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APIMFs and API Prequalification – 4th & 5th of April 20111 |

APIMFs, the APIMF procedure,and API Prequalification

Dr Antony Fake


AbbreviationsAbbreviations

� API – Active pharmaceutical Ingredient.

Drug substance, or active ingredient

� APIMF – Active pharmaceutical ingredient master file.

� FPP – Finished pharmaceutical product


OutlineOutline

� APIMFs

� The APIMF procedure

� Active Pharmaceutical Ingredient (API) Prequalification


Active Ingredient Master File

(APIMF)


What is an APIMF?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.


Common deficienciesCommon 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.


Common deficiencies (2)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.


Expected content of an APIMFExpected 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.


How APIMFs are used in PQHow APIMFs are used in PQ

APIMFsAPIMF

Procedure(FPP Prequalification)

API

Prequalification(New)

APIMFs are used to support FPP Prequalification and API prequalification.


APIMF Procedure

(March 2008)


The APIMF ProcedureThe 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 risk-based approach and is therefore not necessarily undertaken for

every API manufacturer.

� Sources of API are deemed acceptable with respect to a given FPP

application.


The APIMF Procedure (2)The APIMF Procedure (2)

API

FPP

S & E

Components of a FPP applicationfor Prequalification

3.2.SAPIMF

The APIMFProcedure

or or

+

+

EDQM

CEP


The APIMF Procedure (3)The APIMF Procedure (3)

APIMF holder FPP applicant

APIMF submission to APIMF focal point

FPP

submission

APIMF assessment

APIMF acceptance FPP assessment

FPP prequalification

Letter of Access


Advantages of the APIMF ProcedureAdvantages 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 non-

pharmacopoeial APIs.

� FPPs supported by an APIMF have reduced variation

requirements.

� The APIMF holder prepares and maintains the APIMF

information and answers all queries directly.


Post-acceptance: API-related changesPost-acceptance: API-related changes

� 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.

There are advantages for FPP manufacturers using an APIMF


Post-acceptance: API-related changes (2)Post-acceptance: API-related changes (2)

� 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.

Depending on the type of change in the APIMF amendment, an FPP manufacturer will required to:


Statistics Statistics

10 APIMFs22 APIMFsQueued for assessment

58 APIMFs46 APIMFsIn progress

48 APIMFs20 APIMFsAccepted

112 APIMFs88 APIMFsTotal number active

April 2011May 2010


Statistics (2)Statistics (2)

Jan 09 to Mar 2011:

Work-In verses Work-Out

0

5

10

15

20

25

30

35

40

Jan-

09M

ar-0

9M

ay-0

9Ju

l-09

Sep

-09

Nov-

09Ja

n-10

Mar

-10

May

-10

Jul-1

0S

ep-1

0N

ov-10

Jan-

11M

ar-1

1

Month

Pie

ces o

f w

ork

Work out

Work in


API Prequalification

(October 2010)


http://apps.who.int/prequal/info_applicants/API_info_applicants.htm


Goals of API PrequalificationGoals of API Prequalification

� 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.

A new initiative in the Prequalification of Medicines Programme.


Recognising Prequalified APIsRecognising Prequalified APIs

Website (Public) Confirmation Document

+


API PQ Website – List of PQ APIsAPI PQ Website – List of PQ APIs

� The assigned WHO application number.

� The INN name of the active

pharmaceutical ingredient.

� The date of prequalification.

� The name of the applicant company.

� The sites of API manufacture.

� The APIMF version number.

� 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

Intended for: UN agencies, National medicine authorities, FPP manufacturers, public

Published publically


Confirmation of API-PQ DocumentConfirmation of API-PQ Document

� 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.

discretiontheirProvided to the API manufacturer for distribution at

Intended for: UN agencies, National medicine authorities, FPP manufacturers


Application for API pre-qualification

ScreeningApplicant

GMP assessment

Review of GMP

Certification,

Inspection reports,

Site Master Files

(SMF).

Information

requested

Application accepted for

assessment

Assessment

APIMF

Accepted Accepted

Applicant

ManufacturersInspection

Corrective and

preventative actions

Final decision on

prequalification

Listing on WHO websiteVariations

Complaints

Random sampling

Information

requested

Information

requested

Expression of interest (EOI)

Application for API pre-qualification

ScreeningApplicant

GMP assessment

Review of GMP

Certification,

Inspection reports,

Site Master Files

(SMF).

Information

requested

Application accepted for

assessment

Assessment

APIMF

Accepted Accepted

Applicant

ManufacturersInspection

Corrective and

preventative actions

Final decision on

prequalification

Listing on WHO websiteVariations

Complaints

Random sampling

Information

requested

Information

requested

Expression of interest (EOI)

Prequalification Process


2nd Invitation for EOI2nd 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 EOIsfor HIV, anti-TB, Malaria and reproductive health.

� See website for the invitation:http://apps.who.int/prequal/info_applicants/API_info_applicants.htm


2nd Invitation for EOI (2)2nd Invitation for EOI (2)

Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel,

Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone,

Norgestrel, Oxytocin

Reproductive

health

Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide,

Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-

Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin,

Streptomycin, Terizidone

Anti-tuberculosis

Amodiaquine, Artemether, Artesunate, Dihydroartemisinin,

Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Sulfadoxine

Anti-malarial

Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine,

Etravirine, Lamivudine, Lopinavir, Nevirapine, Raltegravir, Ritonavir,

Stavudine, Tenofovir, Zidovudine

HIV

Invited Active Pharmaceutical IngredientDisease


Using APIMFs previously submitted to PQUsing 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.


Using APIMFs previously submitted to PQ (2)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.


QuestionsQuestions

Antony Fake

[email protected]

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