Transcript Experience with prequalification of HIV/AIDS products

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: [email protected]
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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
1. Interchangeability of FPPs
2. Classification of ARV FPPs
3. Deficiencies observed in the evaluation of
dossiers


Regulatory issues
Correspondence with FPP manufacturers
4. Conclusions
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INTERCHANGEABILITY
OF FPPs
Pharmaceutical
equivalence
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
Manufacturin
g
authorization
ACTIVE
INGREDIENTS
GMP
standards
FPP
MANUFACTURER
Marketing
authorization
Pharmacopei
astandards
NATIONAL
DRA1
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PACKING
MATERIALS
NATIONAL
DRA2
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Classification of ARV FPPs
13th MODEL LIST OF
ESSENTIAL MEDICINES and
EXPRESSION OF INTEREST
(January 2004)
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
Innovator’s 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
1.
CERTIFICATE OF SUITABILITY (DRA)
2.
DRUG MASTER FILE


3.
PHARMACOPEIA MONOGRAPH



4.
OPEN PART (APPLICANT)
CLOSED PART (DRA)
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
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
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 impuritieswere 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.
2.
3.
When a multisource FPP does not meet
requirements for pharmaceutical equivalence, then
it is not interchangeable with the innovator FPP.
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.
For FDC FPPs without innovator product,
pharmaceutical R + D rather than pharmaceutical
equivalence should be demonstrated.
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Main points again
4.
5.
6.
Regulatory requirements of NDRAs are not
commensurate with those of the international
standards of WHO.
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.
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
7.
8.
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
谢谢!
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