Prequalification of APIs - Indian Pharmaceutical Association

Prequalification of APIs 

Antony Fake PhD 

WHO Medicines Prequalification Programme 

1 


Mumbai September 2012

2 



Abbreviations 

• API – Active Pharmaceutical Ingredient 

• FPP – Finished Pharmaceutical Product 

• API PQ – API Prequalification 

• APIMF – Active Pharmaceutical Ingredient Master File (DMF) 

• CPQ – Confirmation of API PQ Document 

• SRA – Stringent Regulatory Authority 

• GMP – Good Manufacturing Practice 

• PQP – Prequalification of Medicines Programme 



Overview 

Outline the API PQ procedure 

Updated statistics 

API related changes 

4 



Prequalification of Medicines Programme 

The Prequalification of APIs is an initiative within the existing 

Prequalification of Medicines Programme. 

• Prequalification of medicinal products. 

• Prequalification of Quality Control Laboratories. 

• Capacity building activities. 

• Prequalification of Active Pharmaceutical Ingredients. 

5 



Two uses of APIMFs in PQP 

APIMF 

Procedure 

APIMFs 

API 

Prequalification 

APIMFs are used to support FPP Prequalification and API prequalification. 

6 



APIMF Procedure 

FPP 

Manufacturer 

API 

Manufacturer 

+ 

AP 

RP 

+ 

APIMF assessment is conducted in conjunction with an FPP application 

7 



What is API Prequalification? 

It is a scheme for API manufacturers only 

API 

Prequalification 

API 

Manufacturer 

There is no involvement by FPP manufacturers 

8 



What is API Prequalification? 

• It is a scheme for manufacturers of APIs that are used in medicinal 

products for HIV, TB, Reproductive Health 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. 

9 



Prequalification of Medicines website 

http://www.who.int/prequal 

10 



Why is Prequalification of APIs needed? 

• There is a need to identify sources of good quality API for use in 

medicinal products for HIV, TB, malaria and reproductive health. 

• Primarily for use in medicinal products procured by UN agencies and 

other international procurers, but 

• Also for use in medicinal products procured by countries with limited 

regulatory capacity. 

11 



Why is Prequalification of APIs needed? 

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: 

• There is 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. 

This creates basic problems for FPP manufacturers to find and 

establish contact with potential API manufacturers. 

12 



Benefits to API manufacturers 

• 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, leading to quicker acceptance by other national 

regulatory agencies. 

• There is no fee. 

13 



Benefits 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, which may be used in regulatory submissions. 

• Reduced API assessment requirements (PQP) 

• There is no fee. 

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How are APIs Prequalified 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

15 



3 rd 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 3 rd 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, reproductive health neglected tropical 

diseases. 

• See website for the invitation: 

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

16 



3 rd Invitation for EOI 

Therapeutic area 

HIV 

Anti-malarial 

Anti-tuberculosis 

Invited Active Pharmaceutical Ingredient 

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

Lamivudine, Lopinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, 

Zidovudine 

Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, 

Mefloquine, Piperaquine, Pyrimethamine, Sulfadoxine, Pyronaridine 

Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, 

Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-Aminosalicylic Acid (PAS), 

Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone 

Reproductive 

health 

Neglected Tropical 

Diseases 

Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, 

Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, 

Oxytocin 

Diethylcarbamazine, Mebendazole 

17 



Application 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

18 



Application 

• 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. 

19 



Application 

An application should consist of: 

• 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). 

20 



Assessment – Quality (APIMF) 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

21 



APIMF submission 

There are four options when submitting an APIMF in support 

of PQ. 

Option 1 

New APIMF (PQP only) 

•A new APIMF, with a unique version number is submitted as 

part of the application. 

22 




Option 2 

The APIMF is intended for API PQ use only. 

The technical content of the submitted APIMF is the same as the 

APIMF submitted for the APIMF procedure and subsequent 

amendments. 

•A new APIMF is submitted using a version number differing from 

that used in APIMF procedure. 

•Information in the two APIMFs may diverge over time. 

23 




Option 3 

The APIMF is intended for both API PQ and APIMF procedure. 

The technical content of the submitted APIMF is the same as the 

APIMF submitted for the APIMF procedure and subsequent 

amendments. 

•A new APIMF is submitted using a version number differing from that 

used in APIMF procedure. 

•The same APIMF will be used in both procedures. It replaces the 

existing APIMF used in the APIMF procedure. 

24 




Option 4 

No APIMF is provided. 

•An existing APIMF already held for the APIMF procedure is 

referred to. 

•The existing APIMF will be used for API PQ and APIMF procedure 

•The existing APIMF must met all current requirements. 

25 



APIMF - 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/Generi 

cGuideline_Quality.pdf 

26 



The submitted APIMF should: 

•be prepared in CTD format. 

APIMF Presentation 

•be separated into open (applicant) and closed (restricted) sections. 

•be paginated throughout the entire document. Restarting page numbers 

for each subsection section is not permitted. 

•include a contents page with page number references to each of the 

CTD subsections. 

•be assigned a manufacturer's version number that should be present in 

the footer or header of each page of the APIMF. 

27 



APIMF Presentation 

The submitted electronic APIMF should: 

•have separate files for the open and closed sections. 

•single files should not exceed 30 MB in size. 

•be provided in text-selectable PDF format. 

•have document bookmarks for each of the CTD subsections. In 

additional the use of hyperlinks within the body of the text is 

encouraged. 

•Scanned copies of supporting documents such as Certificates of 

Analysis, authorized specifications, signed protocols, etc are 

permitted. 

28 



Assessment - GMP 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

29 



Assessment – GMP 

There are two ways to demonstrate GMP compliance at the API 

manufacturing facility. 

• 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. 

30 



Assessment – GMP 

Assessment of GMP compliance at the site of API manufacture takes 

into account: 

• 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. 

The WHO will perform an inspection if, after assessment and requests 

for information, GMP compliance can not be established. 

31 



Assessment of GMP 

An SRA is a medicines regulatory authority in a country that is: 

• a member of the ICH: Japan, USA, EU member; or 

• an ICH Observer, e.g. Swissmedic, Health Canada; or 

• associated with an ICH member through a legally binding mutual 

recognition agreement, e.g. Australia, Iceland, Liechtenstein, 

Norway…etc. 

32 



WHO GMP Certificates 

There is no such thing. The WHO does not issue GMP Certificates. 

• There are many certificates circulating that appear to be issued by the 

WHO, but they are not. 

• Certificates might be issued in the WHO format, or the inspection may 

have occurred against WHO criteria, but this is not a WHO inspection. 

• Successful inspections conducted by the WHO are published in 

WHOPIR that can be found at this link: 

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

33 

Prequalification Prequalification of APIs 

of APIs 

1 October 2011, Mumbai Malaysia 

September 2012

Decision 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

34 



Decision 

• Once the APIMF is accepted the applicant will receive an Letter of 

APIMF acceptance. This is not prequalification. 

• Typically a final conclusion over GMP status may still be required, if 

this has not been achieved already. 

• Once both the APIMF and GMP status is accepted the application 

is considered for sign-off. 

• The applicant will be contacted by WHO to confirm final details for 

publishing. Expressions of storage statement may differ to meet 

WHO requirements. 

35 



Publishing 

Invitation 

Application 

Assessment 

(GMP) 

Assessment 

(Quality) 

Decision 

Publishing 

36 



Publishing 

List of PQ APIs 

Website (Public) 

+ WHOPIRs 

Website (Public) 

Confirmation Document (Private) 

37 



Publishing 

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 

38 



WHO List of Prequalified APIs 

Publically available 

• 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 

39 



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. 

• The assigned re-test period. 

• The recommended storage conditions. 

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

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

40 



API-PQ Procedure 

+ 

API 

Manufacturer 

FPP 

Manufacturer 



Confirmation of API PQ document (CPQ) 

It is intended that the CPQ is circulated to relevant parties, such as 

FPP manufacturers. 

Wider recognition of API-PQ is a long term goal. 

Manufacturers of a PQ’d API currently participating in the APIMF 

procedure should circulate the CPQ to associated FPP 

manufacturer’s. 

Normally the FPP manufacturer will then submit the CPQ and 

withdraw from the APIMF procedure. 

FPP manufacturers need to actively request this change. 

This will have post-Prequalification benefits in terms of the number of 

variations they will need to file. 

42 



API Prequalification Performance 

1 April 2011 

1 November 2011 

1 Sept 2012 

Total number of 

applications 

8 

29 

62 

Number of PQ APIs 

2 

5 

18 

• There is positive feedback from FPP manufacturers whenever PQ of 

APIs is discussed. 

• Applications and the number of prequalified APIs continues to 

increase. 

43 



API Prequalification Performance 

APIs have been prequalified for HIV (2), Malaria (15), and TB (4). 

8 manufacturers have successfully PQ’d one or more APIs: 

•Anuh Pharma Ltd (1) 

•Calyx Chemicals & Pharmaceuticals Ltd (4) 

•Ipca Laboratories Ltd (3) 

•Laurus Labs Pvt Ltd (2) 

•Lupin Ltd (1) 

•Mangalam Drugs & Organics Ltd (7) 

•Mylan Laboratories Ltd (1) 

•Sequent Scientific Ltd (2) 

44 



Changes to API Details 

Changes to API details must be announced to the PQP. 

There are two phases to this process 

1.The APIMF holder submits an amendment to PQP for the change. 

2.Prequalified FPP manufacturers submits a variation to PQP for the change. 

This is placing an increasing burden on both PQP and manufacturers. 

This is true for API manufacturers using the APIMF procedure 

or a Prequalified API 

45 




The proposed PQP guidance on the submission of variations in 

support of Prequalified FPP was circulated this year for comment 

and is in the final stages of drafting. 

This guidance refers in many cases to the submission and 

acceptance of APIMF amendments. 

It also introduces the use of CPQ documentation 

46 




The Variation Guidance being finalised proposes that: 

FPP manufacturers using a Prequalified API will only submit a 

variation if a new Confirmation of API PQ document is issued. 

“…Similarly, when an FPP relies upon a CEP or a Prequalified API, FPP 

applicants are required to notify WHO PQP only when the associated CEP or 

Confirmation of API Prequalification document has been revised…” 

This is a distinct advantage for FPP manufacturers. 

47 



48 



Current focus: 

Improving the API PQ process 

•The introduction of the FPP Variation and APIMF Amendment 

guidance. 

•Introduction of mandatory documentation requirements. 

•Reduction of assessment backlogs 

Next: 

Discontinuation of paper submissions. 

Wider recognition and use of CPQs in national authorities. 

However! Feedback on how the assessment process can be 

improved and API PQ value enhanced are welcome at any time. 

49 



Further information 

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

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

AND, ALSO 

Please email me (or visit) if you have any questions. 

Fakea@who.int 

One email could save you a lot of time. 

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