ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS

6TH DRAFT
JULY 2011

	

	LIST OF CONTENTS	Page	
1	INTRODUCTION	1	
2	SCOPE OF THIS GUIDELINE	1	
3	DEFINITION	1	
3.1	Major Variation (MaV)	1	
3.2	Minor Variation (MiV-PA & MiV-N)	1	
4	PROCEDURE AND TIMELINE	1	
5	CHANGES LEADING TO A NEW PRODUCT REGISTRATION	1-3	
6	OTHERS	3	
7	MAJOR VARIATION (MaV)
		
MaV-1	Change and/or additional indication/dosing regimen/patient population/inclusion of clinical information extending the usage of the product	4	
MaV-2	Change of content of product labeling	4	
MaV-3	Change and/or addition of alternative manufacturer/site of drug substance (where European Pharmacopoeia Certificate of Suitability (CEP) is not available)	5	
MaV-4	Addition or replacement of the manufacturing site of the drug product	6	
MaV-5	Addition or replacement of the alternative site for the primary packaging (direct contact with drug product)	6	
MaV-6	Change of the specification drug substance and/or drug product	7	
MaV-7	Change of batch size of sterile drug product	7	
MaV-8	Change of batch size of non-sterile drug product 	8	
MaV-9	Major change in the manufacturing process for the drug product	8	
MaV-10	ReplacementChange or quantitative change of an excipient	9	
MaV-11	Quantitative change in the coating weight of tablets or weight and/or size of capsule shells	10	
MaV-12	Qualitative and quantitative change in composition and/or type of container change or inclusion of primary packaging material for drug product	10	
MaV-13	Change or addition of fill volume and/or change of shape or dimension of container or closure for a sterile solid and liquid drug product 	11	
MaV-14	Inclusion, replacement or deletion of components the solvent/diluent for the drug products including diluents 	11	
MaV-15	Change of Extension of shelf life of the drug product 	12	
MaV-16	Change of storage conditions of the drug product (Lowering from the current approved storage condition)	13	
			
8	MINOR VARIATION PRIOR APPROVAL (MiV-PA)		
MiV-PA1	Change of drug product name	14	
MiV-PA2	Change in name and/or address of the marketing authorization holder	14	
MiV-PA3	Change of product labeling (in accordance to country specific labeling requirement)	15	
MiV-PA4	Addition or replacement of the company or party responsible for batch release	15	
MiV-PA5	Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeia Certificate of Suitability (CEP) is available]	16	
MiV-PA6	Change of batch size of drug substance [excluding drug substance covered by a Certificate of Suitability (CEP)]	16	
MiV-PA7	Change of in-process controls applied during the manufacture of the drug substance (including tightening and addition of new in-process test)	17	
MiV-PA8	Change of manufacturing process of the drug substance	18	
MiV-PA9	Change of the specification of drug substance	19	
MiV-PA10	Revision of Certificate of Suitability (CEP) of drug substance	19	
MiV-PA11	Change of the test procedure of non-compendial drug substance	20	
MiV-PA12	Change of shelf-life or retest period for drug substance	20	
MiV-PA13	Change of storage condition for drug substance	20	
MiV-PA14	Change of batch size of non-sterile drug product	21	
MiV-PA15	Reduction or removal of overage	21	
MiV-PA16	Replacement Change or quantitative change of an excipient	22	
MiV-PA17	Quantitative change in coating weight of tablets or weight and/or size of capsule shell	23	
MiV-PA18	Change of the colouring/flavouring agent of the product [addition, deletion or replacement of colourant(s)/flavour(s)]	23	
MiV-PA19	Change of in-process controls applied during the manufacture of the drug product (including tightening and addition of new in-process test)	24	
MiV-PA20	Minor change of the manufacturing process for non-sterile products.	25	
MiV-PA21	Change of specifications of an excipient	26	
MiV-PA22	Change of a test procedure for an excipient, including replacement of an approved test procedure by a new test procedure	26	
MiV-PA23	Change in the source of empty hard capsule	27	
MiV-PA24	Change of release and shelf-life specifications of the drug product	27	
MiV-PA25	Change of imprints, bossing or other markings on the tablets or printing on capsules including addition or change of inks used for product marking	28	
MiV-PA26	Change of dimensions and/or shape of tablets, capsules, suppositories or pessaries without change in qualitative and quantitative composition and mean mass	29	
MiV-PA27	Change in the test procedure of the drug product (including replacement or addition of a test procedure)	30	
MiV-PA28	Qualitative and quantitative change in the composition of primary packaging material for non-sterile products	30	
MiV-PA29	Addition or replacement of a manufacturer for secondary packaging
	31	
MiV-PA30	Change of pack size/volume and/or shape/dimension of packaging material for volume of non-sterile product	31	
MiV-PA31	Change of outer carton pack sizes for a drug product 	31	
MiV-PA32	Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used)	32	
MiV-PA33	Addition or replacement of measuring device for oral liquid dosage forms and other dosage form	32	
MiV-PA34	Reduction of shelf life of the drug product 
	33	
MiV-PA35	Change of storage conditions of the drug product (Increasing from the current approved storage condition)	33	
			
9	MINOR VARIATION NOTIFICATION (MiV-N)		
MiV-N1	Change of product owner	34	
MiV-N2	Change in ownership of manufacturer	34	
MiV-N3	Change of the name or address (e.g. postal code, street name) of the manufacturer of drug product 	35	
MiV-N4	Change of the name or address (e.g. postal code, street name) of the company or manufacturer responsible for batch release 	35	
MiV-N5	Change of the name and/or address (for example: postal code, street name) of a manufacturer of the drug substance	35	
MiV-N6	Withdrawal/deletion of the alternative manufacturer(s)  (for drug substance and/or drug product and/or packager)	36	
MiV-N7	Renewal of Certificate of Suitability (CEP)	36	
MiV-N8	Change of release and shelf-life specifications of the drug product and/or drug substance and/or excipient, following the updates in the compendium	36	
MiV-N9	Deletion of pack size for a product	36	
			
10	GLOSSARY	37	
11	REFERENCES	37	

ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS

1.	INTRODUCTION 

Throughout the life of a pharmaceutical product, the marketing authorization holder is responsible for the product that is placed in the market and is also required to take into account technical and scientific progress, and to make any amendments that may be required to enable the pharmaceutical products to be manufactured and checked by means of generally accepted scientific methods. Such amendments have to be approved by the regulatory agency.

This guidance document is intended to provide supportive information on the requirements for submission of a variation application to implement a change to a pharmaceutical product. Variation applications are categorized into major variation, minor variation (prior approval) and minor variation (notification). Updating of this guideline will be done on a periodic basis as required.

2. 	SCOPE OF THIS GUIDELINE

This ASEAN Variation Guideline concerns the variation applications submitted by the marketing authorization holder for pharmaceutical products for human use only and not including biotechnology/biosimilar products.

3. 	DEFINITION

3.1 Major variation (MaV)

Variation to a registered pharmaceutical finished product that may affect significantly and/or directly the aspects of quality, safety and efficacy and it does not fall within the definition of minor variation and new registration. 

3.2 Minor Variation (MiV-N & MiV-PA)

Variation to a registered pharmaceutical finished product in terms of administrative data and/or changes with minimal/no significant impact on the aspects of efficacy, quality, and safety.

4. 	PROCEDURE AND TIMELINE

Variation application is submitted along with a declaration letter undersigned by Quality Assurance Manager and Head of Regulatory Officer that declares there is no other change except for the proposed variation

4.1	Minor Variation – Notification 

Type of variation	
Minor variation 
(Notification)
MiV-N
	
Procedure	
Notification
If the notification fulfils the requirements (conditions and supporting documents) as per described under MiV-N, the Regulatory Agency shall acknowledge receipt of a valid notification.
	
Timeline for Regulatory Agency to evaluate variation notification	“Do & Tell”
Acknowledgement of notification will be sent to applicant within 30 working days a duration subject to country specific proposal, following valid receipt of notification.	

4.2	Minor Variation –Prior Approval and Major Variation 

Type of variation	Minor variation
(Prior approval)
MiV-PA	Major variation
MaV	
Procedure	Prior approval

If the application fulfils the requirements (conditions and supporting documents) as per described under  MiV-PA, the Regulatory Agency shall acknowledge receipt of a valid application.	Prior approval

If the application fulfils the requirements (conditions and supporting documents) as per described under  MaV, the Regulatory Agency shall acknowledge receipt of a valid application.	
Timeline for Regulatory Agency to evaluate the variation application	
Within 30 working days a duration subject to country specific proposal upon receipt of a valid application.
and another 30 working days if additional data is required.
	Within 90 working days a duration subject to country specific proposal following receipt of a valid application.	
Implementation of the variation	Within 120 working days a duration subject to country specific proposal after the marketing authorization holder has been informed of the approved variations.	

Note:  
1.	The ‘timeline’ and ‘implementation of the variation’ is subject to country specific proposals.
2.	The regulatory agency reserves the right to re-categorize the application type, where deemed appropriate. Subject to country specific procedure, re-categorization may require the marketing authorization holder to withdraw the original application and resubmit a new application according to the correct category.

5. 	CHANGES LEADING TO A NEW PRODUCT REGISTRATION

Changes requiring a new product registration may vary from country to country. Certain variations described in this guideline may require a new product registration in certain countries. Applicants are advised to check with individual country on the applicability of this variation guideline

6. 	OTHERS

6.1	Lead compendium refers to British Pharmacopeia (BP), United States Pharmacopeia (USP) and European Pharmacopeia (EP).

6.2 	Any variations not yet listed in this guideline should be justified and decided by the Regulatory Agency. Appropriate reference can be made to:
i.	EMA Classification Guidance On Minor Variations of Type IA, Minor Variations of Type IB And Major Variations of Type II,
ii.	SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up And Post-Approval Changes: Chemistry, Manufacturing And Controls, In Vitro Dissolution Testing, And In Vivo Bioequivalence Documentation,
iii.	WHO Guidance On Variations To A Prequalified Product Dossier.

6.3	The Regulatory Agency may in certain cases request for supplementary information, when deemed necessary.

6.4 	Abbreviations: 

C		=   Conditions to be fulfilled
D		=   Documents to be submitted
MaV		=   Major Variation
MiV-N 	=   Minor Variation (Notification)
MiV-PA 	=   Minor Variation (Prior Approval)

7. MAJOR VARIATION

Major Variation (MaV)
	
MaV-1	Change and/or additional indication/dosing regimen/patient population/inclusion of clinical information extending the usage of the product

C	
1.	Product labeling refers to pPackage iInsert (PI), pPatient iInformation lLeaflet (PIL), unit carton label, inner label and/or blister strips.
2.	As a subsequent change due to revision of Summary of Product Characteristics (SmPC) or equivalent document (US PI).

D	
1.	Currently approved product labeling.
2.	Proposed product labeling, a clean and annotated version highlighting the changes made.
3.	Justifications for the changes proposed and supporting clinical documents when applicable.
4.	Clinical expert reports and/or in-house clinical trial reports (where applicable).
5.	Approved PI/SmPC/PIL from an approved reference regulatory agency or the country of origin containing the proposed changes (where applicable).
6.	Approval letters from reference countries or country of origin which have approved the new indication or dosing regimen (where applicable).
7.	Clinical documents as per ASEAN Common Technical Dossier (ACTD) part IV (where applicable).
	
MaV-2	Change of content of product labeling 

C	
1.	Product labeling refers to Package Insert (PI), Patient Information Leaflet (PIL), unit carton label, inner label and/or blister strips.
2.	The change is not a minor variation and not within the scope of MaV-71.
3.	As a subsequent change due to revision of Summary of Product Characteristics (SmPC) or equivalent document (US PI).

D	
1.	Currently approved product labeling.
2.	Proposed product labeling, a clean and annotated version highlighting the changes made.
3.	Justifications for the changes proposed and supporting clinical documents when applicable.
4.	Approved PI/SmPC/PIL from an approved reference regulatory agency or the country of origin containing the proposed changes (where applicable).

MaV-3	Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeia Certificate of Suitability (CEP) is not available]

Following ACCSQ PPWG Meeting in Singapore, the Meeting agreed that where European Pharmacopoeia Certificate of Suitability (CEP) is not available, the variation shall be considered as a MaV application. Please refer to MiV PA10 when CEP is available.

C	
1.	Specifications of drug substances remain unchanged.

D	
1.	Complete CTD section S1-S7, both the open and closed part of the Drug Master File and the Letter of Access.
2.	Tabulation of the differences compared with the registered manufacture information (if applicable).
3.	Batch analysis data (in a comparative tabular format) for at least two pilot batches of the drug substance from the current and proposed manufacturing sites.
4.	A letter of commitment from product license holder to conduct real time and accelerated stability studies for the drug product manufactured with the drug substance from the proposed manufacturing site, and report if any results fall outside shelf life specifications (with proposed action) or when requested. 

MaV-4	Addition or replacement of the manufacturing site of the drug product	

C	
1.	Not applicable to changes relating to manufacturer responsible for batch release or a site where only batch release takes place.
2.	If there are changes to the manufacturing process, MaV-89 is also applicable.

D	
1.	Proof that the proposed site is appropriately authorized for the pharmaceutical form concerned: A valid Good Manufacturing Practice (GMP) certificate or a Certificate of Pharmaceutical Product (CPP) which covers GMP certification.
2.	Comparative batch analysis of drug product of at least two production batches (or one production batch and two pilot batch) form the proposed site and last three batches from the current site; batch analysis data on the next 2 full production batches should be available upon request or reported if outside specifications (with proposed action).
3.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
4.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
5.	For sterile drug products, Validation data of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration at the proposed site for products should be provided upon submission. Validation data should be presented or validation protocol (scheme) should be sufficient. 
6.	Comparative dissolution profile data manufactured in the currently approved and proposed manufacturing site for oral solid dosage forms as per compendium and validation batches.
7.	Product formula.
8.	Release and end-of-shelf life specifications of drug product.
9.	Batch numbering system (where applicable).
10.	Specification of drug substance.
11.	Hold time studies testing of bulk pack during storage and transportation between the bulk production site and primary packager (if applicable).
12.	Official letter authorizing the proposed site to manufacture the product.

MaV-5	Addition or replacement of alternative site for primary packaging (direct contact with drug product)	

C	
1.	No other changes except for the addition or replacement of alternative site for primary packaging (direct contact with drug product).

D	
1.	Proof that the proposed site is appropriately authorized for the packaging activity of the pharmaceutical form concerned: a valid GMP Certificate.or a CPP which covers GMP certification.
2.	Letter of appointment and letter of acceptance for Official letter authorizing the proposed site to package the product and stating the types of activity to be performed by the packager (for contract manufacturer/packager). 
3.	Validation data on primary packaging processes to be provided upon submission of variation change (where applicable).
4.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
6.	Hold-time studies testing of bulk pack during storage and transportation between the bulk production site to primary packager (where applicable).

MaV-6	Change of the specification of drug substance and/or drug product
a)	Specification limits are widened
b)	Deletion of test parameter and limits

C	
(a)	Specification limits are widened
1.	Test procedures remain unchanged.
2.	Not applicable to compendial drug substances/drug products.

(b)	Deletion of test parameter and limits
1.	Test procedures of the other parameters in the drug product specifications remain unchanged.
2.	Not applicable to compendial drug substances/drug products.

D	
(a)	Specification limits are widened
1.	Justification for change substantiated with scientific data to be provided.
2.	Comparative tabulated format  tabulation of the currently approved and revised specification of drug substance/drug product with changes highlighted.
3.	Revised specification of drug substance / drug product.
4.	Batch analysis of the drug substance/drug product for all tests in the new specification for 2 pilot or production scale batches.
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

(b)	Deletion of test parameter and limits
In addition to the above documents except D5,
6.	Certificate of analysis of the drug substance/drug product for all tests with the new specification.

MaV-7	Change of batch size of sterile drug product 

C	
1.	The change does not affect consistency of production.
2.	Release and end-of-shelf life specifications of drug product remain unchanged.
3.	Validation scheme or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data.

D	
1.	Process validation scheme or report appropriate to the batch size changes.
2.	Comparative tabulated format of proposed and currently approved batch manufacturing formula.
3.	Batch analysis data (in a comparative table) of drug product of at least 2 production batches according to currently approved and proposed batch sizes.
4.	Release and end-of-shelf life specifications of the drug product.
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

MaV-8	Change of batch size of non-sterile drug product 

C	
1.	This is applicable to change of batch size more than 10-fold compared to the currently registered batch size.
For ‘Change of batch size up to 10-fold compared to the currently registered batch size’, please refer MiV-PA 314.
2.	The change does not affect consistency of production.
3.	Release and shelf-life specifications of drug product remain unchanged.
4.	Process validation scheme or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data.

D	
1.	Process validation scheme or report appropriate to the batch size changes.
2.	Comparative tabulated format of proposed and current batch manufacturing formula.
3.	Batch analysis data (in a comparative table) of drug product of at least 2  on a minimum of one production batches according to currently approved and proposed batch sizes and letter of undertaking to submit batch data on the next one full production batch.
4.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
5.	Release and shelf life specifications of the drug product.
6.	For oral solid dosage forms, comparative dissolution profile for at least one production batch (where applicable as per compendial requirement).
	
MaV-9	Major change in the manufacturing process for drug product

C	
1.	The same currently approved manufacturing site. If there is a change in manufacturing site, MaV-4 is also applicable.
2.	The change does not cause a negative impact on the quality, safety and efficacy of the drug product.

D	
1.	Description of the new manufacturing process.
2.	Process validation of 3 production batches, or at a minimum, 2-pilot batches plus one production batch with a commitment to conduct two more validation batches upon approval of the variation.
3.	Copy of currently approved release and end-of-shelf life specifications.  Or, alternatively, copy of proposed release and end-of-shelf life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.
4.	Comparative batch analysis data of drug product for a minimum of one production batch at least two production batches (or one production batch and two pilot batches) manufactured according to currently registered and proposed processes.
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
6.	Comparative dissolution profile data between the products manufactured in the currently approved and proposed manufacturing process for oral solid dosage forms as per compendium and validation batches.
7.	Justification for not submitting a new bioequivalence study according to ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).	

MaV-10	ReplacementChange or quantitative change of an excipient

a)	For immediate release oral dosage forms 
(as per Level 2 and 3, Part III Components and Composition, SUPAC guideline)
b)	For modified release oral dosage forms
c)	For other critical dosage forms such as sterile preparations.

C	
1.	Change will need to comply with the finished product specifications for example release and end-of-shelf life specifications of the drug product remains the same, excluding product description.
2.	Validation scheme or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed new product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data.
3.	There is no change in dissolution profile for oral solid dosage forms. The dissolution profile of the proposed product is comparable to that of the current approved product. 
4.	Replacement of an excipient with a comparable excipient of the same functional characteristics.

D	
1.	Justification for the change must be given by appropriate development of pharmaceutics.
2.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
3.	Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation (where applicable).
4.	Justification for not submitting a new bioequivalence study according to ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).
5.	Comparative tabulated format  tabulation of the current and revised product formulation with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).
6.	Release and shelf life specifications.
7.	Batch analysis data (in a comparative table) of drug product of at least 2 production (or one production batch and two pilot batches) according to currently approved and proposed product formula.
8.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
9.	Specifications of the proposed excipient.
10.	For proposed excipients made of ruminants source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from relevant veterinary authority of the issuing country (where applicable).
11.	Revised batch manufacturing formula.
12.	Process Validation scheme or report appropriate to the proposed change in product formula.
13.	Revised ACTD Section P3.2 to P3.5 (where applicable).

MaV-11	Quantitative change in coating weight of tablets or weight and/or size of capsule shells

C	
1.	Applicable only for modified release oral dosage form.
2.	There is no change in dissolution profile for oral solid dosage forms. The dissolution profile of the proposed product is comparable to that of the current approved product. 
3.	The product release and end-of-shelf life specifications have only been updated in respect of product description (where applicable).
4.	For immediate release oral solid dosage forms please refer to MiV-PA 18 17.

D	
1.	Comparative dissolution profile data of at least one pilot/production batch of the drug product between the currently approved and proposed composition.
2.	Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).
3.	Revised release and end-of-shelf life specifications of the drug product.
4.	A declaration that the change does not interfere with the drug product release and shelf life specifications test method.
5.	Current and proposed product and batch manufacturing formula.
6.	Revised draft of product label incorporating the proposed change (where applicable).
7.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

Issue for AMS to comment:
D7: Vietnam proposed to add D7.
	
MaV-12	Qualitative and quantitative change in composition and/or type of container change or inclusion of primary packaging material for sterile drug product

C	
1.	Release and end-of-shelf life specifications of the drug product remain unchanged.
2.	For qualitative and quantitative change in the composition of primary packaging component for non-sterile drug product, please refer to MiV-PA28.

D	
1.	For sterile drug products, Process validation data of the manufacturing and sterilization process.
2.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
3.	Proof must be provided that no interaction between the content and the packaging material occurs (where applicable).
4.	Comparative tabulated format of specifications of the proposed and current primary packaging material.
5.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
6.	Revised ACTD Sections P3 and/or P7 (where applicable).
7.	Appropriate scientific data on new packaging.

MaV-13	Change or addition of fill volume and/or change of shape or dimension of container or closure for a sterile solid and liquid drug product 

C	
1.	Release and end-of-shelf life specifications of the drug product are not affected, except fill volume specification. 
2.	The proposed pack size is consistent with the dosage regimen and duration of use as approved in the package insert.
3.	The packaging material remains the same.

D	
1.	Justification that the proposed pack size is consistent with the dosage regimen and duration of use as approved in the package insert.
2.	Validation data of the manufacturing process, sterilization and container closure system (where applicable).
3.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
4.	Revised drafts of the package insert and labeling incorporating the proposed variation, where applicable.
	
MaV-14	Inclusion, replacement or deletion of components the solvent/diluent for the drug products including diluents 

Following ACCSQ PPWG Meeting in Singapore, this variation is to be revisited for further discussion by AMS
	
C	
1.	The proposed change does not result in any change in the dosage regimen, indication, method of administration of the product.
2.	The proposed change is applicable only if the current form of presentation packaged for sale will not be marketed after the current stocks are exhausted.
3.	For change of shelf life and/or storage condition of the drug product after first opening and/or after dilution/reconstitution, please also refer to MaV-15 and/or MaV-16 (where applicable)

D	
1.	Complete section P for the solvent/diluents and reconstitution stability data (where applicable).
2.	Documentary evidence to certify the manufacturing site of diluents complies with current applicable GMP standards.
3.	Batch numbering system (where applicable).
4.	Authorization letter from product owner to authorize the manufacturing site to manufacture and package the solvent/diluents (where applicable).
5.	Revised artworks for the drug product labels incorporating the changes.
6.	A declaration from the applicant that the release and shelf life specifications of drug product are not affected. 
7.	Justification for the deletion of the solvent/diluent.
8.	A letter of declaration that current product stocks will be exhausted before the proposed presentation is marketed, indicating the tentative date for exhaustion of the current stock.
9.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

Issues for AMS to comment:
D9: Vietnam proposed to add D9. However, the ACCSQ PPWG meeting agreed that Document 1 may suffice and the suggested D9 may not be necessary.	

MaV-15	Change of Extension of shelf life of the drug product 
1)	As a package for sale  and/or
2)	After first opening and/or
3)	After dilution/reconstitution

Malaysia proposed reduction of shelf life to be split into MiV-PA.
Following ACCSQ PPWG Meeting in Singapore, it has been agreed that
reduction of shelf life to be split from MaV-15 to MiV PA-34 with same C and D. (Evaluation of shelf life reduction needs to be done in shorter time frame so prompt action can be taken by MAH)

C	
1.	For (1) & (2) - The studies must show conformance to the currently approved end-of- shelf life specification.
2.	For (3) – The studies must show conformance to the currently approved shelf life specification for the reconstituted product.
3.	For reduction of shelf life, please refer to MiV-PA34.

D	
1.	Results of appropriate real time stability studies covering the duration of proposed shelf-life of at least 2 pilot/production scale batches of the product in the authorized packaging material 
1) as a package for sale and/or
2) after first opening and/or
3) after the dilution/reconstitution
in accordance with the ASEAN Guidelines on Stability Study of Drug Product; results of appropriate microbiological testing should be included (where appropriate).
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
3.	Justification letter for the change of shelf life of the drug product (where applicable).

MaV-16	Change of storage conditions of the drug product (Lowering from the current approved storage condition) 
1)	As a package for sale and/or
2)	After first opening and/or
3)	After dilution/reconstitution

Malaysia proposed increasing of storage condition to be split into MiV-PA.
Following ACCSQ PPWG Meeting in Singapore, it has been agreed that
increasing  from the current approved storage condition to be split from MaV-16 to MiV PA-35 with same C and D. 	

C	
1.	The studies must show conformance to the currently approved end-of-shelf life specification.
1.	For (1) & (2) - The studies must show conformance to the currently approved end-of- shelf life specification.
2.	For (3) – The studies must show conformance to the currently approved shelf life specification for the reconstituted product.
3.	For change of storage condition (increasing from the current approved storage condition), please refer to MiV-PA35.

D	
1.	Results of appropriate real time stability studies covering the duration of currently approved end-of- shelf-life (at proposed storage condition) of at least 2 pilot/production scale batches of the product and in the authorized packaging material in accordance with the ASEAN Guidelines on Stability Study of Drug Product.
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

8. MINOR VARIATIONPRIOR APPROVAL

Minor Variation (MiV-PA)	
Prior Approval	
MiV-PA 1	Change of drug product name 

C	
1.	There is no change to the product (formulation, release and end-of-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 (1) suggest greater safety or efficacy than supported by clinical data (2) imply a therapeutic use (3) imply superiority over another similar product (4) imply the presence of substance(s) not present in the product.

D	
1.	Official letter from product owner or marketing authorization holder authorizing the change of product name (where applicable) and committing to inform users of the relevant changes and that the current product stock will be exhausted before the product labeled with the new name is marketed.
2.	A declaration from the applicant that there is no other changes to the product/label except for the drug product name change.
3.	Revised draft package insert and labeling incorporating the proposed variation.
4.	Updated Certificate of Pharmaceutical ParticularsProduct (CPP) if applicable (from country of origin).
5.	Official letter of commitment to inform users of the relevant changes and that the current product stocks will be exhausted before the product labeled with the new name is marketed.
6.	5. Trademark certificate (where applicable).

MiV-PA 2	Change in name and/or address of the marketing authorization holder 

Following ACCSQ PPWG Meeting in Singapore, this variation is to be re-categorized as MiV-PA from MiV-N.

C	
1.	The name change refers to the renaming of a company or organization.
2.	The change does not include transfer of product license to another company.

D	
1.	Letter by the product owner authorizing the new name of marketing authorization holder to hold the product license.
2.	Statutory document of name and/or address change.

MiV-PA 3	Change of product labeling (in accordance to country specific labeling requirement)

Includes:
a)	Change of the layout/artwork without altering meaning and/or
b)	Addition/deletion/replacement of pictures, diagrams, bar code, logos and/or texts that do not imply an unapproved indication and/or
c)	Addition/strengthening of warnings, precautions, contraindications or adverse events/effects to the approved product labelling
d)	Tightening of product’s target population and/or
e)	Deletion of indication.
f)	Change of distributor’s details

C	
1.	The change is not a MaV and does not contain promotional information.

D	
1.	Current approved product labeling.
2.	Proposed product labeling, a clean and annotated version highlighting the changes made.
3.	Letter of declaration from the applicant stating that no other changes on the label except for the intended change.
4.	Relevant document/reference to support the changes (where applicable).

MiV-PA 4	Addition or replacement of the company or party responsible for batch release

Following ACCSQ PPWG Meeting in Singapore, this variation is to be re-categorized as MiV-PA from MiV-N.
	
C	
1.	Only applicable for batch release.
2.	Method transfer from the currently approved to the proposed site or test laboratory has been successfully completed.
3.	The manufacturer of the drug product remains the same.
	
D	
1.	Official letter from product owner authorizing the company/manufacturer to be responsible for batch release.
2.	A valid GMP certificate or CPP which covers the GMP certificate of the proposed site.
3.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

MiV-PA 5	Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeia Certificate of Suitability (CEP) is available]

Following ACCSQ PPWG Meeting in Singapore, the Meeting agreed that where European Pharmacopoeia Certificate of Suitability (CEP) is not available, the variation shall be considered as a MaV application. Please refer to MaV 3.

C	
1.	Specifications of drug substances remain unchanged.

D	
1.	1.  A valid European Pharmacopoeia Certificate of Suitability (CEP) for the drug substance, latest version, with all annexes issued by EDQM. or Drug Master File or relevant updated drug substance (DS) section or equivalent/audit document.
2.	Provide the differences compared with the registered drug substance manufacturer information (where applicable).  
3.	2.  Batch analysis data (in a comparative tabular format) for at least two pilot batches (minimum pilot scale of the drug substance from the current and proposed manufacturers/ manufacturing sites).
3.  If the re-test period is not stated in the CEP, at least six months real time and accelerated stability data on two pilot batches of the drug substance manufactured from the proposed manufacturing sites should be provided.
4.  A letter of commitment from product license holder to conduct appropriate real time and accelerated stability studies for the drug product manufactured with the drug substance from the proposed manufacturing site, and report if any results fall outside shelf-life specifications (with proposed action) or when requested. 

MiV-PA 6	Change of batch size of drug substance [excluding drug substance covered by a Certificate of Suitability (CEP)]	

C	
1.	The change does not affect the reproducibility of the process.
2.	Specifications of drug substance remain unchanged.
3.	For non-sterile drug substance only. (This is the only variation for change of batch size for drug substance, regardless sterile or non sterile)
3.   Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).

D	
1.	Comparative batch analysis data with specification and results (in a comparative tabulated format) on a minimum of one production or pilot batch manufactured to both the currently approved and proposed batch sizes. Batch data on the next 2 full production batches should be available on request or reported if outside specification (with proposed action).
2.	A letter of declaration from marketing authorized holder that the specifications of drug substance have not changed and the reproducibility of the process has not been affected.
3.	Amended relevant CTD Section S(where applicable).

MiV-
PA 7	Change of in-process controls applied during the manufacture of the drug substance (including tightening and addition of new in-process test)
	
C	
1.	In-process limits are tightened or addition of new tests.
2.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).
3.	The change is not a consequence of any commitment from previous assessments to review specification limits. 
4.	The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
5.	Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.

D	
1.	A description of the analytical method and summary of validation data must be provided for all new analytical methods (where applicable).
2.	Comparative tabulated format Tabulation of the proposed and current in-process controls and the relevant changes.
3.	Comparative batches analysis data of one two production batches of the drug substance for all tests in the proposed specification (if applicable).

MiV-PA 8	Change of manufacturing process of the drug substance 

C	
1.	No adverse change in qualitative and/or quantitative impurity profile which would require further qualifications in safety studies.
2.	Specifications and stability performance of drug substance remain unchanged.
3.	The synthetic route remains the same (for example, intermediates remain the same).
4.	Manufacturing process of drug substance does not use any materials of human / animal origin for which assessment is required of viral safety.
5.	Physical properties of drug substance remain unchanged.
6.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP). 

D	
1.	Certificate of Suitability (CEP) or Drug Master File (DMF), or relevant updated drug substance (DS) section or equivalent/audit document.

For drug substances which are non-compendial and generic products which do not have CEP:

2.	Comparative tabulated format Tabulation of the currently approved and new processes with changes highlighted (where available).
3.	Certificate of analysis for 2 batches of the drug substance.
4.	Batch analysis (in comparative table) of drug product of at least 2 batches (pilot/production scale) manufactured according to the currently approved and proposed processes.
5.	A letter of declaration from marketing authorization 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.
6.	A letter of declaration from the marketing authorization 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 table where possible).
7.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action). To be discussed, proposed to follow Singapore HSA statement. “A declaration from the applicant that the relevant stability studies of the drug substance in accordance with the relevant guidelines have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).” 
8.	For sterile drug substance, process validation report (where applicable).

Issue for AMS to comment: 
D7: APRIA/APC proposed to replace statement as per HSA’s variation guideline. 

MiV-PA 9	Change of the specification of drug substance
a)  Specification limits are tightened
b)  Addition of new test parameter and limits

Note: This is only applicable for drug substances which are non-compendial and generic drug substances without Certificate of Suitability (CEP)	

C	
1.	This is only applicable for drug substances which are non-compendial and generic drug substances without Certificate of Suitability (CEP)
2.	For (b) - applicable to non-compendial method only.
3.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).

D	(a) Specification limits are tightened

1.	Comparative tabulated format Tabulation of the currently approved and revised specification of drug substance with changes highlighted.
2.	Comparative batch analysis of the drug substance for all tests in the new specification for 2 pilot or production scale batches.

(b) Addition of new test parameter and limits
In addition to the above documents,

3.	Description of any new analytical method and summary of the validation data.
	
MiV-
PA 10	Revision of Certificate of Suitability (CEP) of drug substance	
C	
None

D	
1.	A copy of the updated valid European Pharmacopoeia Certificate of Suitability (CEP) for the drug substance, latest version, with all annexes issued by EDQM.
2.	Specifications of drug substance specifications (where applicable).
3.	Results of batch analysis from the drug substance manufacturer* demonstrating compliance with the PhEur monograph and including additional test/limits listed on the CEP (where applicable).
4.	Additional data to address any relevant parameter(s) not addressed in the CEP such as stability data (S7), if a re-test period is not stated on the CEP and physico-chemical characteristics (e.g. particle size, polymorphism etc), if 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.

MiV-PA 11	Change of the test procedure of non-compendial drug substance
(For drug substance which is not listed in compedium)

C	
1.	Results of method validation show new test procedure to be at least equivalent to the former procedure.
2.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).

D	
1.	Description of the analytical methodology, a summary of validation data, and comparative analytical results between the currently approved and proposed test (where applicable).
2.	Specification of the drug substance.
	
MiV-
PA 12	Change of shelf life or retest period for drug substance	

C	
1.	The stability studies must show compliance with specification.
2.	No change in storage condition.
3.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).

D	
1.	Stability data of the drug substance should be presented on at least two pilot or production scale batches of the requested shelf life or retest period.
2.	Specifications of the drug substance. 
	
MiV-
PA 13	Change of storage condition for drug substance	

C	
1.	The stability studies must show compliance with specification.
2.	No change in shelf life/retest period.
3.	Refer to MiV-PA10 if the variation is covered by a Certificate of Suitability (CEP).

D	
1.	Stability data of the drug substance should be presented on at least two pilot or production scale batches of the requested storage condition.
2.	Specifications of the drug substance. 

MiV-PA 14	Change of batch size of non-sterile drug product	

C	
1.	This is applicable to change of batch size up to 10-fold compared to the currently registered batch size.
2.	The change does not affect consistency of production.
3.	Release and end-of-shelf-life specifications of drug product remain unchanged.
4.	Process Vvalidation scheme or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data.
5.	For ‘Change of batch size for sterile products’  please refer to MaV-10 7 and for ‘Change of batch size more than 10-fold compared to the currently registered batch size’ please refer MaV-9 8.

D	
1.	Process validation scheme or report appropriate to the batch size changes.
2.	Comparative tabulated format tabulation of proposed and current batch manufacturing formula.
3.	Batch analysis data (in a comparative table) of at least 2 of drug product on a minimum of one production batches according to currently approved and proposed batch sizes and a letter of undertaking to submit batch data on the next full production batch.
4.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
5.	Release and end-of-shelf life specifications of the drug product.
6.	Revised ACTD/ICTD Section P3.2-3.5 (where applicable).
	
MiV-PA 15	Reduction or removal of overage

C	
1.	Changes of previously approved manufacturing overages of drug substance only.
2.	Release and end-of-shelf-life specifications of drug product remain unchanged.

D	
1.	Justification for the change.
2.	Comparative tabulated format table of currently approved and proposed batch manufacturing formula.
3.	Certificate of analysis for 2 batches of the finished product.
4.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

MiV –PA 16	Replacement Change or quantitative change of an excipient

a)	For immediate release oral dosage forms 
(as per Level 1, Part III Components and Composition, SUPAC guideline)
b)	For other non-critical dosage forms eg. oral liquid, external preparation.
	
C	
1.	Release and end-of-shelf life specifications of the drug product remain unchanged.
2.	Pertinent Process Validation. Validation scheme or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed new product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data.
3.	There is no change in dissolution profile for oral solid dosage forms. The dissolution profile of the proposed product is comparable to that of the current approved product.
4.	Replacement of an excipient with a comparable excipient of the same functional characteristics (where applicable).

D	
1.	Justification for the change must be given by appropriate development of pharmaceutics.
2.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action). 
3.	Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation.
4.	Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies.
5.	Comparative tabulated format Tabulation of the current and revised product formulation with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).
6.	Release and shelf life specifications.
7.	Batch analysis data (in a comparative table) of drug product of at least 2 production (or one production batch and two pilot batches) according to currently approved and proposed product formula.
8.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
9.	Specifications of the proposed excipient.
10.	For proposed excipients made of ruminants source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from relevant veterinary authority of the issuing country (where applicable).
11.	Revised batch manufacturing formula.
12.	A declaration that the new excipient does not interfere with the drug product release and shelf life specifications test method.
13.	Revised ACTD/ICTD Section P3.2-3.5 (where applicable).
14.	Process validation scheme or report appropriate to the proposed change in product formula (where applicable).

MiV –PA 17	Quantitative change in coating weight of tablets or weight and/or size of capsule shell

C	
1.	The dissolution profile of the proposed product is comparable to that of the current approved product. 
2.	The product release and end-of-shelf-life specifications of the drug product remain unchanged except for the product description. 
3.	For modified release oral solid dosage forms please refer to MaV-14 11. 

D	
1.	Comparative dissolution profile data of at least one pilot/production batch of the drug product between the currently approved and proposed composition.
2.	Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).
3.	Revised release and end-of-shelf life specifications of the drug product.
4.	A declaration from marketing authorization holder that the change does not interfere with the drug product release and shelf life specifications test method.
5.	Comparative tabulated format of current and proposed product and batch manufacturing formula.
6.	Revised draft of product label incorporating the proposed change (where applicable).
7.	A declaration from the applicant that the relevant stability studies of the drug product in accordance with the relevant guidelines have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).
	
MiV- PA 18	Change of the colouring/flavouring agent of the product [addition, deletion or replacement of colourant(s)/flavour(s)]

C	
1.	Same functional characteristics, 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 end-of-shelf life specifications of the drug product remain unchanged except for the change in colour/flavour.

D	
1.	Qualitative and quantitative information of the current and proposed colouring/flavouring agent in a comparative table.
2.	Revised product formulation and batch manufacturing formula.
3.	Revised release and end-of-shelf life specifications of the drug product.
4.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
6.	For proposed excipients made of ruminants source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued from relevant veterinary authority of the issuing country (where applicable).
7.	A letter of commitment to inform the users of relevant changes and that the current product stock will be exhausted before the new product is marketed.
8.	A declaration from marketing authorization holder that the change does not interfere with the drug product release and shelf life specifications test method.

MiV-PA 19	Change of in-process controls applied during the manufacture of the drug product (including tightening and addition of new in-process test) 

C	
1.	Release and end-of-shelf life specifications of drug product remain unchanged.
2.	The change is not a consequence of any commitment from previous assessments to review specification limits.
3.	The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
4.	Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.

D	
1.	A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable).
2.	Revised in-process specifications together with justification and relevant process validation data.
3.	Comparative batch analysis of drug product of at least 2 production/pilot batches.
4.	Comparative tabulated format tabulation change of the in-process controls.

MiV- PA 20	Minor change of the manufacturing process for non-sterile products.

C	
1.	The same currently approved manufacturing site.
2.	The overall manufacturing principle remains the same.
3.	The change does not cause negative impact on the quality, safety and efficacy of the drug product.
4.	Release and end-of-shelf-life specifications of drug product remain unchanged.
5.	The dissolution profile of the proposed product is comparable to that of the current approved product.

D	
1.	Description of the new manufacturing process.
2.	Process validation of three production batches, or at a minimum 2 pilot batches plus one production batch with a commitment to conduct 2 more validation batches upon approval of the variation (or as per ASEAN guideline on Submission of Manufacturing Process Validation data).
3.	For solid oral dosage forms, comparative dissolution profile data of at least one representative production batch of the drug product between the currently approved and proposed solid oral dosage forms formulation.
4.	Copy of currently approved release and end-of-shelf life specifications. Or, alternately, copy of revised release and end-of-shelf life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.
5.	Justification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance (where applicable).
6.	Batch analysis of the drug product (in a comparative tabulated form) of drug product on a minimum of one batch manufactured to both the currently approved and the proposed process; batch data on the next 2 full production batches should be made available upon request.
7.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action). To be discussed, proposed to follow Singapore HSA statement. “A declaration from the applicant that the relevant stability studies of the drug product in accordance with the relevant guidelines have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).” 
8.	Comparative tabulated format of present and proposed process with changes highlighted.

Issues for AMS to comment: 
D7: APRIA/APC proposed to replace statement as per HSA’s variation guideline. 
D2: Thailand proposed D2 should not be required for non-sterile products. It is not required in EMA variation guideline

MiV-PA 21	Change of specifications of an excipient 
a) Specification limits are tightened
b) Addition of new test parameter and limits

C	
1.	Applicable to non compendial excipients. For compendial excipients, please refer to MiV-N8.
2.	Release and end-of-shelf-life specifications of drug product remain unchanged.
3.	The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
4.	For tightening of specifications only

D	
1.	Comparative tabulated format Tabulation of the current and revised specification of the excipient with changes highlighted.
2.	Batch analysis of the excipient for all tests in the new specification.(outside scope of current ACTD/ACTR)
3.	Description of new method and summary of analytical validation (applicable for addition of new parameter).
4.	Justification for proposed change.

MiV-PA 22	Change of a test procedure for an excipient, including replacement of an approved test procedure by a new test procedure 

C	
1.	Appropriate method validation studies have been performed in accordance with the ASEAN Guidelines For Validation of Analytical Procedures.
2.	Results of method validation show new test procedure to be at least equivalent to the former procedure.
3.	There have been no changes of the total impurity limits.
4.	Only applicable to the currently approved test parameters.
5.	No new unqualified impurities are detected.

D	
1.	Description of the analytical methodology with a comparative tabulation of the changes. 
2.	Validation data is only needed for non-compendial materials or methods (where applicable).
3.	Verification data is needed for compendial methods.(out of scope of current ACTD/ACTR.
3.    Comparative validation results showing that the current and proposed tests are           
       equivalent.

MiV-PA 23	Change in the source of empty hard capsule

C	
1.	From animal-derived  TSE-risk material to vegetable-sourced or synthetic empty hard capsules or vice versa.
2.	No change in the formulation and manufacturing process of drug product.
3.	Not applicable to change from hard capsule to soft gel.
4.	Excipient and finished product release and end of shelf life specifications remain the same. 

D	
1.	Comparative dissolution profile data of three one batches representative of pilot/production batch of the drug product using hard capsule between the two sources (where applicable).
2.	Certificate of Analysis of the empty hard capsule of the proposed new source.
3.	Technical specifications and composition of the empty hard capsule of the new source.
4.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).
5.	For empty hard capsule made of ruminants source, Transmitting Animal Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from relevant veterinary competent authority of the issuing country.
6.	Declaration from the manufacturer or the marketing authorization holder of the material that it is purely of vegetable, animal or synthetic origin.”

MiV-PA 24	Change of release and shelf-life specifications of the drug product
a) Specification limits are tightened  
b) Addition of new test parameter and limits

Following ACCSQ PPWG Meeting in Singapore, this variation is to be revisited for further discussion by AMS
•	Vietnam and Cambodia proposed to include “Stability data should be submitted (where applicable)” as D4.	

C	
1.	Applicable to non-compendial method.
2.	The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
3.	The test methods remain the same or changes in the test methods are minor.
4.	If there are changes to the test procedure, MiV-PA27 is also applicable

D	
(a) Specification limits are tightened
1.	Comparative tabulated format tabulation of the current and revised release and shelf life specifications of the drug product with changes highlighted.
2.	Comparative batch analysis of the drug product for all tests in the new specification of at least 2 batches.

(b) Addition of new test parameter and limits 
(If there are changes to the test procedure, MiV-PA27 is also applicable)
In addition to the above documents:
3.	Description of any new method and summary of analytical validation data for non-compendial method.
4.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action). (where applicable).

MiV-PA 25	Change of imprints, bossing or other markings on tablets or printing on capsules including addition or change of inks used for product marking

C	
(a) - Except score/break-line
1.	New markings do not cause confusion with other registered products.
2.	Any ink proposed must comply to relevant pharmaceutical legislation or of food grade and not a listed banned substance.
3.	Release and end-of-shelf life specifications of the drug product remain unchanged except for appearance.

(b) – On score/break-line
In addition to the above conditions, 
4.	Score/break-line is not meant for cosmetic purpose.
5.	Applicable to addition or removal of score/break-line.

D	
(a) - Except score/break-line
1.	Details and specifications of the proposed new inks (where applicable).
2.	Certificate of analysis of ink / printing material (pharmaceutical grade and of food grade).
3.	Detailed drawing or written description of the current and proposed imprint/bossing/markings.
4.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
5.	Release and end-of-shelf life specifications of the drug product with the new product description.
6.	A letter of commitment to inform the users of relevant changes and that the current product stock will be exhausted before the new product is marketed.

(b) – On score/break-line
In addition to the above documents,
7.	Justification for the change (i.e. change in dosing regimen).
8.	Certificate of analysis of 2 production/pilot scale batches.
9.	Data on test of content uniformity of the subdivided parts of the tablets at release should be submitted.

MiV- PA 26	Change of dimensions and/or shape of tablets, capsules, suppositories or pessaries without change in qualitative and quantitative composition and mean mass 
a)  Immediate release oral solid dosage form, suppositories and pessaries
b)  Other than immediate release oral solid dosage forms, suppositories and pessaries.

C	
1.	If appropriate, the dissolution profile of the proposed product is comparable to that of the current approved product. 
2.	Release and end-of-shelf life specifications of the drug product remain unchanged except for appearance dimension and/or shape

D	
(a) Immediate release oral solid dosage form, suppositories and pessaries
1.	Detailed drawing or written description of the current and proposed appearance.
2.	Release and end-of-shelf life specifications of the drug product.
3.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
4.	Comparative dissolution data on at least one pilot/production batch of the currently approved and proposed dimensions.
5.	Data on test of content uniformity of the subdivided parts of tablets at release as conformed to compendial requirement should be submitted (only applicable for drug product with score/break-line).

(b) Other than immediate release oral solid dosage forms, suppositories and pessaries
In addition to the above condition,
6.	Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).

MiV-PA 27	Change in the test procedure of the drug product (including replacement or addition of a test procedure)

C	
1.	Drug product specifications are not adversely affected unless the specifications are tightened.
2.	Results of method verification/validation show new test procedure to be at least equivalent to the former procedure.
3.	The change should not be the result of unexpected events arising during manufacture or because of stability concerns.

D	
1.	Description of the analytical methodology.
2.	Appropriate verification/validation data and comparative analytical results between the currently approved and proposed test.
3.	Certificate of analysis of the finished product of 2 production batches when made available.
4.	Justification for the proposed change.
5.	Comparative tabulated format table of the currently approved and proposed release and shelf life specifications of the drug product.

MiV-PA 28	Qualitative and quantitative change in the composition of primary packaging material for non-sterile products

C	
1.	Release and end-of-shelf-life specifications of drug product remain unchanged.
2.	The proposed packaging material must be at least equivalent to or better than to the approved material in respect of its relevant properties.
3.	The change only concerns the same packaging type (for example from blister to blister).

D	
1.	Justification for the change in packaging material and appropriate scientific studies on the new packaging.
2.	For semisolid 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).
3.	Comparative tabulated format table of the currently approved and proposed specifications of the primary packaging material (where applicable).
4.	Revised drafts of the package insert incorporating the proposed variation (where applicable).
5.	Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf life specifications (with proposed action).

MiV-
PA 29	Addition or replacement of a manufacturer for secondary packaging

Following ACCSQ PPWG Meeting in Singapore, this variation is to be re-categorized as MiV-PA from MiV-N.

C	
None

D	
1.	Proof that the proposed site is appropriately authorized (accredited by the authority) for the packaging activity concerned: A valid GMP certificate or CPP which covers the GMP certification.
2.	Official letter from product owner authorizing the new manufacture or packager to perform secondary packaging.
3.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
	
MiV-PA 30	Change of pack size/volume and/or shape/dimension of packaging material for volume of non-sterile product
	
C	
1.	Release and end-of-shelf life specifications of the drug product remain unchanged.
2.	The new size is consistent with the dosage regimen and duration of use as approved in the package insert.
3.	With  Change in the dimension of the primary packaging material (where applicable).
4.	For ‘Change of volume for a sterile drug product’, please refer to MaV-11 13.
5.	The change only concerns the same packaging type and material.
	
D	
1.	Justification for the proposed pack size.
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
3.	A letter of declaration that stability study will be conducted in accordance with the relevant guideline for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
	
MiV- PA 31	Change of outer carton pack sizes for a drug product 

Following ACCSQ PPWG Meeting in Singapore, this variation is to be re-categorized as MiV-PA from MiV-N.

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.	The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved product labeling.

D	
1.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
2.	Letter of declaration from the applicant stating that no other changes except for the ‘Change of outer carton pack sizes for a drug product’.

MiV-
PA 32	Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used)

Following ACCSQ PPWG Meeting in Singapore, the Meeting agreed to accept this new variation proposed by Singapore.
	
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 information as appropriate. 
	
MiV-PA 33	Addition or replacement of measuring device for oral liquid dosage forms and other dosage form

C	
1.	The size and where applicable, the accuracy of the proposed measuring device must be compatible with the approved posology.
2.	The new device is compatible with the drug product.

D	
1.	Description of the device (including a drawing), where appropriate.
2.	The composition of the device material.  Where applicable the materials should comply with the Pharmacopoeia.
3.	Justification that size and accuracy of the device are adequate for the posology as is approved in the product labeling.
4.	Revised draft of the package insert and labeling incorporating the proposed variation (where applicable).

MiV-PA 34	Reduction of shelf life of the drug product 
1)	As a package for sale and/or
2)	After first opening and/or
3)	After dilution/reconstitution

Following ACCSQ PPWG Meeting in Singapore, this variation is to be revisited for further discussion by AMS

Vietnam: “Should the company take any action towards packages for sale which were circulated before the new shelf life is allowed?”
	
C	
1.	For (1) & (2) - The studies must show conformance to the currently approved end-of- shelf life specification.
2.	For (3) – The studies must show conformance to the currently approved shelf life specification for the reconstituted product.
3.	For extension of shelf life, please refer to MaV-15.	

D	
1.	Results of appropriate real time stability studies covering the duration of proposed shelf-life of at least 2 pilot/production scale batches of the product in the authorized packaging material 
1)	as a package for sale and/or
2)	after first opening and/or
3)	after the dilution/reconstitution
in accordance with the ASEAN Guidelines on Stability Study of Drug Product; results of appropriate microbiological testing should be included (where appropriate).
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
3.	Justification letter for the change of shelf life of the drug product (where applicable).
	
MiV-PA 35	Change of storage conditions of the drug product (Increasing from the current approved storage condition)
1)	As a package for sale and/or
2)	After first opening and/or
3)	After dilution/reconstitution

Following ACCSQ PPWG Meeting in Singapore, this variation is to be revisited for further discussion by AMS

C	
1.	For (1) & (2) - The studies must show conformance to the currently approved end-of- shelf life specification.
2.	For (3) – The studies must show conformance to the currently approved shelf life specification for the reconstituted product.
3.	For change of storage condition (lowering from the current approved storage condition), please refer to MaV-16..

D	
1.	Results of appropriate real time stability studies covering the duration of currently approved end-of- shelf-life (at proposed storage condition) of at least 2 pilot/production scale batches of the product and in the authorized packaging material in accordance with the ASEAN Guidelines on Stability Study of Drug Product.
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
	
9. MINOR VARIATION NOTIFICATION

Minor Variation (MiV-N)	
Notification	
MiV- N1	Change of product owner

C	
1.	The license holder remains the same.
2.	The manufacturing site remains the same.

D	
1.	Declaration on the transfer of ownership between old product owner and new owner.
2.	Official letter from the new product owner declaring the change, and authorizing the local license holder to be responsible for the product license.
3.	If the new product owner is not the manufacturer of the drug product, an official letter by the new product owner authorizing the manufacturer to manufacture the drug product on its behalf.
4.	If the new product owner is not the manufacturer of the drug product, 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.
5.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
	
MiV- N2	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.	Letter of justification on the transfer of ownership such as a valid GMP certificate.
2.	Official letter stating the transfer of ownership from old manufacturer to new manufacturer (where applicable).
3.	In case of a contract manufacturer, official letter from product owner declaring the change and authorizing the new manufacturer to manufacture the drug products on its behalf.
4.	In case of a contract manufacturer, 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.
5.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

MiV- N3	Change of the name or address (e.g. postal code, street name) of the manufacturer of drug product 

C	
1.	The manufacturing site remains the same.
2.	Not applicable to the case in which it involves change in ownership of the manufacturer. (For change in ownership of manufacturer, please refer MiV-N2)
3.	No other changes except for the change of the name and/or address of a manufacturer of the drug product.

D	
1.	Official letter from product owner authorizing the manufacturer with new name/address to manufacture the drug product.
2.	A valid GMP certificate or CPP which covers the GMP certification with new name and/or address.
3.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
	
MiV-
N 4	Change of the name or address (e.g. postal code, street name) of the company or manufacturer responsible for batch release 

C	
1.	The manufacturer of the drug product remains the same.
2.	Not applicable to the case in which it involves change in ownership of the manufacturer. (For change in ownership of manufacturer, please refer MiV-N2)
3.	The batch release site remains the same.

D	
1.	Official letter from product owner authorizing company/manufacturer with new name/address responsible for batch release.
2.	A valid GMP certificate or CPP which covers the GMP certification with new name or address (where appropriate).
3.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).
4.	A declaration from the applicant that the change does not involve a change of batch release site.

MiV-
N5	Change of the name and/or address (for example: postal code, street name) of a manufacturer of the 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.

MiV-N6	Withdrawal/deletion of the 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.

MiV-N7	Renewal of Certificate of Suitability (CEP)
	
C	
1.	Only applicable if the renewal of CEP does not involve any variation.
	
D	
1.	A copy of the updated valid European Pharmacopoeia Certificate of Suitability (CEP) for the drug substance, latest version, with all annexes issued by EDQM.

MiV-N8	Change of release and shelf-life specifications of the drug product and/or drug substance  and/or excipient, following the updates in the compendium.

C	
1.	Applicable to compendial specifications only.
2.	Change is made exclusively to comply with an update of the relevant monograph of the compendium.

D	

1.	Tabulation of the current and revised release and shelf life specifications of the drug product with changes highlighted.
2.	Batch analysis of the drug product for all tests in the new specification of at least 2 batches.
3.	Revised release and end-of-shelf life specifications.
	
MiV-N9	Deletion of pack size for a product

C	
1.	The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved product labeling.

D	
1.	Reason for deletion.
2.	Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

10. GLOSSARY 

Issue to be discussed : To state “Refer to ACTD/ACTR Glossary”.

11. REFERENCES

1.	European Medicine Agency Variation Guideline, 2008
2.	Communication from the Commission — Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products - Official Journal of the European Union (C 17/1 of 22.01.2010)
3.	Commission Regulation (EC) No 1234/2008 Official Journal of the European Union (L334 of 12 December 2008)
4.	WHO Guidance on Variations To A Prequalified Product Dossier, 2007
5.	SUPAC Guideline Immediate Release Solid Oral Dosage Forms, Scale-up and post approval changes: Chemistry, manufacturing and controls, in vitro dissolution testing and in vivo bioequivalence documentation, November 1995
6.	WHO Technical Report Series, No. 953, 2009
7.	WHO Quality Assurance of Pharmaceuticals – A Compendium of Guidelines and Related Materials – Volume 1
8.	ASEAN Guideline on Stability Study of Drug Product, 22 February 2005
9.	ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration
10.	ASEAN Guideline for Validation of Analytical Procedures
11.	ASEAN Guideline for the Conduct of Bioavailability and Bioequivalence Studies, 21 July 2004