Variations - an introduction to the variation procedure - Effective immediately

The applicant of a prequalified medicinal product will invariably be required to make changes to the supplied product during the product's life cycle, either as a result of technical progress or to improve safety or performance of the product.

Even when a change to a prequalified product is accepted by the WHO, the applicant may also need to seek approval from the relevant national medicines authority of the country in which it is marketed.

Guidance on the submission of variations to the Prequalification of Medicines Programme is detailed in the technical report series document TRS943, Annex 6.  However, please note the following points regarding the published document:

• The procedure described in this guidance document is applicable only to active pharmaceutical ingredients (APIs) and excipients manufactured by chemical synthesis or semisynthetic processes and to finished pharmaceutical products (FPPs) containing such APIs and excipients.

• The list of variations described in this document is not exhaustive.  if a change is not described in this document, then WHO should be contacted for clarification on how to proceed.

• Whenever there is a reference to "Guideline on submission of documentation for prequalification of multi-source (generic) finished pharmaceutical products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis", reference should now be made to the "Guideline on submission of documentation for a multi-source (generic) finished pharmaceutical product (FPP): quality part" ("New generic guideline" below).

• Whenever there is a reference to the PQIF, reference should now be made to the QOS-PD.

• There have been changes in technical and procedural requirements since the publishing of this guidance.  These changes are announced on this web site and a summary of these changes can be found in the section entitled "A summary of changes to the procedure published in TRS943, Annex 6".

The current procedure and requirements for submitting variations is outlined in the following sections.

Types of variations

There are four types of changes described in the published TRS943, Annex 6, minor variations (Notifications), minor variations, major variations and changes requiring a new dossier or extension to an existing dossier.

For each of the minor variation categories there are specific associated conditions.  If these specific conditions cannot be met, then the change is considered a major variation.

How to submit a variation

Commencing immediately, to ensure the efficient review and processing of variations, the following documentation should be provided with each variation.

• An application form.

• An updated Quality Information Summary (QIS) (if applicable).

• Any documentation required to support the variation being sought.

Application form

An application form has been introduced to the variation procedure.  All sections of this form should be completed and the document signed.  Electronic versions of the application form, both as a Word Document and a scanned signed PDF file, should be provided in addition to the printed version.

Quality Information Summary (QIS)

Medicinal products prequalified in accordance with the new generic guideline will have an agreed upon Quality Information Summary (QIS) associated with the FPP.  QIS documents will also become a feature of re-qualified FPPs.

The QIS provides a summary of the key quality information from the product dossier.  An updated QIS (in Word format only) should be submitted with each variation if the FPP has an associated QIS.

For FPPs that have an agreed QIS, the QIS should be revised and submitted with every variation application.  Any revised sections within the QIS should be highlighted.  If there is no change to the QIS as a result of the variation, the current QIS should still be submitted and a statement made in the covering letter that there has been no change made to the QIS.

Supporting documentation

Appropriate documentation should be provided to support the variation including, at a minimum, the documents specified in TRS943, Annex 6.

Only replacement sections for the parts of the FPP dossier affected by the change should be provided.  All revised sections submitted should be in CTD format regardless of the original dosser format.

Where to submit the variation application

A paper and electronic version (CD) of the variation submission should be submitted to:

CONFIDENTIAL
Attention: Dr Matthias Stahl
WHO Prequalification of Medicines Programme
UNICEF Supply Division
UNICEF Plads - Freeport
2100 Copenhagen
Denmark

Grouping of variations

Each change normally requires the submission of a separate variation.  Grouping of variations is acceptable only under two circumstances.

1.  If the variations are consequential to each other e.g. introduction of a new impurity specification that requires a new test method.

2.  The same change affects multiple FPPs, e.g. 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.

Updated stability requirements for variations

Revised stability requirements for generic FPPs were introduced to the PQ Programme as part of the new generic guideline.  TRS943 Annex 6 does not reflect this revision in stability requirements.  Therefore, commencing immediately, when stability data is required to support an FPP related variation, the following requirements apply:

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

For complicated FPPs the minimum number of FPP batches required to support the variation is now two, both of which must be at least pilot scale.

Information regarding API-related changes

Changes to the preparation and control of an active pharmaceutical ingredient (API) are considered to be a change to the prequalified FPP details and therefore require the submission of a variation from the FPP applicant.

It is the obligation of API manufacturers to inform associated FPP manufacturers of changes made to the preparation and control of the API.  It is the FPP manufacturer's responsibility to notify the WHO of these changes in the form of a variation.

When there has been a change to the API preparation or control the FPP manufacturer should only use such API once a variation approval letter has been received.

The submission of API-related variations by an FPP manufacturer will differ depending on the manner in which the API information was submitted with the FPP application at the time of prequalification.

Scenario 1: A prequalified FPP where API information was provided in the dossier

If the prequalified FPP does not rely upon a Certificate of Suitability (CEP) or APIMF then all changes to the preparation and control of the API must be submitted by the FPP manufacturer in the form of a variation in accordance with the categories described in TRS943, Annex 6.

Scenario 2: A prequalified FPP supported by a CEP

If the prequalified FPP relies upon an EDQM CEP then if an updated CEP is issued by the EDQM, the revised CEP should be submitted by the FPP manufacturer as a variation (variation #13).  Any changes to details not covered by the CEP, such as particle size, or even potentially retest period should be notified as a variation from the FPP manufacturer in accordance with the categories described in TRS943, Annex 6.

Scenario 3: Prequalified FPP supported by an associated APIMF

When an FPP is prequalified based upon an accepted APIMF, any changes in API details should first be announced to the WHO by the APIMF holder in the form of an amendment to the APIMF. A variation should not be submitted by the FPP manufacturer until the amendment is accepted.

Commencing immediately the following changes to the published variation procedure have been introduced.

• Some API-related changes announced in APIMF amendments will require the submission of a variation, such as a change in active pharmaceutical ingredient specification or test method.

• Variations for other changes, such as API batch size, additional manufacturing blocks, API retest/storage condition, or process changes, when supported by an applicable amendment acceptance letter can be implemented by the FPP manufacturer immediately.  In general, such changes must not have resulted in changes to the accepted API test methods or specifications.  The FPP manufacturer has 12 months from the date of implementation to submit an APIMF-related notification form (see section below).

• Some API-related changes announced in APIMF amendments will no longer require the submission of a variation, or APIMF-related notification from associated FPP manufacturers.  In general, this will occur when the amendment relates to details present in the closed section of an APIMF only.  However, it remains the API manufacturer's responsibility to communicate relevant changes to the FPP manufacturer even if a variation is no longer required.  The FPP manufacturer in turn should determine that the change to the API has not adversely affected their FPP and data confirming this should be available for inspection.

In all cases, the type of variation required, if any, will be stated in the APIMF amendment acceptance letter.

APIMF-related notification form

This is a new procedure and fundamentally relies upon the previous acceptance of the APIMF amendment.  However, like all changes it remains the responsibility of the FPP manufacturer to ensure the announced change have not adversely affected the quality of their product.

The key features of the APIMF-related notification are:

• Changes announced in an APIMF-related notification form can be implemented by FPP manufacturers immediately.

• The FPP manufacturer has 12 months from the data of implementation of the change to submit the APIMF-related notification form.

• It is possible to group several such changes together in one API-related notification form provided they relate to only one APIMF.

• It is possible to submit one APIMF-related notification form for multiple FPPs provided the changes announced relate to only one APIMF.

• APIMF-related notification forms are not routinely assessed, but are subject to audit by the prequalification team.

• The FPP applicant will receive an email confirming receipt, but no letter of acceptance will be provided.

• If the notification is audited and found to be unacceptable the FPP manufacturer will be contacted and further action may be required.

The procedure for submitting an APIMF-related notification is as follows and should be strictly adhered to.

• The FPP applicant should complete the APIMF-related notification form.

• This form and copies of the associated APIMF amendment letters should be sent as attachments by email to stahlm@who.int.  no additional supporting information is required.

• The FPP applicant will receive an email confirming receipt.

• If the notification is audited and found to be unacceptable the FPP manufacturer will be contacted and further action may be required.

Related link:  APIMF-related Notification Form

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

The Prequalification of Medicines Programme would like to clarify the circumstances under which an applicant can apply for the minor variation, variation 12.

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.

Please note that the addition of a site of manufacture not meeting these requirements is considered to be major variation.  In such a situation, information regarding manufacture and control of the API must be submitted and reviewed either through APIMF procedure or by the provision of  complete module 3.2.S by the FPP manufacturer.  Other relevant documentation (relevant parts of the dossier) to prove that the change in source of API will not have an impact on the quality of the prequalified product should also be provided.

Information regarding changes to the details of innovator FPPs or generic FPPs prequalified on the
      basis of approval by a stringent regulatory authority (SRA)¹

Prequalification of such medicinal products is made solely on the basis of approval by the SRA.  Variations to and renewal of the marketing authorization of a product that has been prequalified by WHO based on the approval by an SRA, remain the responsibility of the relevant SRA.

Once the product has been prequalified, WHO should be provided with a copy of the regulatory acceptance letter of any change to the main characteristics of the product immediately after the variation has been approved by the relevant SRA.  The main characteristics of the product are listed below in the Table.

The Table should be filled out and submitted together with the information regarding the variation.

If the change affects the information in SmPC, PIL and/or container labels (immediate and outer), copies of these should be provided in electronic format (CD/DVD).

Other supportive information may be requested once the variation has been submitted.

Note: WHO should always be notified of any change in the name and contact information of the person responsible for communication with WHO on any issues related to the product.

• Table  [Doc]

1.  Stringent regulatory authority (SRA): a regulatory authority which is: (a) a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or (b) an ICH observer, being the European Free Trade Association (EFTA), as represented by Swiss Medic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).