Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines

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Workshop on Quality Assurance and GMP of
Multisource HIV/AIDS medicines
Experience with prequalification of HIV/AIDS
products product dossier assessment

• János Pogány, pharmacist, PhD,
• consultant to WHO
• Shanghai, 01 March 2005
• E-mail pogany_at_axelero.hu

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ABBREVIATIONS and NOTES

• API(s) Active pharmaceutical ingredient(s)
• ARV Antiretroviral
• EOI Expression of interest
• FPP(s) Finished pharmaceutical product(s)
• ICH International Conference on Harmonization
• MLEM Model List of Essential Medicines
• NDRA National Drug Regulatory Authority
• Ph.Eur. European Pharmacopoeia
• IP International Pharmacopoeia
• USP United States Pharmacopeia
• Text in green refers to WHO guidelines or
  requirements
• Text in yellow indicates an assessment issue

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SUBJECTS FOR DISCUSSION

• Interchangeability of FPPs
• Classification of ARV FPPs
• Deficiencies observed in the evaluation of
  dossiers
• Regulatory issues
• Correspondence with FPP manufacturers
• Conclusions

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INTERCHANGEABILITYOF FPPs

• Pharmaceutical equivalence

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INTERCHANGEABILITY (IC)

• INTERCHANGEABILITY (IC) OF MULTISOURCE FPPs
  (ESSENTIAL SIMILARITY WITH INNOVATOR FPP)
• PHARMACEUTICAL EQUIVALENCE (PE) BIOEQUIVALENCE
  (BE)
• IC PE BE

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PHARMACEUTICAL EQUIVALENCE

• FPPs MEET SAME OR COMPARABLE STANDARDS
  (pharmacopoeia, marketing authorization)
• SAME API (chemical and physical equivalence)
• SAME DOSAGE FORM AND ROUTE OF ADMINISTRATION
• SAME STRENGTH
• COMPARABLE LABELING
• WHO-GMP (batch-to-batch uniformity of quality)
• STABILITY EQUIVALENCE

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FACTORS INFLUENCING PE
INACTIVE INGREDIENTS
ACTIVE INGREDIENTS
PACKING MATERIALS
GMP standards
Manufacturing authorization
FPP MANUFACTURER
Marketing authorization
Pharmacopeiastandards
NATIONAL DRA1
NATIONAL DRA2
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Classification of ARV FPPs

• 13th MODEL LIST OF ESSENTIAL MEDICINES and
  EXPRESSION OF INTEREST (January 2004)

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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.

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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.

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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

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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

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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.

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CLASSIFICATION MATRIX
Market availability of FPP Therapeutic experience Quality standard
Monopoly   Limited to well established Innovators specification
Oligopoly   Less than five years In-house generic specification
Oligopoly, innovator exists Well established In-house generic specification
Oligopoly, innovator does not exist Well established In-house generic specification
Multisource Well established Official compendia
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ARV APIs and FPPs

• are typically available from more than one
  manufacturer but not always from many suppliers
• except (Lopinavir Ritonavir) and Tenofovir,
  others are well-established by WHO criteria
• FPPs contain an API not yet official in an
  internationally recognized pharmacopoeia.

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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

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HIGH-RISK APIs and FPPs

• Reference standard/comparator is not available
  for
• Pharmaceutical equivalence studies
• Bioequivalence studies
• APIs and FPPs are not official in the
  internationally used major pharmacopoeias
• WHO guides/SOPs apply to multisource FPPs. ICH
  guides should be used for evaluation.
• Require particular attention by NDRA as regards
  assessment of applications for marketing
  authorization.

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HIGH-RISK ARV APIs

• Abacavir
• Efavirenz
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Stavudine
• Tenofovir

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HIGH-RISK ARV FPPs

• ABACAVIR tablets 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

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Deficiencies observed in the evaluation of
dossiers

• REGULATORY ISSUES

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GLOBAL ISSUES

• API or FPP originate LEGALLY from countries
  where
• Manufacture of APIs is not regulated
• Pharmaceutical exports and imports are not
  regulated
• Marketing Authorizations MA(s) of FPPs are
  issued without evaluation by the national drug
  regulatory authority (NDRA) for locally developed
  and manufactured FPPs
• Nevertheless, WHO-type certificates are issued

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GLOBAL ISSUES

• Pharmaceutical R D studies are not yet required
  for MA
• Stability studies were not required for MA
• Validation studies are not yet required for MA
• Bioequivalence studies are not yet required for
  MA
• National Good Manufacturing Practices are not
  commensurate WHO-GMP requirements

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Deficiencies observed in the evaluation of
dossiers

• ILLUSTRATIVE EXAMPLES FROM CORRESPONDENCE WITH
  MANUFACTURERS

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CRITICAL API DEFICIENCIES

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

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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)
  standards were not described. Analytical
  validation information -including experimental
  data for the analytical procedures used for
  testing the API and impurities- were not provided.

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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.

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CRITICAL FPP DEFICIENCIES

• Pharmaceutical R D data were only exceptionally
  submitted. When provided, they did not capture
  the failures.
• A dissolution method was not integrated in the
  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 profiles were not provided. Batch
  size!!!

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CRITICAL FPP DEFICIENCIES

• Documented evidence was not provided that
  packaging materials had been selected to ensure
  the quality of the FPP throughout its shelf life.
  
• Validation reports were not provided on pilot
  batches and the first three production scale
  baches.
• Annual quality review data and analysis were not
  submitted.

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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 products were 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)

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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 organized
  separately and each attribute was not evaluated
  in the report.
• Shelf life acceptance criteria were not derived
  from consideration of all available stability
  information.

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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 inserts distributed to the patients
  were not in conformity with the SmPC and the
  stability results (e.g., storage conditions).

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Main points again

1. When a multisource FPP does not meet requirements
   for pharmaceutical equivalence, then it is not
   interchangeable with the innovator FPP.
2. Many ARV APIs are not yet official in
   internationally used major pharmacopoeias and
   specifications have to be developed in house,
   including reference standards, validated
   analytical methods for assay and impurity tests.
3. For FDC FPPs without innovator product,
   pharmaceutical R D rather than pharmaceutical
   equivalence should be demonstrated.

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Main points again

1. Regulatory requirements of NDRAs are not
   commensurate with those of the international
   standards of WHO.
2. ARV FPPs had been on the market for years but
   most of them did not meet basic standards of
   quality at the beginning of the project.
3. Lack of SmPC for health professionals and
   leaflets for patients information are critical
   deficiencies in case of FPPs without innovator
   product.

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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

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THANK YOU
??!