Handling of variations to Marketing Authorisation in EU region

Handling of variations to Marketing Authorisation in EU region

Handling of variations to Marketing Authorisation in EU region

High level summary for basic understanding

When the pharmaceutical manufacturer deals with the European regulatory region to market and distributes medicines, understanding variations to Marketing Authorisation concerning post-marketing change is essential. The knowledge of handling post-marketing changes is necessary for Quality Assurance specialists, Regulatory Affairs specialists, and Production Heads.

The post Marketing Authorisation changes are of various types and will undergo different types of approval processes. We will discuss the types of variations and classification; Type IA, Type IAIN, Type IB, Type II variations, and what Extension applications are. Furthermore, variations are broadly classified as Minor Variations (Type-1A & Type-1B variations) and Major Variations (Type-II variations).

1. What is a Variation….?

“A variation to the terms of a marketing authorization is an amendment to the contents of the documents of the approved dossier.” 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.

2. Categorization of changes in general

In general terms, the changes are categorized into three types depending on the nature of the category:
a. Administrative changes
b. CMC (Chemistry, Manufacturing and Controls) – Quality changes
c. Safety, Pharmacovigilance (PV), Efficacy etc.

3. Types of variations and approval requirements from the agencies

Classification of variations to Marketing Authorisation in EU

3.1 Types of variations are broadly classified in following types

Minor Variations: Type-1A & Type-1B variations
Major Variations: Type-II variations
Extension applications 

3.2 Classification of variation with respect to types

Type IA – “Do and tell” for changes implemented in previous 12 months

Type IAIN – “Do and tell” and requires immediate notification after implementation

Type IB – “Tell, wait and do” and requires notification before implementation (wait 30 days after submission of procedure)

Type II – More detailed changes (“Tell and do”) and requires approval before implementation (usually 60 day review; range 30-90 days)

Extension applications – e.g. additional strengths, pharmaceutical form and route of administration (up to 210 day review)

4. Detailed explanation of all types variations to the Marketing Authorisation in EU region

4.1 Type IA variations

Type lA variations are the minor variations that have only a minimal impact or no impact on the quality, safety, or efficacy of the medicinal product, and do not require prior approval before implementation (“Do and Tell” procedure).

i. Type lA variations requiring immediate notification (‘IAIN’)

ii. Type lA variations NOT requiring immediate notification (‘lA’) – Variations that do not require immediate notification may be submitted by the marketing authorisation holder (MAH) within 12 months after implementation.

a. Certain minor variations of Type IA require immediate notification after implementation, to ensure the continuous supervision of the medicinal product.
b. This should be submitted immediately and generally within 2 weeks of implementation of the change.
c. For quality changes, implementation is when the change was done in a quality system.

Examples of Type IAIN variation:

i. Change in the name and/or address of the marketing authorization holder

ii. Change in the name and/or address of a manufacturer/ importer of the finished product (including batch release or quality control testing sites)

iii. Changes in imprints, bossing, or other markings iv. Changes in the shape or dimensions of the pharmaceutical form; particularly immediate-release tablets, capsules, suppositories, and pessaries.

Examples of Type IA variation:

i. Addition of Physico-chemical test in the specification.

ii. Deletion of the non-significant test (ex: Identification test in Stability study).

iii. Tightening of specification limits (ex: Tightening of test limit for water content, residual solvents, and related substances, etc.

iv. Certificate of Suitability (CEP) updates/ renewal.

v. Finished Product (FP) batch size increase/ decrease within 10 fold for immediate-release products.

4.2 Type IB variations

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a minor variation or Type 1B as a variation. This is neither a Type lA 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.
Marketing Authorization Holder (MAH) must wait for 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 variation:

i. Major change in the approved analytical method

ii. FP Mfg. site changes

iii. Shelf-life extension

iv. Change in storage condition

v. Minor changes to approved manufacturing process

vi. SmPC / PIL changes in-line with innovator product 

4.3 Type II variations

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a major variation of Type II as a variation that 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 variation: 

i. Addition of alternate/new API DMF supplier

ii. Relaxation of approved specification

iii. Major change in approved manufacturing process

iv. Major change in approved composition 

4.4. 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 Applications:

i. 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.

ii. Change to strength, pharmaceutical form, route of administration:
a. Change of bioavailability;

b. Change of pharmacokinetics e.g. changes in rate of release;

c. Change or addition of a new strength/ potency;

d. Change or addition of a new pharmaceutical form;

e. Change or addition of a new route of administration.

f. Such applications will be evaluated in accordance with the same procedure as for the granting of the initial marketing authorisation to which it relates.

g. The extension can either be granted as a new marketing authorisation or will be included in the initial marketing authorisation to which it relates.

5. Timelines for approval of variation to marketing authorisation

Timelines for Type IA of variation approval

Type IATimelines
Receipt of Type IA variation notificationDay 0
Chicking startsDay 1
Acknowledgment of acceptance or refusalby Day 30

Note: Type IA notification is a ‘Do and tell’ procedure. Hence, changes must be implemented prior to submission of notification

Timelines for Type IB of variation approval

Type IBTimelines
Receipt of Type IB variation notificationDay 0
Chicking startsDay 1
The gernarl pre-assessment processing time is 14 days. Detailed assessment is done within 30 days. The outcome would be either approval or a request for further information (RFI) letter within the 30 days.by Day 30
Response to Request for Information (RFI) letter (If any)Within 30 days
Assessment of the response submitted by firmWithin 30 days

Note: This is a general timeline. This may differ based on circumstances.

Timelines for Type II of variation approval

Type IITimelinesTimelinesTimelines
Assessment StartsDay 0Day 0Day 0
Approval, refusal or withdrawalDay 22Day 60Day 90
Request for further information (RFI) (If any)Day 21Day 59Day 89
Timescale for receipt of responseDay 10Day 60Day 90
Response received – clock on completion of processingBy 30 daysBy 90 daysBy 120 days

Note: The timeline for Type II variations are 30-days, 60-days or 90-days depending upon complexity of the variation application.

6. References for types variations to the Marketing Authorisation in EU region

i. Variations Regulation (1234/2008) as amended by (712/2012)
ii. Variations Guidelines (2013/C 223/01)
iii. 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.

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