Multisource Generic FPPs

Classification of variations and assessment timelines

The WHO variation guidelines classify four types of variation:

  • annual notification (AN)
  • immediate notification (IN)
  • minor variation (Vmin)
  • major variation (Vmaj).

A variation is classified according to its potential adverse effect on the quality, safety and/or efficacy of the product concerned. Each type of variation has its own approval mechanism and timeline. Applicants must satisfy themselves that they meet all of the prescribed conditions for the change and submit all required documentation with the variation application.

 Variations Approval Mechanism and Timelines (PDF) 

A variation is classified as major (Vmaj) if it could have major effects on the overall quality, safety and efficacy of the FPP. If a change is not described in the WHO guidelines, it is considered to be a major variation by default.

The general principle for determining the category of any given change is to start by determining whether the conditions and documentation requirements for the least significant category (AN → IN → Vmin) can be met. If the change does not comply with those conditions, the applicant should proceed to check compliance with the next category. Should the change not meet the conditions of either the AN or IN or Vmin category it will be considered to be a major variation (Vmaj) by default.

The list of variations described in the variation guidelines is not exhaustive. If a change is not described, it  will considered to be a major change by default. In such cases, WHO should be contacted for clarification on how to make the required submission; reclassification may be possible, depending on the nature of the change.

The variation guidelines explain the potential impacts on product quality of the different changes and are therefore useful as a risk management tool for promoting or enhancing best practices.

Grouping of changes (variations) for submission

In general, each change requires submission of a separate variation. Grouping of variations is acceptable only under the following circumstances.

  • the variations are consequential to each other, e.g. introduction of a new impurity specification that requires a new test method
  • the same change affects multiple FPPs from the same applicant e.g. addition of a new API manufacturing site for multiple FPPs
  • each of the changes is of the AN type.

For the purpose of classification, an application involving two or more types of variation will be considered as of the highest risk type. For example, a variation submission that includes both a minor variation (Vmin) and a major variation (Vmaj) will be classified as a major variation (Vmaj).

Care should be exercised whenever several changes to the same FPP are envisaged. Although individual changes may be classified as of a particular reporting type, classification in a higher risk category may be warranted as a result of the composite effect of these changes. In such cases, applicants are advised to contact WHO for guidance, before submission of the variation application.

API-related changes

An API manufacturer that makes a change to the preparation and/or control of any of its APIs should inform FPP manufacturers that incorporate any of those APIs in their own products. In the case of a prequalified FPP, it is the responsibility of the FPP applicant to submit a variation application to PQTm. However, the notification requirements for API-related changes differ depending on which of the four options for submitting information relating to the API was selected when the application for FPP prequalification was made:

  • option 1: by referring to an API that had already been prequalified
  • option 2: by submitting a copy of a European Pharmacopoeia Certificate of Suitability (CEP) issued by European Directorate for the Quality of Medicines and HealthCare (EDQM) for an API
  • option 3: through use of the APIMF procedure
  • option 4: through provision of a full description within the FPP dossier.

A scenario is given below for each option, for illustrative purposes.

  • Scenario 1: A prequalified FPP supported by a prequalified API (CPQ)

The API supplier is responsible for seeking approval for an API-related change from WHO. The API supplier is also responsible for informing any FPP manufacturer using its API of any changes it has made to its preparation and control. Manufacturers of prequalified APIs should refer to the amendment guidance.

The FPP applicant does not need to make a variation submission to WHO unless the associated Confirmation of API Prequalification document (CPQ) issued by WHO has been revised. (Please refer to variation number 6 of the guidelines.) However, any changes to API details not covered by the CPQ — such as particle size or polymorphic form — should be submitted as a variation by the FPP manufacturer, in accordance with the variation categories described in the variation guidelines.

  • Scenario 2: A prequalified FPP supported by a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP)

The API supplier is responsible for seeking approval from the European Directorate for the Quality of Medicines and HealthCare for any change to the API. The API supplier is also responsible for informing any FPP manufacturer using its API of any changes it has made to its preparation and control.

The FPP applicant does not need to make a variation submission to WHO unless the associated CEP has been revised. (Please refer to variation number 5 the guidelines.) However, any changes to API details not covered by the CEP — such as particle size, polymorphic form or retest period, if applicable — should be submitted as a variation by the FPP manufacturer, in accordance with the variation categories described in the variation guidelines.

  • Scenario 3: Prequalified FPP supported by an associated APIMF

If an FPP has been prequalified upon the basis of an APIMF that has been accepted by WHO, the APIMF holder should notify WHO of any changes in API details, in the form of an amendment to the APIMF. A variation should not be submitted by the FPP manufacturer until the amendment has been accepted.

Upon acceptance of the APIMF amendment, the FPP manufacturer should submit the type of variation required as defined in the variation guidelines. In some instances, though — for example, if the APIMF amendment related to the restricted part (confidential information) part of the APIMF — submission of a variation may be unnecessary.

API manufacturers should refer to the amendment guidance.

 

  • Scenario 4: A prequalified FPP for which API information was provided in full, within the FPP dossier

If the prequalified FPP does not rely upon a prequalified API or CEP or APIMF, any change to the preparation and control of the API is the responsibility of the FPP manufacturer and must be submitted to WHO as a variation, in accordance with the categories described in the variation guidelines.

New applications/extension applications

Certain changes alter the terms of the accepted FPP dossier. In these cases a new FPP dossier must be submitted. Examples of such changes are listed in Appendix 1 of the WHO Guidelines on variations to a prequalified product.

Labelling information

In the case of any change to product information (Summary of Product Characteristics, Patient Information Leaflet or labelling) not covered by the variation categories described in the WHO variation guidelines (see below), PQTm should be notified and the revised labelling submitted to PQTm. An email acknowledging receipt will be sent to the applicant within 7 calendar days following receipt. Acceptance by WHO PQTm is required before the changes can be implemented. The timeline for assessment will vary depending on the nature of the changes.

 

This information is intended for FPP manufacturers who submitted complete active pharmaceutical ingredient (API) information with their finished pharmaceutical product (FPP) dossier at the time of prequalification.

FPP manufacturers who submitted API information through the APIMF procedure or that use a prequalified API typically will not be required to take any action.  The API manufacturer themselves are responsible for submitting  an amendment to their APIMF to introduce a new source of non-plant-derived-artemisinin (refer to Clarification: Introduction of a supplier of non-plant-derived-artemisinin below and in the Amendments to APIMFs section ).

Manufacturers of non-plant-derived-artemisinin should refer to the prequalification guidance Clarification on the Process for Introducing a Supplier of Non-plant-derived Artemisinin.

FPP manufacturers who wish to introduce a source of non-plant-derived-artemisinin should submit a as per the standard variation procedure.

The following documentation should be submitted with the application.

  • A copy of the letter of access provided by the supplier of the non-plant-derived artemisinin.
  • The name and address of the manufacturing site producing the non-plant-derived-artemisinin.
  • A brief description of the preparation of the non-plant derived artemisinin, but including, at a minimum, all reaction intermediates, reagents and solvents.
  • A single harmonized set of specifications, issued by the active pharmaceutical ingredient (API) manufacturer for the control of artemisinin (irrespective of source) and a justification for these specifications.
  • A certificate of analysis for a batch of non-plant-derived-artemisinin issued by the artemisinin supplier and issued by the API manufacturer upon re-testing.
  • Data verifying that the use of non-plant-derived-artemisinin affords the target API, or a preceding intermediate of the same quality and does not lead to carry-over of unacceptable impurity content.
  • A revised finished pharmaceutica product (FPP) dossier to include details of the new supplier. Note that despite being considered, in principle, an API intermediate, it is suggested that information on this substance be included in section 3.2.S.2.3 (and applicable annexes), as would be expected when including information on any other additional API starting material supplier. Additionally, it is suggested that the information be included in section 3.2.S.2.3 rather than in section 3.2.S.2.4 given the advantages in maintaining information on all sources of artemisinin in a single place within the dossier.

Currently accepted supplier of non-plant-derived-artemisinin

The following company has been accepted as a supplier of non-plant-derived-artemisinin:

Company: Sanofi-Aventis SpA

Manufacturing site:
Sanofi-Aventis SpA
Via R Lepetit 142
Garesso, 12075
Italy

Date of acceptance by WHO: 7 May 2013