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APIMFs, the APIMF procedure,
and API Prequalification
Dr Antony Fake
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APIMFs and API Prequalification – 4th & 5th of April 2011
Abbreviations
API – Active pharmaceutical Ingredient.
Drug substance, or active ingredient
APIMF – Active pharmaceutical ingredient master file.
FPP – Finished pharmaceutical product
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APIMFs and API Prequalification – 4th & 5th of April 2011
Outline
APIMFs
The APIMF procedure
Active Pharmaceutical Ingredient (API) Prequalification
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APIMFs and API Prequalification – 4th & 5th of April 2011
Active Ingredient Master File
(APIMF)
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APIMFs and API Prequalification – 4th & 5th of April 2011
What is an APIMF?
It describes the preparation, control and stability of the API.
It is Module 3.2.S of the ICH CTD format.
It is prepared by the API manufacturer (or agent).
It typically has an open and restricted section.
The open section is shared with FPP manufacturers and WHO
The restricted section is shared only with the WHO.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Common deficiencies
Lack of discussion in the relevant sections of the APIMF, just data
being submitted.
Choice of API starting material. The molecule is often too complex.
Lack of information on the source and preparation of the API
starting material.
Long-term stability study storage conditions not at 30°C/65%RH or
30°C/75%RH.
Use of recovered solvents not described in sufficient detail.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Common deficiencies (2)
Cover letters not referencing an APIMF number, or no cover letter
at all.
Unlabelled CDs and DVDs.
Consistency in APIMF version numbering.
Poor summary of changes document.
Poorly updated APIMFs.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Expected content of an APIMF
An excellent guide to the expected content of an APIMF can be
found in the document: Guideline on submission of documentation
for a multisource (generic) finished pharmaceutical product (FPP):
Quality Part.
Throughout this year, information on the expected content of
APIMF amendments (changes) will be published on the PQ website
to help applicants.
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APIMFs and API Prequalification – 4th & 5th of April 2011
How APIMFs are used in PQ
APIMF
Procedure
APIMFs
(FPP Prequalification)
API
Prequalification
(New)
APIMFs are used to support FPP Prequalification and API prequalification.
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APIMFs and API Prequalification – 4th & 5th of April 2011
APIMF Procedure
(March 2008)
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APIMFs and API Prequalification – 4th & 5th of April 2011
The APIMF Procedure
It is solely used to support the evaluation of FPP prequalification
applications and has been active since March 2008.
Verification of the API manufacturers GMP is undertaken on a riskbased approach and is therefore not necessarily undertaken for
every API manufacturer.
Sources of API are deemed acceptable with respect to a given FPP
application.
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APIMFs and API Prequalification – 4th & 5th of April 2011
The APIMF Procedure (2)
API
+
FPP
APIMF
+
S&E
The APIMF
Procedure
Components of a FPP application
for Prequalification
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APIMFs and API Prequalification – 4th & 5th of April 2011
or
EDQM
CEP
or
3.2.S
The APIMF Procedure (3)
FPP applicant
APIMF holder
APIMF submission to
APIMF focal point
Letter of Access
FPP
submission
APIMF assessment
APIMF acceptance
FPP assessment
FPP prequalification
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APIMFs and API Prequalification – 4th & 5th of April 2011
Advantages of the APIMF Procedure
It allows the submission of confidential information by the API
manufacturer without disclosure to the FPP applicant.
One APIMF may be used to support multiple FPP applications
without the need for repeated evaluations.
It is applicable to both pharmacopoeial and nonpharmacopoeial APIs.
FPPs supported by an APIMF have reduced variation
requirements.
The APIMF holder prepares and maintains the APIMF
information and answers all queries directly.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Post-acceptance: API-related changes
There are advantages for FPP manufacturers using an APIMF
Normally all API-related changes would require the submission of a
variation from associated FPP manufacturers.
For FPPs supported by an APIMF there are reduced requirements.
The process is initiated by the APIMF holder through the
submission of an amendment.
The amendment acceptance letter will confirm if a variation is
required by the associated FPP manufacturer.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Post-acceptance: API-related changes (2)
Depending on the type of change in the APIMF amendment, an
FPP manufacturer will required to:
Take no further action (i.e. no variation required)
– Typically for changes to the closed part of the APIMF only.
Submit an APIMF-related notification
– Typically for changes that do not impact on API specs and methods.
– It may be implemented immediately.
– FPP manufacturer has 12 months to submit the API-related notification.
Submit a variation
– Typically for changes to API specifications or test methods.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Statistics
May 2010
April 2011
Total number active
88 APIMFs
112 APIMFs
Accepted
20 APIMFs
48 APIMFs
In progress
46 APIMFs
58 APIMFs
Queued for assessment
22 APIMFs
10 APIMFs
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APIMFs and API Prequalification – 4th & 5th of April 2011
Statistics (2)
Jan 09 to Mar 2011:
Work-In verses Work-Out
40
35
Pieces of work
30
25
Work out
20
Work in
15
10
5
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APIMFs and API Prequalification – 4th & 5th of April 2011
API Prequalification
(October 2010)
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APIMFs and API Prequalification – 4th & 5th of April 2011
http://apps.who.int/prequal/info_applicants/API_info_applicants.htm
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APIMFs and API Prequalification – 4th & 5th of April 2011
Goals of API Prequalification
A new initiative in the Prequalification of Medicines Programme.
To identify APIs that are of an assured quality and manufactured in
accordance with GMP.
To publicly recognise these APIs.
To maximize the usefulness of prequalification status to API
manufacturers, FPP manufacturers, UN agencies and national
medicine authorities.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Recognising Prequalified APIs
+
Website (Public)
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APIMFs and API Prequalification – 4th & 5th of April 2011
Confirmation Document
API PQ Website – List of PQ APIs
Published publically
The assigned WHO application number.
The APIMF version number.
The INN name of the active
pharmaceutical ingredient.
The API specification version number.
The primary and secondary packaging components.
The assigned re-test period.
The recommended storage conditions.
Confirmation of API PQ document issue date
The date of prequalification.
The name of the applicant company.
The sites of API manufacture.
Intended for: UN agencies, National medicine authorities, FPP manufacturers, public
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APIMFs and API Prequalification – 4th & 5th of April 2011
Confirmation of API-PQ Document
Provided to the API manufacturer for distribution at their discretion
The assigned WHO application number.
The INN name of the active pharmaceutical ingredient.
API manufacturer company name.
The API specification version number.
A copy of the API specifications.
A copy of the assay and related substances test methodology.
Intended for: UN agencies, National medicine authorities, FPP manufacturers
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APIMFs and API Prequalification – 4th & 5th of April 2011
Prequalification Process
Expression of interest (EOI)
Application for API pre-qualification
Applicant
Information
requested
Screening
Application accepted for
assessment
APIMF
Assessment
GMP assessment
Information
requested
Applicant
Information
requested
Review of GMP
Certification,
Inspection reports,
Site Master Files
(SMF).
Corrective and
preventative actions
Inspection
Accepted
Accepted
Final decision on
prequalification
Variations
Complaints
Random sampling
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Listing on WHO website
APIMFs and API Prequalification – 4th & 5th of April 2011
Manufacturers
2nd Invitation for EOI
A 2nd invitation for Expressions of Interest (EOI) has now been
announced.
It essentially covers those APIs listed in the associated FPP EOIs
for HIV, anti-TB, Malaria and reproductive health.
See website for the invitation:
http://apps.who.int/prequal/info_applicants/API_info_applicants.htm
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APIMFs and API Prequalification – 4th & 5th of April 2011
2nd Invitation for EOI (2)
Disease
HIV
Invited Active Pharmaceutical Ingredient
Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine,
Etravirine, Lamivudine, Lopinavir, Nevirapine, Raltegravir, Ritonavir,
Stavudine, Tenofovir, Zidovudine
Anti-malarial
Amodiaquine, Artemether, Artesunate, Dihydroartemisinin,
Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Sulfadoxine
Anti-tuberculosis
Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide,
Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, ParaAminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin,
Streptomycin, Terizidone
Reproductive
health
Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel,
Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone,
Norgestrel, Oxytocin
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APIMFs and API Prequalification – 4th & 5th of April 2011
Using APIMFs previously submitted to PQ
Many API manufacturers have APIMFs
accepted in the APIMF procedure.
API manufacturers that have APIMFs currently
accepted or pending with WHO PQ are
encouraged to consider API-PQ.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Using APIMFs previously submitted to PQ (2)
An APIMF submitted and accepted in the FPP prequalification
programme need not be resubmitted if:
– We hold a revised up-to-date version of the APIMF
– The APIMF includes signed, dated and version controlled API
specifications.
Reference to an existing APIMF should be stated in the cover
letter.
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APIMFs and API Prequalification – 4th & 5th of April 2011
Questions
Antony Fake
Fakea@who.int
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APIMFs and API Prequalification – 4th & 5th of April 2011