Active Pharmaceutical Ingredient Prequalification · 2016-06-13 · API Prequalification is...

CPHi Mumbai 20131 |

11

3.2.S.3.2 Impurities,

Malaysia, 29 September 2011

Active Pharmaceutical Ingredient Prequalification

Dr Antony Fake

WHO Prequalification of Medicines Programme

CPHi Mumbai 20132 |

CPHi Mumbai 20133 |

AbbreviationsAbbreviations

• PQP – Prequalification of Medicines Programme

• API – Active Pharmaceutical Ingredient – Drug substance.

• FPP – Finished Pharmaceutical Product

• APIMF – A Drug Master File

• API-PQ – Active Pharmaceutical Ingredient Prequalification

• CPQ document – Confirmation of API Prequalification document

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In order to have good quality medicines you must have:

� Good quality Active Pharmaceutical Ingredients.

Prequalification ProgrammePrequalification Programme

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The API Prequalification Procedure is one of three activities undertaken by the Prequalification of Medicines Programme. These are:

• Prequalification of Medicines (2001).

• Prequalification of Quality Control Laboratories (2004).

• Prequalification of Active Pharmaceutical Ingredients (2011).

Prequalification of Medicines ProgrammePrequalification of Medicines Programme

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• Prequalification of Medicines Programme (PQP) is run by the World Health Organization and is based in Geneva.

• PQP has an interest in: HIV/AIDS, Tuberculosis, anti-Malarial, Reproductive Health, Neglected tropical diseases, and Zinc medicines.


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Prequalification of Medicines websitePrequalification of Medicines website

http://www.who.int/prequal

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• PQP originated from recognition by international medicine procurers that medicines procured should be of good quality.

• The therapeutic areas of interest to procurers were largely not addressed by Stringent Regulatory Authorities (SRAs).

• An independent quality assurance body was required to assess many medicines of interest to procurers. WHO was asked to host this programme.

• To-date PQP has prequalified nearly 400 medicines.

www.who.int/prequal/info_applicants/info_for_applicants.htm


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API PrequalificationAPI Prequalification

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What is API Prequalification?What is API Prequalification?

• It is a scheme for manufacturers of APIs that are used in medicinal products for HIV, TB, Reproductive Health, Neglected tropical diseases and Malaria.

• It seeks to verify and identify APIs that are of good quality and manufactured in compliance with GMP.

• It commenced as a pilot project in October 2010.

• It is part of the Prequalification of Medicines Programme, WHO based in Geneva.


Why is Prequalification of APIs needed?Why is Prequalification of APIs needed?

• There is often a relative scarcity of API.

• There are significant geographical distances between API and FPP manufacturers, i.e. between China and India.

• The quality of the API manufacturer may not be clear.

Medicine manufacturers involved in the PQ programme (and in general) have difficulties in finding sources of quality APIs for malaria, HIV, reproductive health and TB, because:

This creates basic problems for FPP manufacturers to find and establish contact with potential API manufacturers.


Why is Prequalification of APIs needed?Why is Prequalification of APIs needed?

API Prequalification is intended to facilitate the identification of API sources by drug product manufacturers and support the availability of quality medicines.

API Prequalification is intended to act as a resource for national regulatory authorities who do not have the means to undertake API assessment themselves.

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


Benefits to API manufacturersBenefits to API manufacturers

• Public recognition as a source of quality API, manufactured in compliance with GMP.

• Serves as a point of difference between good quality and poor quality APIs.

• Opportunities to verify compliance with GMP.

• Opportunities to compile, revise and refine their regulatory documentation.

• API’s can be prequalified independent of an FPP application.

• Recognition by national regulatory authorities.


Benefits to FPP manufacturersBenefits to FPP manufacturers

• Ease of identifying potential sources of quality API.

• Identifying API manufacturers with robust quality systems in place.

• Identifying API manufacturers that maintain good regulatory documentation.

• Reduced API assessment requirements (PQP)

• Reduced post-prequalification variation (changes) requirements.

• Recognition by national regulatory authorities


ApplicationApplication

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing


5th Invitation for EOI5th Invitation for EOI

• Not all APIs are invited to apply for prequalification.

• APIs are publicly invited through a published invitation for expression of interest (EOI). A 5th EOI has been announced.

• It essentially covers those APIs listed in the associated FPP EOIs for HIV, anti-TB, Malaria, reproductive health neglected tropical diseases.

http://www.who.int/prequal/info_applicants/API_EOI.htm


5th Invitation for EOI5th Invitation for EOI

APIs FOR MEDICINAL PRODUCTS FOR HIV AND RELATED DISEASES

Abacavir Atazanavir Darunavir Didanosine Efavirenz Emtricitabine Etravirine Lamivudine Lopinavir

Nelfinavir Nevirapine Raltegravir Ritonavir Stavudine Tenofovir Zidovudine

APIs FOR ANTIMALARIAL MEDICINAL PRODUCTS

Amodiaquine Artemether Artesunate Dihydroartemisinin Lumefantrine Mefloquine Piperaquine

Pyrimethamine Pyronaridine Sulfadoxine

APIs FOR ANTI-TUBERCULOSIS MEDICINAL PRODUCTS

Amikacin Capreomycin Cycloserine Ethambutol Ethionamide Isoniazid Kanamycin Levofloxacin Moxifloxacin Ofloxacin

Para-Aminosalicylic Acid (PAS) Para-Aminosalicylate sodium (PAS Sodium) Prothionamide Pyrazinamide Rifampicin

Streptomycin Terizidone

APIs FOR NEGLECTED TROPICAL DISEASE MEDICINAL PRODUCTS

Albendazole Diethylcarbamazine citrate Mebendazole Praziquantel

APIs FOR REPRODUCTIVE HEALTH PRODUCTS

Desogestrel Estradiol cypionate Estradiol valerate Ethinylestradiol Etonogestrel Levonorgestrel Medroxyprogesterone acetate

Mifepristone Misoprostol Norethisterone enanthate Norgestrel Oxytocin

API FOR PRODUCTS USED IN THE TREATMENT OF DIARRHOEA

Zinc sulfate



Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing



• An application for API Prequalification is made by the API manufacturer, or agent.

• An applicant does not need to be supplying API to a WHO Prequalified FPP to seek API prequalification.

• Fees were introduced in September 2013


FeesFees

� No Fee – for first time applicants

� No Fee – for first application of a specific API

� $3000 – for second application of a specific API

� $5000 – for third application of a specific API

� $8000 – for further applications

The fee covers both assessment and inspection activities

See http://apps.who.int/prequal/info_applicants/eoi/FPPs_APIs_invited.xlsx for

information on numbers of applications received.



• The PQ application form.

• An APIMF (if not previously provided).

• A Site Master File (if not previously provided).

• Any further evidence of GMP at the facility (optional).

An application should consist of:


Assessment – Quality (APIMF)Assessment – Quality (APIMF)

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing


Assessment – Quality (APIMF)Assessment – Quality (APIMF)

• PQP does not align itself with any particular pharmacopoeia or regulator guidance.

• PQP recognises the major pharmacopoeias (Ph.Int., EP, USP, JP) and international guidance , ICH, FDA, EMA, EDQM etc.


APIMF - Technical contentAPIMF - Technical content

Excellent technical guidance can be found in the module 3.2.S sections (pages 11 to 31) of the recently published guideline :

Guideline on submission of documentation for a multisource

(generic) finished pharmaceutical product (FPP): quality part.

http://www.who.int/prequal/info_general/documents/generic_guide/GenericGuideline_Quality.pdf


Assessment – GMPAssessment – GMP

• By providing evidence of current compliance:

• GMP certificates, inspection reports, CAPAs, the most

recently completed Product Quality Review (PQR) report.

or

• By inspection by the WHO.

There are two ways to demonstrate GMP compliance at the API manufacturing facility.



• Inspections performed previously by WHO, a member of PIC/S, or an SRA.

• Inspection must have occurred within 3 years of application.

• Inspections must be API specific.

Assessment of GMP compliance at the site of API manufacture takes into account:

The WHO will perform an inspection if, after assessment and requests for information, GMP compliance can not be established.



• Each inspection will consist of a PQP lead inspector and a PQP co-inspector.

• In addition, an inspector from the responsible national agency is always invited as an observer

• An inspector from a “developing/recipient” country may also be invited.


PublishingPublishing

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing



List of PQ APIsWebsite (Public)

Confirmation Document - CPQ (Private)

+ WHOPIRsWebsite (Public)



The date of prequalification is the date when the API is published on the WHO List of Prequalified Active Pharmaceutical ingredients.

http://www.who.int/prequal/info_applicants/API_PQ-List.htm


WHO List of Prequalified APIsWHO List of Prequalified APIs

• WHO application number.

• INN name.

• Date of prequalification.

• Name of the applicant

• 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

Publically available


WHOPIRWHOPIR

� WHO does not issue GMP Certificates.

� The outcome of successful inspections are published on the PQP website.

http://www.who.int/prequal/WHOPIR/pq_whopir.htm

� Unsuccessful inspections are not published.


Confirmation of API PQ document (CPQ)Confirmation of API PQ document (CPQ)

• 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.

• The assigned re-test period.

• The recommended storage conditions.

• A copy of the assay and related substances test methods.

discretiontheirProvided to the API manufacturer for distribution at

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


� API Prequalification is a standalone procedure for API manufacturers only.

� API prequalification includes a quality and GMP assessment.

� Prequalified APIs are publicly listed as APIs of verified quality and GMP.

� Efforts are being to increase the recognition of PQ APIs by NMRA to further increase the value of participation.

Summary: API PrequalificationSummary: API Prequalification


Further informationFurther information

The PQ website is a good source of information, please read.

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

Or email me at:

[email protected]

Thank you

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