applicable).

D28 Change in the Specification Parameters and/or Limits or Test Procedure of

Primary Packaging Material

C 1. The primary packaging material remain unchanged.

2. Tightening of specification limits. Any change should be within the range of
approved limits.
3. Addition of a new specification parameter to the specification with its corresponding
test method. Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way.
4. Deletion of a non-significant specification parameter (e.g., deletion of obsolete
parameter)

D 1. Comparative tabulated format of the approved and proposed specifications of the

primary packaging material.
2. Revised CTD Sections S6 or P7 (where applicable).
3. Declaration of compliance to the appropriate international standards or
pharmacopoeia.

D29 Obsolete

D30 Update of Anatomical Therapeutic Chemical (ATC) code

C 1. The revised ATC code is as per the code assigned by the World Health
Organization Collaborating Centre for Drug Statistics Methodology (WHOCC) and is
consistent with the current approved therapeutic use of the product in Singapore.

D 1. Revised drafts of the package insert and labelling incorporating the change of ATC
code (where applicable).

________________________________________________________________

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 AUGUST 2024
GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
– GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL THERAPEUTIC PRODUCTS
APPENDIX 13C - PART C: CHECKLIST ON DOSSIER REQUIREMENTS FOR MIV-2 (DO-AND-TELL) VARIATION
REVISION HISTORY

Guidance Version (Publish Date)

TPB-SUB-018-005 (uploaded 31 July 2024)

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