Variations - summary of the variation procedure - Effective immediately

An overview of changes made to the procedure published in TRS943, Annex 6

To facilitate the review and processing of variations, and in light of recent changes to the generic guideline, modifications have been made to the variation procedure published in TRS943, annex 6.  These changes are incorporated into the advice provided on this webpage, but for convenience these are summarized on this page.

Stability requirements

When stability data are required to support a variation reduced data requirements now apply, as per the new generic guideline, namely:

• For uncomplicated FPPs (e.g. immediate release solid oral dose forms), the minimum number of FPP batches required to establish the shelf-life is now two, of which one batch must be at least pilot scale.

• For complicated FPPs, the minimum number of FPP batches required to establish the shelf-life is now two, both of which must be pilot scale or larger.

Grouping

Clarification has been provided as to when it is permissible to group variations together as one application.  It is permissible to group variation if:

• The variations are consequential, to each other i.e. introduction of a new impurity specification that requires a new test method.

• The same change affects multiple FPPs i.e. addition of a new API manufacturing site for multiple FPPs.

If an application involves two or more types of variations, it will be considered as the most complicated type. For example, if a variation groups both a minor change and a major change, it will be referred to as a major change, i.e. the timeline of major change applies.

Application form

An application form has been introduced for variation submissions.

Quality Information Summary (QIS)

FPPs that have an associated Quality Information Summary must now submit a copy of this document (in Word format only) with each variation submission.

Use of CTD formatting

All revised sections of an FPP dossier submitted in support of a variation should be in CTD format regardless of the original dossier format.

APIMF-related variations

To reduce the regulatory burden on both FPP manufacturers and WHO, a new approach to the submission of variations arising from APIMF amendments has been introduced.  This new approach only applies to FPPs that rely upon, and have access to, an accepted APIMF.

• Some API-related changes announced in APIMF amendments will no longer require the submission of a variation from associated FPP manufacturers.  In general, this will occur when the amendment relates to details present in the closed section of an APIMF only.

• Variations for a change in API batch size (minor #9), additional manufacturing blocks (minor #12), or API retest/storage condition (minor #15), when supported by an applicable amendment acceptance letter may be implemented at the time of submission.

Clarification of minor variation 5c

Clarification of the circumstances under which an applicant can apply for the minor variation 5c - replacement or addition of a manufacturing site for an FPP.

This type of variation is intended for an additional site of manufacture for an immediate release product (e.g., tablet, capsule, semi-solids, liquids), without change in the batch formula, manufacturing process, equipment class, process controls and specifications.  The conditions as outlined under minor change N° 5 are fulfilled.

For a minor change N° 5c, commencing immediately, the following reduced requirements apply:

• Documentation N° 7: batch analysis data of one production batch and comparative data on the last three batches from the previous site; batch data on the next two production batches should be available on request or reported if outside specifications (with proposed action).

• Documentation N° 9: for solid dosage forms, data of comparative dissolution tests in the release medium [refer to Appendix 1 of the New Generic Guideline], with demonstration of dissolution profile similarity, performed on one production batch of each of the previous site and the new site should be submitted.

In addition, comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies should be included in the validation protocol.  The applicant should commit to place the first production scale batch manufactured at the new FPP site on long-term stability study.

Clarification of minor variation 12

Clarification of the circumstances under which an applicant can apply for the minor variation 12 has been provided.

This type of variation is intended for an additional site of manufacture that is part of the same company (pharmaceutical group) as the currently approved manufacturer and where the manufacturing and controls details are identical, i.e. the conditions as outlined under minor change no.12 are fulfilled.

The addition of a site of manufacture not meeting these requirements is considered to be major variation.