API Master File (APIMF) Procedure

Information on the preparation control and stability of an active pharmaceutical ingredient (API) intended for use in a prequalified multisource (generic) finished pharmaceutical product (FPP) can be provided by the API master file (APIMF) procedure. This procedure has become increasingly popular with API manufacturers since it preserves the confidentiality of the API information.

Alternatively, the information on the API can be provided by submitting:

  • the reference number and details of the WHO-prequalified API, together with additional supporting information
  • submitting a copy of the relevant Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) issued by the European Directorate for the Quality of Medicines and HealthCare, together with additional supporting information
  • submitting a complete ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) module 3.2.S for the API, as part of the FPP dossier submitted for evaluation.

How the APIMF procedure works

The FPP applicant submits the open part (non-confidential information) (OP) of the APIMF as part of its application for FPP prequalification. In so doing the applicant demonstrates that it has at least basic knowledge about the API used in the manufacture of its product.

In addition, the FPP applicant requests the API manufacturer to provide it with a Letter of Access granting the WHO Prequalification Team: medicines (PQTm) permission to review the restricted part (RP) (i.e. containing confidential information) of the APIMF when evaluating the relevant FPP for prequalification.

In the Letter of Access the API manufacturer should commit to informing WHO of any changes it has made to the details of either the OP or restricted part (RP) of the APIMF, and to inform the FPP applicant of any changes made or likely to be made to the preparation, control and/or stability of the API.

Thereafter the API manufacturer provides PQTm with both the OP and the RP of the APIMF for review.

It is the responsibility of the FPP applicant to ensure that the API manufacturer provides WHO with the complete APIMF (i.e. both the OP and the RP).

PQTm will contact the APIMF holder directly if it has any questions arising from its assessment of the RP, or requires any further information about the APIMF. Once assessment has been completed (i.e. the APIMF is considered to be acceptable), the APIMF details are considered to form part of the FPP dossier.

Reassessment of the APIMF is not required if further FPP applications are made although the “acceptability” of the API manufacturer will always be reviewed with respect to any FPP application for prequalification.

Please note:

  • Both the APIMF procedure and the API prequalification procedure may be used in support of an FPP application, and both procedures make extensive use of APIMFs. But they are separate procedures.
  • Acceptance of an APIMF within the APIMF procedure does not mean that the API is prequalified. However, APIMF holders who have had their APIMF accepted within the APIMF procedure may wish to build upon this acceptance and apply for API prequalification.
  • API prequalification is a standalone procedure for API manufacturers and does not need to be applied when an application for FPP prequalification is made.
  • The same APIMF can be used as part of a submission for API prequalification and as part of a submission for FPP prequalification.

 

Guidance documents

Guidelines on active pharmaceutical ingredient master file procedure (2008)

A review of API quality deficiencies found in APIMFs submitted to WHO and assessed during a 6-year period (2007–2012) was published in April 2014 in the Journal of Pharmacy & Pharmaceutical Sciences (Vol 17, No. 2). The results of the review are compared to those of similar studies reported by the European Directorate for the Quality of Medicines, the European Medicines Agency and the US Food and Drug Administration. The article can be accessed freely at: http://ejournals.library.ualberta.ca/index.php/JPPS/issue/view/1547

Application form

Application for active pharmaceutical ingredient master file (APIMF) procedure (15 January 2016)

 

Documents to be submitted with an application for the APIMF procedure

Submission of an application for the APIMF procedure involves preparation and submission of:

  • the covering letter (in Word or text-selectable PDF (portable document) format)
  • the APIMF procedure application form (in both Word and PDF format)
  • a completed Letter of Access (in PDF format)
  • the APIMF correctly formatted (see Documentation requirements for submission of an APIMF).

Responses to requests from the WHO Prequalification Team: medicines for information should include:

  • the covering letter (paper format)
  • a labelled CD or DVD containing:
    • an electronic version of the covering letter (in Word or text-selectable PDF format)
    • the applicant’s responses to the questions raised (in Word or text- selectable PDF format)
    • if requested, an electronic version(s) of any APIMF subsections that have been updated (see Documentation requirements for submission of   an APIMF below).

APIMFs and revised subsections submitted as amendments should be submitted in electronic format only. Paper copies should not be submitted unless these have been requested by the WHO Prequalification Team: medicines.

APPLICATION FORM & TEMPLATE

How to organize the APIMF

All APIMFs should follow the format for module M4Q-R1 of the common technical document (CTD) format of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (commonly known as ICH). This includes following the M4Q-R1 headings and sub-headings.

The APIMF should be divided into two parts (one each for the open part (OP) and the restricted part (RP) of the APIMF). It can be submitted as two documents. Each document should include a table of contents with headings listed in accordance with the 3.2.S.1 to 3.2.S.7 section levels of M4Q-R1. Alternatively, NeeS (non-eCTD electronic Submission) requirements) can be followed. I.e. each of the two parts of the APIMF can be divided into multiple sub-sections (i.e. documents). NeesS guidance includes information specific to the submission of information within the European Union but it provides excellent technical guidance on electronic document formats.

Documents should be paginated throughout. Page numbers may be set at 1 at the start of each section or subsection.

The use of PDF bookmarks or hyperlinks is encouraged. Ideally, bookmarks will be inserted to at least the 3.2.S.X.X level. In very detailed sections, use of additional bookmarks is suggested.

Officially certified translations should be provided for any documents that are not in English.

Submitted documents should enable an assessor to navigate between sections easily and to copy critical information. Inclusion of summaries, conclusions, and most importantly analysis and discussion of raw data, will facilitate assessment of the API information provided.

Since further questions may arise, APIMF holders should not submit a revised version of their APIMF when they submit responses to these, unless specifically requested to do so and/or any issues have been resolved.

Version numbering

Each of the two documents should be assigned a unique document version number. This number should appear on the document cover page, together with the name of the API and the APIMF holder’s name, indicate whether it refers to the open or RP of the APIMF, and give the date of issue. For example:

Drugs Inc/Artemether/OP/01/Feb-2013.

If a replacement subsection of an APIMF is issued by the applicant, it is referred to as an amendment and should be assigned an amendment version number. The amendment version number should include reference to the “parent” OP document. For example:

Drugs Inc/Artemether/OP/01/Feb-2013/Amend 01 – April-2013.

A change to the open-part version number, from OP/01 to OP/02 for example, would indicate the availability of a complete and revised version of the OP document. This new version (AP/02) would be assumed to incorporate all the accepted amendments made to the earlier version (AP/01), including all applicable CTD headings.

Example of the life cycle of an APIMF
The table below presents an example of the life cycle of an APIMF. Three amendments to the OP were received, following submission of the original APIMF. Each time an amendment was received, the amendment number and date were added to APIMF version number. Finally, a year after submission of the APIMF, a revised version of the OP was submitted, consolidating the previous amendments. Since no changes were made to details in the RP, submission of a revised RP was not necessary.

 

Submission type Submitted document version Current APIMF version number

APIMF submission

Nevirapine/OP/00/Feb-2013

Nevirapine /RP/00/Feb-2013

Nevirapine/OP/00/Feb-2013

Nevirapine /RP/00/Feb-2013

1st amendment

Nevirapine /OP/00/Feb-2014/Amend 01 – April-2013

Nevirapine/OP/00/Feb-2013

Nevirapine /RP/00/Feb-2013

Nevirapine /OP/00/Feb-2014/Amend 01 – April-2013

2nd amendment

Nevirapine /OP/00/Feb-2013/Amend 02 – June-2013

Nevirapine/OP/00/Feb-2013

Nevirapine /RP/00/Feb-2013

Nevirapine /OP/00/Feb-2013/Amend 01 – April-2013

Nevirapine /OP/00/Feb-2013/Amend 02 – June-2013

3rd amendment

Nevirapine /OP/00/Feb-2013/Amend 03 – Oct-2013

Nevirapine/OP/00/Feb-2013

Nevirapine/RP/00/Feb-2013

Nevirapine/OP/00/Feb-2013/Amend 01 – April-2013

Nevirapine/OP/00/Feb-2013/Amend 02 – June-2013

Nevirapine/OP/00/Feb-2013/Amend 03 – Aug-2013

Revised APIMF submission

Nevirapine/OP/01/Feb-2014

Nevirapine/RP/00/Feb-2013

Nevirapine/OP/01/Feb-2014

Nevirapine/RP/00/Feb-2013

Electronic requirements

No single electronic file should exceed 50 MB in size.

File or folder names should not exceed 64 characters in length.

Path lengths should not exceed 180 characters, including the file name, and extension. Abbreviated file or folder names can be used.

The use of special characters in folder or file names should to be avoided in order to prevent software conflicts. These special characters include:

  • angle brackets (<>)
  • ampersand (&)
  • asterisk (*)
  • backslash (\)
  • braces ({})
  • colon (:)
  • forward slash (/)
  • number sign (#)
  • percent (%)
  • plus sign (+)
  • pipe (|)
  • question mark (?)
  • quotation mark (")
  • tilde (~).
 
GUIDANCE Document

 

 

 

An application for the APIMF procedure and subsequent responses to questions raised by PQTm assessors should be sent to:

WHO Prequalification Team: medicines
World Health Organization
HIS/EMP/RHT/PQT Room 613
20, Avenue Appia
1211 Geneva 27
Switzerland