J nos pog ny pharmacist phd consultant to who shanghai 01 march 2005 e mail pogany@axelero hu
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János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: [email protected] Workshop on Quality Assurance and GMP of Multisource HIV /AIDS medicines. Experience with prequalification of HIV /AIDS products: product dossier assessment. ABBREVIATIONS and NOTES.

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J nos pog ny pharmacist phd consultant to who shanghai 01 march 2005 e mail pogany@axelero hu

János Pogány, pharmacist, PhD,

consultant to WHO

Shanghai, 01 March 2005

E-mail: [email protected]

Workshop on Quality Assurance and GMP of Multisource HIV/AIDSmedicines

Experience with prequalification of HIV/AIDS products: product dossier assessment

Dr. Pogány - WHO, Shanghai


Abbreviations and notes

ABBREVIATIONS and NOTES

API(s)Active pharmaceutical ingredient(s)

ARVAntiretroviral

EOIExpression of interest

FPP(s)Finished pharmaceutical product(s)

ICHInternational Conference on Harmonization

MLEMModel List of Essential Medicines

NDRANational Drug Regulatory Authority

Ph.Eur.European Pharmacopoeia

IPInternational Pharmacopoeia

USPUnited States Pharmacopeia

Text in green refers to WHO guidelines or requirements

Text in yellow indicates an assessment issue

Dr. Pogány - WHO, Shanghai


Subjects for discussion

SUBJECTS FOR DISCUSSION

  • Interchangeability of FPPs

  • Classification of ARV FPPs

  • Deficiencies observed in the evaluation of dossiers

    • Regulatory issues

    • Correspondence with FPP manufacturers

  • Conclusions

Dr. Pogány - WHO, Shanghai


Interchangeability of fpps

INTERCHANGEABILITYOF FPPs

Pharmaceutical equivalence


Interchangeability ic

INTERCHANGEABILITY (IC)

INTERCHANGEABILITY (IC) OF MULTISOURCE FPPs = (ESSENTIAL SIMILARITY WITH INNOVATOR FPP) =

PHARMACEUTICAL EQUIVALENCE (PE) + BIOEQUIVALENCE (BE)

IC = PE+ BE

Dr. Pogány - WHO, Shanghai


Pharmaceutical equivalence

PHARMACEUTICAL EQUIVALENCE

  • FPPs MEET SAME ORCOMPARABLESTANDARDS (pharmacopoeia, marketing authorization)

    • SAME API (chemical and physical equivalence)

    • SAME DOSAGE FORM AND ROUTE OF ADMINISTRATION

    • SAMESTRENGTH

    • COMPARABLE LABELING

  • WHO-GMP(batch-to-batch uniformity of quality)

  • STABILITY EQUIVALENCE

Dr. Pogány - WHO, Shanghai


Workshop on quality assurance and gmp of multisource hiv

FACTORS INFLUENCING PE

INACTIVE INGREDIENTS

ACTIVE INGREDIENTS

PACKING MATERIALS

GMP standards

Manufacturing

authorization

FPP MANUFACTURER

Marketing

authorization

Pharmacopeiastandards

NATIONAL DRA1

NATIONAL DRA2

Dr. Pogány - WHO, Shanghai


Classification of arv fpps

Classification of ARV FPPs

13th MODEL LIST OF ESSENTIAL MEDICINESandEXPRESSION OF INTEREST(January 2004)


Blue book definitions

BLUE BOOK DEFINITIONS

MULTISOURCE1 (generic) pharmaceutical products are pharmaceutically equivalent products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.

1 Many manufacturers by definition.

Dr. Pogány - WHO, Shanghai


Blue book definitions1

BLUE BOOK DEFINITIONS

WELL-ESTABLISHED drug products

  • have been marketed for at least five years in countries that undertake active post­marketing monitoring;

  • have been widely used to permit the assumption that safety and efficacy are well known; and

  • have the same route of administration and strength, and the same or similar indications as in those countries where the innovator FPP was approved.

Dr. Pogány - WHO, Shanghai


Well established criterion

WELL-ESTABLISHED CRITERION

  • Zidovudine (Retrovir™, 19 March 1987*)

  • Didanosine (Videx™, 9 October 1991*)

  • Stavudine(Zerit™, 24 June 1994*)

  • Lamivudine (Epivir™, 17 November 1995*)

  • Saquinavir (Invirase™, 6 December 1995*)

  • Indinavir (Crixivan™, 13 March 1996*)

  • Nevirapine (Viramune™, 21 June 1996*)

  • Ritonavir (Norvir™, 1 March 1996*)

    *Approval date of the first pharmaceutical dosage form for sales in the USA

Dr. Pogány - WHO, Shanghai


Well established criterion1

WELL-ESTABLISHED CRITERION

  • Nelfinavir(Viracept™, 14 March 1997*)

  • Abacavir (Ziagen™, 17 December 1998 *)

  • Efavirenz (Sustiva™, 17 September 1998 *)

  • Lopinavir + Ritonavir (Kaletra™, 15 September 2000*)

  • Tenofovir(new class, Viread™, 26 October 2001*)

    *Approval date of the first pharmaceutical dosage form for sales in the USA

Dr. Pogány - WHO, Shanghai


Fixed dose combinations eoi 1

FIXED-DOSE COMBINATIONS (EOI)1

  • LAMIVUDINE + STAVUDINE

  • LAMIVUDINE + ZIDOVUDINE

  • LAMIVUDINE + STAVUDINE + EFAVIRENZ

  • LAMIVUDINE + STAVUDINE + NEVIRAPINE

  • LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ

  • LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE

    1 There is no innovator for the above FDCs.

    Well-established criterion refers to co-administration.

Dr. Pogány - WHO, Shanghai


Classification matrix

CLASSIFICATION MATRIX

Dr. Pogány - WHO, Shanghai


Arv apis and fpps

ARV APIs and FPPs

  • are typically available from more than one manufacturerbut not always from many suppliers;

  • except (Lopinavir + Ritonavir) and Tenofovir, others are well-establishedby WHO criteria;

  • FPPs containan API not yet official in an internationally recognized pharmacopoeia.

Dr. Pogány - WHO, Shanghai


Low risk apis

LOW-RISK APIs

  • CERTIFICATE OF SUITABILITY (DRA)

  • DRUG MASTER FILE

    • OPEN PART (APPLICANT)

    • CLOSED PART(DRA)

  • PHARMACOPEIA MONOGRAPH

    • LITERATURE EVIDENCE OF STABILITY

    • SYNTHESIS IMPURITIES ARE CONTROLLED BY MONOGRAPH (toxicology of additional impurities)

    • CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS CONTROLLED

  • FPP IS REGISTERED IN THE ICH REGION

Dr. Pogány - WHO, Shanghai


High risk apis and fpps

HIGH-RISK APIs and FPPs

  • Reference standard/comparator is not available for:

    • Pharmaceutical equivalence studies

    • Bioequivalence studies

  • APIsand FPPsarenot official inthe internationally used major pharmacopoeias

  • WHO guides/SOPsapply to multisource FPPs. ICH guidesshould be used for evaluation.

  • Require particular attention by NDRA as regards assessment of applications for marketing authorization.

Dr. Pogány - WHO, Shanghai


High risk arv apis

HIGH-RISK ARV APIs

  • Abacavir

  • Efavirenz

  • Indinavir

  • Lopinavir

  • Nelfinavir

  • Ritonavir

  • Stavudine

  • Tenofovir

Dr. Pogány - WHO, Shanghai


High risk arv fpps

HIGH-RISK ARV FPPs

  • ABACAVIRtablets 300mg, oral solution 20 mg/ml

  • TENOFOVIR tablets 300mg

  • LAMIVUDINE +STAVUDINE

  • LAMIVUDINE + ZIDOVUDINE

  • LAMIVUDINE + STAVUDINE + EFAVIRENZ

  • LAMIVUDINE + STAVUDINE + NEVIRAPINE

  • LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ

  • LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE

Dr. Pogány - WHO, Shanghai


Deficiencies observed in the evaluation of dossiers

Deficiencies observed in the evaluation of dossiers

REGULATORY ISSUES


Global issues

GLOBAL ISSUES

API or FPP originate „LEGALLY” from countries where:

  • Manufacture of APIsisnot regulated

  • Pharmaceutical exports and importsare not regulated

  • Marketing Authorizations [MA(s)] of FPPs areissued without evaluation by the national drug regulatory authority (NDRA) for locally developed andmanufacturedFPPs

  • Nevertheless, WHO-type certificates are issued

Dr. Pogány - WHO, Shanghai


Global issues1

GLOBAL ISSUES

  • Pharmaceutical R + D studiesarenotyetrequiredfor MA

  • Stability studieswere not requiredfor MA

  • Validation studies arenotyetrequired for MA

  • Bioequivalence studies arenotyetrequiredfor MA

  • NationalGood Manufacturing Practices are not commensurate WHO-GMP requirements

Dr. Pogány - WHO, Shanghai


Deficiencies observed in the evaluation of dossiers1

Deficiencies observed in the evaluation of dossiers

ILLUSTRATIVE EXAMPLES FROM CORRESPONDENCE WITH MANUFACTURERS


Critical api deficiencies

CRITICAL API DEFICIENCIES

  • Synthesis impurities, including residual solvents, which may be present in API, were not characterised and analysed.

  • Residual solventswere included in the DMF but not in the API specification (skip testing).

  • Class2 solvents: pyridine and chloroform were used in the synthesis and not tested in the API.

  • “Further efforts are made to improve the process.”

Dr. Pogány - WHO, Shanghai


Critical api deficiencies1

CRITICAL API DEFICIENCIES

  • Individual impurity limits were not based on batch analysis results and they were not in line with the ICH guidelines (e.g., NMT 1.0% instead of NMT 0.1%).

  • The preparation and quality specification of primary (absolute) and secondary (working) standardswere not described. Analytical validation information-including experimental data for the analytical procedures used for testing the API and impurities-were not provided.

Dr. Pogány - WHO, Shanghai


Critical api deficiencies2

CRITICAL API DEFICIENCIES

  • Forced degradation studies were not done:

    • to document the intrinsic stability of the molecule (sensitivity of the API to potential effects of the external environment – selection of containers)

    • to identify the likely degradants

      • for demonstration of the stability-indicating power of assay method

      • for the stability studies of the FPP

  • Available stability data revealed possible degradation and justified only a one (1) year re-test date.

Dr. Pogány - WHO, Shanghai


Critical fpp deficiencies

CRITICAL FPP DEFICIENCIES

  • Pharmaceutical R + D data were only exceptionallysubmitted. When provided, they did not capture the failures.

  • A dissolutionmethod wasnot integrated inthe quality control and stability programs.

  • A tabulated summary of the compositions of the pivotal (clinical, bioequivalence and validation) FPP batches and presentation of the relevant dissolution profileswere not provided. Batch size!!!

Dr. Pogány - WHO, Shanghai


Critical fpp deficiencies1

CRITICAL FPP DEFICIENCIES

  • Documented evidencewasnot providedthat packaging materialshad been selected to ensure the quality of the FPP throughout its shelf life.

  • Validation reportswerenot providedon pilot batches and the first three production scale baches.

  • Annual quality reviewdata and analysiswerenot submitted.

Dr. Pogány - WHO, Shanghai


Specification deficiencies

SPECIFICATION DEFICIENCIES

  • The maximum acceptable deviation in the API content of the FPP was frequently reported as±10% of the label claim at batch release.

  • Degradation productswere not reported and justificatication was not offered for their absence.

  • Analytical methods were frequently not validated,or not properly validated, or not verified.

  • Microbiological purity was not tested (skip testing)

Dr. Pogány - WHO, Shanghai


Stability deficiencies

STABILITY DEFICIENCIES

  • A systematic approach was not adopted in the presentation and evaluation of the stability information, which did not include results from the physical, chemical, biological and microbiological tests, and excluded particular attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms, hardness of tablets, LOD, etc.).

  • Data for all attributes were not organizedseparately and each attribute was not evaluated in the report.

  • Shelf life acceptance criteria were not derived from consideration of all available stability information.

Dr. Pogány - WHO, Shanghai


Health information deficiencies

HEALTH INFORMATION DEFICIENCIES

  • A Summary of Product Characteristics (SmPC) –aimed at medical practitioners and other health professionals and approved by the competent authority at the time of licensing–was not submitted, a major deficiency when an innovator product does not exist, e.g., generic ARV FDCs.

  • The package insertsdistributed to the patientswere not in conformity with the SmPC and the stability results (e.g., storage conditions).

Dr. Pogány - WHO, Shanghai


Main points again

Main points again

  • When a multisource FPP does not meet requirements for pharmaceutical equivalence, then it is not interchangeable with the innovator FPP.

  • Many ARV APIsarenotyet officialin internationally used major pharmacopoeias and specificationshave to be developed in house, including reference standards, validated analytical methods for assay and impurity tests.

  • For FDC FPPs without innovator product, pharmaceutical R + D rather than pharmaceutical equivalence should be demonstrated.

Dr. Pogány - WHO, Shanghai


Main points again1

Main points again

  • Regulatory requirements ofNDRAsarenot commensurate with those of theinternational standards of WHO.

  • ARV FPPshad been on the market for years but most of them did not meet basic standards of qualityat the beginning of the project.

  • Lack ofSmPC for health professionals and leaflets for patients information are critical deficiencies in case of FPPs without innovator product.

Dr. Pogány - WHO, Shanghai


Conclusions

CONCLUSIONS

  • It takes time to get into compliance

    • Develop new formulations

    • Data to be generated, tests carried out

    • GMP upgrade needed

  • Success with antiretroviral FPPs justifies joint efforts of manufacturers and WHO

  • Dr. Pogány - WHO, Shanghai


    Thank you

    THANK YOU

    谢谢!

    Dr. Pogány - WHO, Shanghai


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