Active Pharmaceutical Ingredients

Prequalification of active pharmaceutical ingredients (APIs) is an independent procedure that identifies APIs that are of good quality and manufactered in compliance with WHO Good Manufacturing Practices (GMP). If a prequalified API is used in the manufacture of a finished pharmaceutical product (FPP) for which prequalification is sought, prequalification of that FPP is greatly facilitated.

API prequalification should  not be confused with the API master file procedure (APIMF). Under this procedure an API manufacturer is invited to provide its APIMF in support of an application for prequalification of an FPP.

In order to become prequalified an active pharmaceutical ingredient (API) must be of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP). Evaluation of an API for prequalification has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards, and verification that the site(s) of API manufacture comply with WHO GMP requirements.

Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. A prequalified API is therefore clearly identifiable with a specific APIMF version. An APIMF version may be altered during prequalification assessment, or as a result of post-prequalification changes. Therefore, the version number of the current APIMF is included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference for the production and quality control of that API.

As well having their prequalified API(s) included in the WHO List of Prequalified Active Pharmaceutical Ingredients, successful applicants receive a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification for each API for which they attain prequalification. This contains information regarding the accepted active ingredient specifications, and the assay and related substances test methods. It may be provided by the applicant to interested parties.

Routes to API prequalification

There are three possible routes to API prequalification.

  1. Full assessment of an APIMF not previously assessed by WHO.
  2. Abridged assessment of an APIMF previously assessed by WHO in support of an application for FPP prequalification.
  3. Abridged assessment of an APIMF accepted previously by an Authority applying stringent standards.

Manufacturing site requirements

All applicants must submit a site master file (SMF) for each manufacturing site of each API and intermediate involved in the preparation of the API for which prequalification is sought. An SMF is a document prepared by the manufacturer containing information with respect to the production and/or control of pharmaceutical manufacturing operations carried out at a named site, and to any closely integrated operations at adjacent and/or nearby buildings. If only part of the API production is carried out at a site ― such as analysis or packaging ― the SMF need describe only that operation.

Each API or intermediate manufacturing site must comply with WHO GMP. Manufacturers who submit an application for prequalification should therefore request inspection by WHO of the relevant manufacturing site(s) so that compliance with WHO GMP can be assessed. However, applicants whose manufacturing site(s) have already undergone a WHO GMP inspection, or inspection within the past two years by a member of the Pharmaceutical Inspection Co-operation Scheme (PICs) evidence of this inspection as part of their application for API prequalification, in lieu of a request for inspection by WHO.