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Documents to be submitted

Submission of an application for active pharmaceutical ingredient (API) prequalification involves preparation and submission of a number of documents in electronic format, as follows:

• the covering letter (in Word or text-selectable PDF (portable document) format)
• a completed API prequalification application form (in both Word and PDF format)
• the API master file (APIMF) correctly formatted (see below, How to organize the APIMF for a full assessment)
• a site master file (SMF) for each manufacturing site (Word or text-selectable PDF)
• evidence of compliance with WHO Good Manufacturing Practices (GMP), or a request for inspection by WHO for each manufacturing site (Word or text-selectable PDF).

How to organize the APIMF for full assessment

An APIMF submitted as part of an application for full assessment should follow the format for module M4Q-R1 of the common technical document 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 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.

If the APIMF is being used only for API prequalification, dividing it into an open (i.e. applicant’s) part and a restricted (i.e. confidential) part (as required under the APIMF amendment procedure) is not mandatory. Nevertheless, division of the document into an open part and a restricted part is strongly encouraged. The document version number should appear on the cover page of each of the open and restricted parts, together with the name of the API and APIMF holder's name.

If the APIMF is divided into two parts the recommended system of version numbering (see section below) should be adhered to.

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 the originals of which 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.

Version numbering

The open and restricted parts of the document should each 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 restricted part 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" open part 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 open part 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.

In the table, an example of the life-cycle of an APIMF is depicted. Three amendments to the open section 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 open part was submitted, consolidating the previous amendments. Since no changes were made to details in the restricted part, the submission of a revised restricted part was not necessary.

Non-eCTD electronic submission (NeeS) requirements

Applicants may choose to submit their APIMFs in accordance with non-eCTD (Common Technical Document) electronic submission (NeeS) requirements, or as two bookmarked text-selectable PDF documents (an open part and a restricted part). But whichever route is chosen, APIMF holders should refer to the NeeS guidance. It includes information specific to the submission of information within the European Union but it it provides excellent technical guidance on electronic document formats.

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 (~)

A site master file (SMF) must be submitted – as an electronic copy (i.e. on CD/DVD) – for each manufacturing site of the API.

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.

Evidence of compliance with WHO Good Manufacturing Practices (GMP)

WHO assessment of GMP compliance at the site of API manufacture may take into consideration inspections performed previously at that site by WHO or by a stringent regulatory authority (SRA) or by a member of the Pharmaceutical Inspection Convention and Pharmaceutical  Inspection Co-operation Scheme (jointly referred to as PIC/S). 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 available information that demonstrates WHO GMP compliance at the API manufacturing site should therefore be submitted. It 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 report.

Where to send an application for product evaluation of an API and responses to requests for further information

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

World Health Organization
WHO Prequalification Unit: medicines
MHP/RPQ/PQT Room M613
20, Avenue Appia
1211 Geneva 27
Switzerland.

Please include a paper cover letter with the CD/DVD submission to facilitate processing.

or

2. Via a secure link to an online document repositories. The link should be sent in an email to the following email address: APIassessment@who.int. The subject line of the emails should clearly indicate the application and the specific medicine procedure referred to. The date of receipt will be the date the file is successfully downloaded.