Basic information for beginners...

1. VariationsBy,CHANDRAMOHAN

2. • What is a Variation…?
• Variation Guidelines
• Types of variations
 Type-1A
 Type-1B
 Type-II
 Extension
• Renewals

3. What is a Variation…?
• A variation is a change to the terms of a marketing authorisation. This section
provides guidance for marketing authorisation holders on the regulatory
requirements and procedures for the different types of variations.

4. 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 234/2008
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.

6. Types of variations

7. Types of variations
Variations are broadly classified in to two categories:
Minor Variations: Type-1A & Type-1B 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’)
• Type IA variations NOT requiring immediate notification (‘IA’) (Variations which
do not require immediate notification may be submitted by the marketing authorisation
holder (MAH) within 12 months after implementation).

9. Type IA variations
Why certain minor variations of Type IA require immediate notification ?
Certain minor variations of Type IA require immediate notification after implementation, in
order to ensure the continuous supervision of the medicinal product.
When should I submit my Type IAIN variation?
This should be submitted immediately and generally within 2 weeks of implementation of the
change.
What is meant by 'implementation' for Type IA variations?
For quality changes, implementation is when the company makes the change in its own
quality system.

10. 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.

11. 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).

12. 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

13. 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

14. 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.

15. Grouping of variations
• 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.
• Examples are any group of IA changes, a group comprising a Type IB or Type II change plus one
or more of the same or lower category which are consequential to the first, and a group of
administrative changes to labelling.
• If a projected group is not listed in Annex III, the regulation and supporting guidances permit the
MAH to request agreement of the relevant authority(ies) to grouping of related changes where a
single data package and evaluation are meaningful.
• 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

16. 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

17. 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

18. 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.

19. 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

20. 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.

21. EU: Renewals
Renewal applications should be submitted in EU-CTD format and have
to contain following modules:
Module 1
Module 2