Classification of changes for veterinary medicines

The update of Part 2C can be submitted as a grouped application, if conditions 5 or 6 of Annex III of the Variation Regulation (EC) 1234/2008 apply.

An update or change of a stand-alone ASMF is not foreseen and can only be addressed in connection with a marketing authorisation. The type of the variation(s) is dependent on the type of the single changes introduced in the updated version. The update – including changes to the open and/or restricted part - can be submitted as a grouped application, if condition 5 of Annex III of the Variation Regulation (EC) 1234/2008 applies.

However, in case of substantial changes in the updated version of Part 2C or the ASMF it is recommended to submit a single variation of type II under category B.I.z. It is a prerequisite for the validation of these single variations that the “present/proposed” section of the application form is filled out completely and correctly.

We encourage a close dialogue between MAH and ASMF holder to establish the correct identification/classification of all the changes introduced within a new version of an ASMF to avoid validation issues.

In all cases, updates of the ASMF must be submitted by the ASMF holder (applicant's and restricted part to EMA, applicant's part to MAH) whilst the variation as such has to be submitted by the MAH.

Any pre-submission queries of any intended submission related to these changes should be addressed to vet.applications@ema.europa.eu.

In line with the Marketing Authorisation Holder's (MAH) obligation to keep the dossier up to date, a new or updated Certificate of Suitability (CEP) for an active substance (AS), excipient or starting material/reagent/intermediate used in the manufacturing process of the AS should be submitted as a variation. It is however understood that only the versions of the CEP (i.e. updated certificates) which were used in the manufacturing process of a batch of finished product (FP)/ AS need to be included in the dossier.

CEP updates should be submitted under the appropriate variation classification scope within subsection B.III.1. Each CEP update should be submitted as a variation scope, i.e. an update covering more than one CEP version should be submitted as a grouped variation.

When applying for an update of an approved CEP, the MAH should refer to the previously agreed version of the CEP within the 'Present/Proposed' section of the application form.

If with the submission one or more revisions of the CEP are omitted, the MAH should confirm in the variation application form (section 'Precise scope and background for change') that substance/material from the omitted CEP version(s) was not used in the manufacture of the FP and/or AS during the validity of this certificate(s). Additionally it should be confirmed that any changes introduced by the omitted CEP update(s), do not affect the quality of the AS and/or FP. In case such confirmation is missing, a negative Type IA notification may be issued.

The MAH should also clearly indicate in the 'Present/Proposed' section all changes introduced in the CEP between the latest approved version and the new revision, including all revisions that were not notified. Any changes e.g. to manufacturing sites, additional residual solvents introduced in the CEP by subsequent updates should be declared.

Example:

Submission of an updated CEP version for an already approved manufacturer: R0-CEP-xxxx-xx-rev.02 when the current certificate in the dossier is: R0-CEP-xxxx-xx-rev.00.

If, during the validity of R0-CEP-xxxx-xx-rev.01, material of the CEP was used in the manufacture of the FP and/or the AS, then the MAH should submit a grouping of two IA variations to include both certificates (rev. 01 and rev. 02) in the Module 3 or Part 2 (NTA). The foreseen conditions for each of the respective variations should be met.

If, during the validity of R0-CEP-xxxx-xx-rev.01, material of the CEP was not used in the manufacture of the FP and/or AS, the MAH should only submit a single Type IA variation to include the updated certificate R0-CEP-xxxx-xx-rev.02 in Module 3 or Part 2 (NTA). The foreseen conditions for the variation should be met.

The MAH should also confirm in the variation application form that material/substance from R0-CEP-xxxx-xx-rev.01 was not used in the manufacture of the FP and/or AS during the validity of this certificate and that changes introduced by the revision R0-CEP-xxxx-xx-rev.01 do not affect the quality of the AS and/or the FP. MAH should also clearly list within the 'Present/Proposed' section of the application form all changes introduced to the CEP with revisions 01 and 02.

If a new WCB is introduced using the limits/conditions as detailed in an approved qualification protocol, the new WCB is covered by the existing quality assurance system and there is no need to file a variation.

If the documentation of the WCB in the dossier does not include an approved qualification protocol for introducing new WCBs, the MAH should file a variation B.I.a.2.a) as a type IB (upgraded from type IA as condition 5 (immunological) is not met).

To introduce a qualification protocol for preparation of a new WCB, the MAH should file a type II variation under B.I.a.2.c. The addition of the new WCB can be covered as part of this single type II variation.

Changes to an approved standard procedure (protocol) should be filed using a type IB variation (B.I.a.2.a), or a type II variation (B.I.a.2.c), as relevant depending on the complexity of the change. The addition of a new WCB can be covered as part of this single variation.

If a new reference standard is introduced using the limits/conditions as detailed in an approved qualification protocol, the new reference standard is covered by the existing quality assurance system and there is no need to file a variation.

If no qualification protocol has been approved, the old material is still available and the MAH is able to provide comparability test results using both reference standards, the MAH should file a type IB variation either under B.I.b.2.e for active substance or under B.II.d.2.d for finished product.

If no qualification protocol has been approved and the old material is not available anymore and thus no direct comparison between old/new material is possible the MAH should file a type II variation either under B.I.b.2.d for active substance or under B.II.d.2.c for finished product.

To introduce a qualification protocol for the preparation of a new reference standard, the MAH should file a type II variation either under B.I.b.2.d for active substance or under B.II.d.2.c for finished product. Upon approval of the variation, the introduction of a new reference standard according to the protocol will be covered by the existing quality assurance system.

Provided that Part 2 is not impacted, the changes listed below (not an exhaustive list) are covered under the company's quality management system and do not require a variation to the Marketing Authorisation.

• Transfer of a manufacturing activity from one building to another in the same authorised site
• Transfer of a manufacturing activity from one room to another in the same authorised building
• Transfer of QC activity from one building to another in the same authorised site
• New filing line identical to an already approved one in an authorised room, building, manufacturing site
• New isolator in an authorised building
• New media or buffer preparation room in an authorised building
• Changes in the layout of an authorised manufacturing site

If as a result of any of the changes listed above, any amendments are introduced to Part 2, such as changes to the manufacturing site address detail, changes to the manufacturing process, changes to the batch size, etc., the MAH should file the appropriate variation(s).

Provided that the new equipment is equivalent to the one currently used, and operates in the approved range of process parameters, the change is covered by company's quality assurance system.

If the introduction of new equipment has any impact on the processes and details registered in Part 2, the MAH should file the appropriate variation(s).