Amendments to APIMFs

The holder of an approved active pharmaceutical ingredient master file (APIMF) will have submitted the APIMF to WHO in support of:

  • an application for prequalification of an API
  • or in support of an application for prequalification of a finished pharmaceutical product (FPP).

But over time APIMF holders are likely to make changes to the details of their APIMF that reflect changes in API preparation and/or control.

Changes to the information contained in an APIMF, whether administrative or substantive, are referred to as "amendments".

Guidance on amendments

As well as ensuring the accuracy of the information contained in the APIMF throughout its lifecycle, the APIMF holder is also responsible for:
  • providing all necessary documents to WHO to demonstrate that a change will not or has not had a negative effect on the API's quality or safety
  • communicating information about any changes made to the API to FPP manufacturers who manufacture FPPs with that API.

WHO has issued amendment guidance (which applies only to to APIs manufactured by chemical synthesis or semi-synthetically) to help APIMF holders:

  • determine what type of amendment applies in each case
  • understand the documentation that must accompany and an amendment application.

The aim of the guidance is twofold:

  • to minimize any time that an APIMF holder must wait before receiving approval of an amendment
  • to reduce the assessment burden on WHO assessors.

Classification of amendments and assessment timelines

WHO amendment guidance classifies amendments as major (Amaj), minor (Amin), for  immediate notification (AIN) or annual notification (ANN) depending on the level of risk associated with the change

Each type of amendment has its own approval mechanism and timeline, as summarized in the amendments table Amendments approval mechanism and timeline table (PDF).

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

If notification and documentation requirements cannot be met for either the AAN, AIN or Amin categories, the change will be considered to be a major amendment by default.

The list of amendments described in the amendment guidance is not exhaustive. If a change is not described, it should be considered as a major change. WHO should be contacted for clarification on how to make the required submission.

Grouping of changes (amendments) for submission

A single change may result in several amendments to an APIMF. This is acceptable.

Several unrelated changes may be submitted as a single amendment, provided they relate to a single APIMF.

A single amendment application may be submitted for multiple APIMFs provided the change concerned affects each of the APIMFs in the same way, e.g. the addition of the same artemisinin supplier to APIMFs for artesunate and artemether.

An application involving two or more types of change will be considered as the highest risk type, e.g. an amendment grouping both a minor amendment (Amin) and a major amendment (Amaj), or both a minor amendment (Amin) and an amendment for immediate notification (AIN), will be classified as a major amendment (Amaj).

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

The amendment guidance explains the potential impacts of the different changes and is therefore useful as a risk management tool for promoting or enhancing best practices.

Updated APIMF versions

A complete and updated APIMF outlining the accepted preparation, control and stability of the API is an important resource for both assessors and FPP manufacturers wishing to use the APIMF. APIMFs may be used to support several different applications for FPP prequalification, submitted at different times. However, since changes to API details can occur regularly, the originally submitted APIMF will soon accumulate a series of amendments following the introduction of amended APIMF subsections.

For this reason, regular submission of a complete and updated APIMF is important. Such an APIMF enables WHO and the applicant to confirm that they have a common understanding of the accepted amendments.

APIMF holders are therefore requested to submit an updated new version of their APIMF(s) every 24 months. If no changes were made to the API during this period, an amendment attesting to this fact must be submitted. The 24-month period should be calculated from the date of acceptance of the APIMF or date of acceptance of the most recently updated APIMF. An updated APIMF may, however, be requested within a shorter interval if WHO considers this to be necessary.

An updated APIMF can include AAN but not AIN, Amin or Amaj changes unless the latter have already been accepted. Conversely, an updated APIMF should not be submitted as supporting documentation for an amendment. Only the revised sections relating to the amendment are required to be submitted.

The submission of an updated APIMF is covered by amendment number 1 of the Guidance on amendments to an APIMF submitted in support of a prequalified FPP or API.