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Variations
By,CHANDRAMOHAN
• What is a Variation…?
• Variation regulations and guidelines
• Types of variations
 Type-IA
 Type-IB
 Type-II
 Extension
 Unforeseen variations (Z category)
• Grouping of variations
• Work sharing of variations
• Fee
• eAF
• Renewals
What is a Variation…?
• A variation is a change to the terms of a marketing authorisation.
Variations in European Union (EU) are regulated by following regulations and Guidelines:
Commission Regulation (EC) No. 712/2012 of 3 August 2012 amending Regulation (EC) No. 1234/
2008 concerning examination of variations to the terms of marketing authorisations for medicinal
products for human use and veterinary medicinal products.
Annex I – Extensions of marketing authorisations.
Annex II – Classification of variations.
Annex III – Cases for grouping variations.
Annex IV – Elements to be submitted.
Annex V – Variations concerning a change to or addition of therapeutic indication, addition of non-
food producing target species, replacement or addition of a stereotype, strain, antigen etc.
Guidelines of 16.05.2013 on the details of the various categories of variations, on the operation of the
procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of
24 November 2008 concerning the examination of variations to the terms of marketing authorisations
for medicinal products for human use and veterinary medicinal products and on the documentation to
be submitted pursuant to those procedures.
Variations Regulation (1234/2008)
as amended by (712/2012)
Variations Guidelines
(2013/C 223/01)
Handling of variations in the Centralised Procedure
Pre-submission queries service(PQS):
• For IA/IBs
IAquery@ema.europa.eu
IBquery@ema.europa.eu
• For Type IIs /other:
Procedure designated PM
Procedure Manager (PM) - oversees all aspects of the managementof procedure;
- a first point of contact with MAHs and Rapporteurs
Procedure assistant (PA) – supports PM and MAH (Annexes, EPARupdates)
• For IAs and IBs, a procedure specific PM is assigned upon receipt of submission. For IBs, MAH is
informed of the assigned PM at start of procedure or during validation phase (if VSI during
validation)
Types of variations
Variations are broadly classified in to two categories:
Minor Variations: Type-IA & Type-IB variations
Major Variations: Type-II variations
Type IA variations
Type IA variations: Type IA variations are the minor variations which have only a minimal impact or
no impact at all, on the quality, safety or efficacy of the medicinal product, and do not require prior
approval before implementation ("Do and Tell" procedure).
Such a minor variations are “classified” two subcategories, which impact on their submission:
• Type IA variations requiring immediate notification (‘IAIN’) This should be submitted immediately
and within 2 weeks of implementation of the change. Certain minor variations of Type IA require
immediate notification after implementation, in order to ensure the continuous supervision of the
medicinal product.
• Type IA variations NOT requiring immediate notification (‘IA’) This should be submitted within 12
months after implementation.
• If a rejection of the IA notification is received, the implementation of the change should be stopped,
but can discuss with HA.
Examples of Type IA Variations
Examples of Type IAIN Variation:
• Change in the name and/or address of the marketing authorisation holder
• Change in the name and/or address of a manufacturer/importer of the finished product (including
batch release or quality control testing sites)
• Changes in imprints, bossing or other markings
• Change in the shape or dimensions of the pharmaceutical form particularly Immediate release
tablets, capsules, suppositories and pessaries.
Examples of Type IA Variation:
• Addition of physico-chemical test in specification.
• Deletion of non-significant test (ex: Identification test in Stability study).
• Tightening of specification limits (ex: Tightening of test limit for water content, Residual solvents
and Related substances..etc.
• CEP updates/renewal.
• API and FP Batch size increase/decrease within 10 fold.
Type IB Variations
• Commission Regulation (EC) No 1234/2008 ('the Variations Regulation') defines a
minor variation or Type IB as a variation which is neither a Type IA variation nor
Type II variation nor an Extension.
• Such minor variations must be notified to the National Competent Authority/
European Medicines Agency by the Marketing Authorisation Holder (MAH)
before implementation.
• However, the MAH must wait a period of 30 days to ensure that the notification is
acceptable by the Agency before implementing the change (Tell, Wait and Do
procedure).
Examples of Type IB Variations
Type IB Changes - Min to moderate impact on product quality (Tell, Wait and
Do procedure):
• Major change the approved analytical method
• FP Mfg. site changes
• Shelf-life extension
• Change in storage condition
• Minor changes to approved manufacturing process
• Change in batch size beyond 10 fold category
• SmPC /PIL changes in-line with innovator product
Type II Variations
• Commission Regulation (EC) No 1234/2008 ('the Variations Regulation')
defines a major variation of Type II as a variation which is not an extension
and which may have a significant impact on the Quality, Safety or Efficacy of
a medicinal product.
Examples of Type II Variations
Type II Changes (Significant impact on product quality, safety & efficacy):
• Addition of alternate/new API DMF supplier
• Relaxation of approved specification
• Major change in approved manufacturing process
• Major change in approved composition
Extension Applications
Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC) No
1234/2008 are regarded as "extensions" of the marketing authorisation.
Examples of extension changes:
1. Changes to the active substance(s)
• Replacement of a chemical active substance by a different salt/ester complex/derivative. with the
same therapeutic moiety, where the efficacy/safety characteristics are not significantly different;
2. Change to strength, pharmaceutical form, route of administration
• Change of bioavailability;
• Change of pharmacokinetics e.g. change in rate of release;
• Change or addition of a new strength/ potency;
• Change or addition of a new pharmaceutical form;
• Change or addition of a new route of administration.
• Such applications will be evaluated in accordance with the same procedure as for the granting of
the initial marketing authorisation to which it relates.
• The extension can either be granted as a new marketing authorisation or will be included in the
initial marketing authorisation to which it relates.
Unforeseen variations (Z category)
• The request shall apply only to variations whose classification is not provided for in the guideline
(i.e. unforeseen variations).
• The EMEA will deliver a recommendation within 45 days of the receipt of the request.
• Unforeseen variations (change is not specifically classified in Variation Regulation or as CMDh Art
5 recommendation) should be submitted as Type IB or Type II, depending on the impact of the
change(s) on the quality, safety and efficacy of the finished product.
Grouping of variations
• Submit several changes to one MA that are related.
• It is possible to group variations of different categories the same marketing authorisation (MA) and
submit them in one submission, under a single application form, to the same relevant authority.
This is permissible where variations are covered under the cases listed in Annex III to the
variations regulation.
• 14 cases of Groupings listed in Annex III
• CMDh Guidance for Examples for Acceptable and Not-Acceptable Groupings for MRP/DCP
Products -Doc. Ref: CMDh/173/2010/Rev.10 July 2013
• Time line follows that of the highest category variation e.g group contains Type II and Type IB –
follows Type II timeline
• Fee is higher (and varies in MS)
Worksharing of variations
• Same group of variations affecting more than one marketing authorisation from the same MAH in
one application.
• Only for Type IB or Type II variation (not for IA)
• Extensions are excluded from worksharing.
• Article 20 of Commission Regulation (EC) N° 1234/2008 (the ‘Variations Regulation’)
• Based on Articles 7 and 20 of the Variations Regulation, when a group of variations only consists
of Type IA/ IAIN variations affecting several marketing authorisations, this is considered as a
“group” of variations and not a “worksharing” procedure.
• It is possible to include a group of Type IA/ IAIN Variation(s) with a Type IB or Type II variation,
which is submitted for a worksharing procedure. In such case, the review of the Type IA/ IAIN
variation will be performed as part of the worksharing procedure.
The following documents should be submitted for filing of Variations applications:
• Cover letter.
• The completed EU variation application form
• Reference of variation guidelines, indicating that all conditions and documentation requirements
are met.
• Relevant documentation in support of the proposed variation including any documentation
specified in the Annex to these guidelines.
• In case that the variations affect the summary of product characteristics, labelling or package
leaflet: the revised product information presented in the appropriate format.
• Update or Addendum to the detailed critical summaries (quality, safety, efficacy as appropriate)
Examples of the variation applications:
Type IA
Type IB
Type II
Documentation Required For Variation Filling
How shall my Type IA/ IAIN notification be processed (timetable) by Health Authority?
• A ‘notification of receipt’ letter would be issued by the Agency within five days of receipt of a
Type IA application.
• Within 30 days of receipt, the notification would be reviewed. The Health authority will check
the correctness of the application form, ensure the required documentation is present and
compliance with the required conditions.
• The outcome of the process, an approval and/or refusal, would be communicated to the MAH via
the post or the portal.
• There will be no interaction with the marketing authorisation holder (MAH) during the
procedure, and no request to provide missing information.
• Type IA notification is a ‘Do and tell’ procedure, therefore changes must be implemented prior to
submission of notification.
Variation Approval Timeline
Receipt of Type IA variation notification Day 0
Start of MHRA check Day 1
Acknowledgement of acceptance or refusal By Day 30
Variation Approval Timeline
How shall my Type IB notification be processed (timetable) by Health
Authority?
• For Type IB notifications, the target pre-assessment processing time is 14 days.
• Substantive assessment is done within 30 days, and leads either to approval or a
Request For Further Information (RFI) letter within that 30 days.
• The company’s response to the RFI letter needs to be received within 30 days.
• Assessment of that response is within a further 30 days.
Variation Approval Timeline
How shall my Type II notification be processed (timetable) by Health Authority?
Type II variations follow a 30-day, 60-day or 90-day procedure (Depending upon
complexity of the variation application)
Stage 30-Day procedure 90-Day procedure 120-Day procedure
Start assessment – clock on Day 0 Day 0 Day 0
Assessment done
Approved, refused or withdrawn (procedure finalised) Day 22 Day 60 Day 90
or
Request for further information (RFI) issued – clock off
(procedure suspended)
Day 21 Day 59 Day 89
Amended application for applications with an RFI step
Timescale for receipt of response 10 days 60 days 90 days
Response received – clock on completion of processing
(excluding clock off time)
By day 30
By day 90 By day 120
Fee
• The fee will be charged upon validation of the procedure and should be paid within 30
days of the date of the invoice (“Due Date”).
• For an application that has been found not to be valid, an administrative fee for the
validation of the application shall be charged.
• A scope can be withdrawn from the application during the entire procedure:
- withdrawal during validation (i.e. before start of the procedure): no fee is charged;
- withdrawal during evaluation phase: the full fee will be charged.
Where to find the eAF
The application form can be found at:
http://esubmission.ema.europa.eu/eaf/index.html
EU: Renewals
Introduction
• A marketing authorisation is valid for five years, and is renewable upon application by
the Marketing Authorisation Holder.
• Once renewed the marketing authorisation will be valid for an unlimited period,
unless the competent authority decides, on justified grounds relating to
pharmacovigilance.
• The authorisation may be renewed upon application by the marketing authorisation
holder at least nine months before its expiry.
• In the case a MAH does not submit the renewal application, the MA will expire by
law.
• Certain changes to the marketing authorisation particulars may be made at renewal,
and these changes shall not trigger a variation procedure.
EU: Renewals
Renewal applications should be submitted in EU-CTD format and have
to contain following modules:
Module 1
Module 2
EU Variations-Chandra.pptx

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EU Variations-Chandra.pptx

  • 2. • What is a Variation…? • Variation regulations and guidelines • Types of variations  Type-IA  Type-IB  Type-II  Extension  Unforeseen variations (Z category) • Grouping of variations • Work sharing of variations • Fee • eAF • Renewals
  • 3. What is a Variation…? • A variation is a change to the terms of a marketing authorisation.
  • 4.
  • 5. Variations in European Union (EU) are regulated by following regulations and Guidelines: Commission Regulation (EC) No. 712/2012 of 3 August 2012 amending Regulation (EC) No. 1234/ 2008 concerning examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. Annex I – Extensions of marketing authorisations. Annex II – Classification of variations. Annex III – Cases for grouping variations. Annex IV – Elements to be submitted. Annex V – Variations concerning a change to or addition of therapeutic indication, addition of non- food producing target species, replacement or addition of a stereotype, strain, antigen etc. Guidelines of 16.05.2013 on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures. Variations Regulation (1234/2008) as amended by (712/2012) Variations Guidelines (2013/C 223/01)
  • 6. Handling of variations in the Centralised Procedure Pre-submission queries service(PQS): • For IA/IBs IAquery@ema.europa.eu IBquery@ema.europa.eu • For Type IIs /other: Procedure designated PM Procedure Manager (PM) - oversees all aspects of the managementof procedure; - a first point of contact with MAHs and Rapporteurs Procedure assistant (PA) – supports PM and MAH (Annexes, EPARupdates) • For IAs and IBs, a procedure specific PM is assigned upon receipt of submission. For IBs, MAH is informed of the assigned PM at start of procedure or during validation phase (if VSI during validation)
  • 7. Types of variations Variations are broadly classified in to two categories: Minor Variations: Type-IA & Type-IB variations Major Variations: Type-II variations
  • 8. Type IA variations Type IA variations: Type IA variations are the minor variations which have only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product, and do not require prior approval before implementation ("Do and Tell" procedure). Such a minor variations are “classified” two subcategories, which impact on their submission: • Type IA variations requiring immediate notification (‘IAIN’) This should be submitted immediately and within 2 weeks of implementation of the change. Certain minor variations of Type IA require immediate notification after implementation, in order to ensure the continuous supervision of the medicinal product. • Type IA variations NOT requiring immediate notification (‘IA’) This should be submitted within 12 months after implementation. • If a rejection of the IA notification is received, the implementation of the change should be stopped, but can discuss with HA.
  • 9. Examples of Type IA Variations Examples of Type IAIN Variation: • Change in the name and/or address of the marketing authorisation holder • Change in the name and/or address of a manufacturer/importer of the finished product (including batch release or quality control testing sites) • Changes in imprints, bossing or other markings • Change in the shape or dimensions of the pharmaceutical form particularly Immediate release tablets, capsules, suppositories and pessaries. Examples of Type IA Variation: • Addition of physico-chemical test in specification. • Deletion of non-significant test (ex: Identification test in Stability study). • Tightening of specification limits (ex: Tightening of test limit for water content, Residual solvents and Related substances..etc. • CEP updates/renewal. • API and FP Batch size increase/decrease within 10 fold.
  • 10. Type IB Variations • Commission Regulation (EC) No 1234/2008 ('the Variations Regulation') defines a minor variation or Type IB as a variation which is neither a Type IA variation nor Type II variation nor an Extension. • Such minor variations must be notified to the National Competent Authority/ European Medicines Agency by the Marketing Authorisation Holder (MAH) before implementation. • However, the MAH must wait a period of 30 days to ensure that the notification is acceptable by the Agency before implementing the change (Tell, Wait and Do procedure).
  • 11. Examples of Type IB Variations Type IB Changes - Min to moderate impact on product quality (Tell, Wait and Do procedure): • Major change the approved analytical method • FP Mfg. site changes • Shelf-life extension • Change in storage condition • Minor changes to approved manufacturing process • Change in batch size beyond 10 fold category • SmPC /PIL changes in-line with innovator product
  • 12. Type II Variations • Commission Regulation (EC) No 1234/2008 ('the Variations Regulation') defines a major variation of Type II as a variation which is not an extension and which may have a significant impact on the Quality, Safety or Efficacy of a medicinal product. Examples of Type II Variations Type II Changes (Significant impact on product quality, safety & efficacy): • Addition of alternate/new API DMF supplier • Relaxation of approved specification • Major change in approved manufacturing process • Major change in approved composition
  • 13. Extension Applications Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC) No 1234/2008 are regarded as "extensions" of the marketing authorisation. Examples of extension changes: 1. Changes to the active substance(s) • Replacement of a chemical active substance by a different salt/ester complex/derivative. with the same therapeutic moiety, where the efficacy/safety characteristics are not significantly different; 2. Change to strength, pharmaceutical form, route of administration • Change of bioavailability; • Change of pharmacokinetics e.g. change in rate of release; • Change or addition of a new strength/ potency; • Change or addition of a new pharmaceutical form; • Change or addition of a new route of administration. • Such applications will be evaluated in accordance with the same procedure as for the granting of the initial marketing authorisation to which it relates. • The extension can either be granted as a new marketing authorisation or will be included in the initial marketing authorisation to which it relates.
  • 14. Unforeseen variations (Z category) • The request shall apply only to variations whose classification is not provided for in the guideline (i.e. unforeseen variations). • The EMEA will deliver a recommendation within 45 days of the receipt of the request. • Unforeseen variations (change is not specifically classified in Variation Regulation or as CMDh Art 5 recommendation) should be submitted as Type IB or Type II, depending on the impact of the change(s) on the quality, safety and efficacy of the finished product.
  • 15. Grouping of variations • Submit several changes to one MA that are related. • It is possible to group variations of different categories the same marketing authorisation (MA) and submit them in one submission, under a single application form, to the same relevant authority. This is permissible where variations are covered under the cases listed in Annex III to the variations regulation. • 14 cases of Groupings listed in Annex III • CMDh Guidance for Examples for Acceptable and Not-Acceptable Groupings for MRP/DCP Products -Doc. Ref: CMDh/173/2010/Rev.10 July 2013 • Time line follows that of the highest category variation e.g group contains Type II and Type IB – follows Type II timeline • Fee is higher (and varies in MS)
  • 16. Worksharing of variations • Same group of variations affecting more than one marketing authorisation from the same MAH in one application. • Only for Type IB or Type II variation (not for IA) • Extensions are excluded from worksharing. • Article 20 of Commission Regulation (EC) N° 1234/2008 (the ‘Variations Regulation’) • Based on Articles 7 and 20 of the Variations Regulation, when a group of variations only consists of Type IA/ IAIN variations affecting several marketing authorisations, this is considered as a “group” of variations and not a “worksharing” procedure. • It is possible to include a group of Type IA/ IAIN Variation(s) with a Type IB or Type II variation, which is submitted for a worksharing procedure. In such case, the review of the Type IA/ IAIN variation will be performed as part of the worksharing procedure.
  • 17. The following documents should be submitted for filing of Variations applications: • Cover letter. • The completed EU variation application form • Reference of variation guidelines, indicating that all conditions and documentation requirements are met. • Relevant documentation in support of the proposed variation including any documentation specified in the Annex to these guidelines. • In case that the variations affect the summary of product characteristics, labelling or package leaflet: the revised product information presented in the appropriate format. • Update or Addendum to the detailed critical summaries (quality, safety, efficacy as appropriate) Examples of the variation applications: Type IA Type IB Type II Documentation Required For Variation Filling
  • 18. How shall my Type IA/ IAIN notification be processed (timetable) by Health Authority? • A ‘notification of receipt’ letter would be issued by the Agency within five days of receipt of a Type IA application. • Within 30 days of receipt, the notification would be reviewed. The Health authority will check the correctness of the application form, ensure the required documentation is present and compliance with the required conditions. • The outcome of the process, an approval and/or refusal, would be communicated to the MAH via the post or the portal. • There will be no interaction with the marketing authorisation holder (MAH) during the procedure, and no request to provide missing information. • Type IA notification is a ‘Do and tell’ procedure, therefore changes must be implemented prior to submission of notification. Variation Approval Timeline Receipt of Type IA variation notification Day 0 Start of MHRA check Day 1 Acknowledgement of acceptance or refusal By Day 30
  • 19. Variation Approval Timeline How shall my Type IB notification be processed (timetable) by Health Authority? • For Type IB notifications, the target pre-assessment processing time is 14 days. • Substantive assessment is done within 30 days, and leads either to approval or a Request For Further Information (RFI) letter within that 30 days. • The company’s response to the RFI letter needs to be received within 30 days. • Assessment of that response is within a further 30 days.
  • 20. Variation Approval Timeline How shall my Type II notification be processed (timetable) by Health Authority? Type II variations follow a 30-day, 60-day or 90-day procedure (Depending upon complexity of the variation application) Stage 30-Day procedure 90-Day procedure 120-Day procedure Start assessment – clock on Day 0 Day 0 Day 0 Assessment done Approved, refused or withdrawn (procedure finalised) Day 22 Day 60 Day 90 or Request for further information (RFI) issued – clock off (procedure suspended) Day 21 Day 59 Day 89 Amended application for applications with an RFI step Timescale for receipt of response 10 days 60 days 90 days Response received – clock on completion of processing (excluding clock off time) By day 30 By day 90 By day 120
  • 21. Fee • The fee will be charged upon validation of the procedure and should be paid within 30 days of the date of the invoice (“Due Date”). • For an application that has been found not to be valid, an administrative fee for the validation of the application shall be charged. • A scope can be withdrawn from the application during the entire procedure: - withdrawal during validation (i.e. before start of the procedure): no fee is charged; - withdrawal during evaluation phase: the full fee will be charged.
  • 22. Where to find the eAF The application form can be found at: http://esubmission.ema.europa.eu/eaf/index.html
  • 23. EU: Renewals Introduction • A marketing authorisation is valid for five years, and is renewable upon application by the Marketing Authorisation Holder. • Once renewed the marketing authorisation will be valid for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance. • The authorisation may be renewed upon application by the marketing authorisation holder at least nine months before its expiry. • In the case a MAH does not submit the renewal application, the MA will expire by law. • Certain changes to the marketing authorisation particulars may be made at renewal, and these changes shall not trigger a variation procedure.
  • 24. EU: Renewals Renewal applications should be submitted in EU-CTD format and have to contain following modules: Module 1 Module 2