Prequalification of Active Pharmaceutical Ingredients - Information required

What information is required?

What is to be submitted?

Any manufacturer/applicant who wishes to participate in WHO prequalification of active pharmaceutical ingredients (APIs) is requested to submit a/and:

• covering letter

• completed application form

• active pharmaceutical ingredient master file (APIMF)

• site master file (SMF) (for each manufacturing site)

• evidence of compliance with Good Manufacturing Practices (GMP), or a request for inspection by WHO (for each manufacturing site)

Cover letter and application form

Both a paper copy and an electronic copy (CD/DVD) of the cover letter and application form are required.

The cover letter should clearly identify that the information is being submitted for the purpose of prequalification of an API.

An application form should be completed and accompany the submission.

Active pharmaceutical ingredient master file (APIMF)

Both a paper copy and an electronic copy (CD/DVD) of the APIMF are required.

The submitted APIMF should be:

• prepared in CTD format

• accompanied by a Module 2 summary

• assigned a manufacturer's version number which should be included in the footer of each page of the APIMF.  The style of the version number should be such that subsequent amendments are easily identifiable as pertaining to the original version.

The electronic version of the APIMF should be in text-selectable PDF format.  The use of hyperlinks and bookmarks is encouraged.  Scanned copies of the paper APIMF are not acceptable, with the exception of supporting documents such as Certificates of Analysis, authorized specifications, signed protocols, etc.

If the applicant has previously submitted an APIMF with respect to a finished pharmaceutical product (FPP) WHO-prequalification procedure then reference to this existing APIMF can be made, provided the APIMF meets the above requirements.

Site master file

An SMF must be submitted - as an electronic copy (CD/DVD) only - for each API manufacturing site.

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 the named site and any closely integrated operations at adjacent and/or nearby buildings. If only part of a pharmaceutical operation is carried out at the site, the SMF need describe only those operations, e.g. analysis, packaging.

Layout of the SMF

• Guidelines for drafting an SMF

Evidence of GMP

An electronic copy (CD/DVD) of documentation verifying compliance with GMP is required.

WHO assessment of GMP compliance at the site of API manufacture may take into consideration inspections performed previously by WHO or by a stringent regulatory authority (SRA) or a member of the Pharmaceutical Inspection Cooperation Scheme (PIC/S) as described at http://www.picscheme.org.  Please note that, in order to be taken into consideration, any such inspection should have been performed within two years of submission of application and must be relevant to the specific API for which evaluation by WHO is now being requested. Any information that can be submitted in support of GMP compliance at the API manufacturing site is therefore advantageous. This information may include, but is not limited to, GMP certificates, inspection reports and corrective and preventive action reports and the most recently completed Product Quality Review (PQR) report.

For the purpose of inspections of API manufacturers, an SRA is a medicines regulatory authority in a country that is:

• a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (commonly know as ICH) (that is Japan, the USA or a member of the European Union); or

• an ICH Observer, for example a member of the European Free Trade Association (EFTA), currently represented by Swissmedic and Health Canada (subject to change); or

• associated with an ICH member through a legally binding mutual recognition agreement, including Australia, iceland, Liechtenstein or Norway (subject to change).

For further information on the provision of evidence of GMP, please contact: prequalinspection@who.int