Download Guidelines on Assessment of Applications for Prequalification

WHO Training Workshop on Pharmaceutical
Quality, GMP and Bioequivalence
Expression of Interest and
Guidelines on Assessment of
Applications for Prequalification
János Pogány, pharmacist, PhD
consultant to WHO
Tanzania, 21 August 2006
E-mail: [email protected]
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Abbreviations
API
DRA
EoI
FDC
FPP
GMP
ICH
MA
PQ
TRS
Active Pharmaceutical Ingredient
Drug Regulatory Authority
Expression of Interest
Fixed-Dose Combination
Finished Pharmaceutical Product
Good Manufacturing Practices
International Conference on Harmonization
Marketing Authorization
Prequalification
Technical Report Series
Yellow → emphasis
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Green → WHO
Pogány - Tanzania
Blue → ICH region
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Objectives of the workshop
WHO Prequalification Program is motivated:
 to involve countries that want to benefit
from the (currently free-of-charge) PQ
Program, and
 to provide more information to African
regulators about the ongoing activities and
discuss how countries could cooperate in
the area of dossier assessment and GMP
inspection.
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Subjects for discussion
1.
2.
3.
4.
5.
6.
Interchangeability of multisource (generic)
FPPs
EoI for Antimalarial Drugs
Global quality issues
Prequalification Experience – Illustrative
deficiencies
Pharmaceutical Quality Information Form
Main points again
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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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CRITICAL VARIABLES OF FPP QUALITY
INACTIVE
INGREDIENTS
Manufacturin
g
authorization
ACTIVE
INGREDIENTS
GMP
standards
FPP Manufacturing
process
Marketing
authorization
Pharmacopeia
standards
NATIONAL
DRA1
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PACKING
MATERIALS
NATIONAL
DRA2
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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
Dissolution profile equivalence, when applicable
Comparable labeling
 WHO-GMP (batch-to-batch uniformity of
quality)
 Stability equivalence
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High quality-risk APIs
 FPP is not registered in the ICH region and associated
countries
 API is not official in the internationally used major
pharmacopoeias and ICH guidelines should be used
for evaluation
 Reference standard/comparator is not available for:


Pharmaceutical equivalence studies
Bioequivalence studies
 Require particular attention by NDRA as regards
assessment of applications for marketing
authorization
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Low quality-risk APIs
Certificate of suitability (CEP) is submitted (DRA)
2. Drug Master File
1.


3.
Pharmacopeia monograph is available



4.
Open part (APPLICANT)
Closed part (DRA)
Literature evidence of stability
Synthesis impurities and degradants are controlled by
monograph
Class1 solvents excluded; class2 / class 3 solvents controlled
FPP is registered in the ICH region (DRA)
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EXPRESSION of INTEREST
(4th edition, May 2005)
Artemisinin-based
Antimalarial FPPs
EoI – Oral Preparations
 Artesunate* + Amodiaquine
 Artemether* + Lumefantrine*
 Artesunate* + Mefloquine
 Artesunate* + SP (sulphadoxine / pyrimethamine)
* Assessed originally by ICH guidelines * High quality-risk API
+ ... FDC or co-blistered (co-packaged) FPPs
All oral FPPs include paediatric formulations.
(EOI is included in the Notes Page of this and the subsequent slides)
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EoI – Other dosage forms
 Artemether Injection and rectal FPPs
 Artemotil (arteether) Injection
 Artesunate Injection and rectal FPPs
Only FPPs listed in the EOI are assessed.
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History and Current Status
 First EOI published on 8 May 2002
 Assessment of dossiers started in July
2002
 FPPs [51 applications (2 cancelled) - five
(three FPPs) approvals as at 1 July 2006].
Antimalarial FPPs –manufactured in
Africa – have not yet been prequalified.
 Problems delaying prequalification are
discussed in forthcoming slides
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GLOBAL
QUALITY ISSUES
ANTIMALARIAL FPPs
Global regulatory issues
 If the product has been locally developed and
manufactured, the national DRA must evaluate
the data set itself (p. 23)1.
 If an evaluation report —critical summary and
interpretation of the data, with conclusions—
is not available it is not possible to seek a
WHO-type certificate (p. 23)1.
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Global regulatory issues
API or FPP originate „legally” from countries where:



Manufacture of APIs is not regulated
Pharmaceutical exports and imports are
not regulated
MA of FPPs is issued without evaluation
or with a check-list assessment by the
national NDRA
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Global regulatory issues




Formal stability studies are not required for
MA
Biostudies are not required for MA
National Good Manufacturing Practices
(GMP) do not comply with WHO-GMP
requirements
API was not official in internationally used
major pharmacopoeias (artemisinines and
ARVs)
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Artemisin-derivative issues
 No innovator FPP is registered in the ICH region. No
comparator was available for:


Pharmaceutical equivalence studies
Bioequivalence studies
 The APIs and FPPs were not official in the
internationally used major pharmacopoeias
 WHO guides/SOPs apply to multisource FPPs. ICH
guides had to be used.
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PREQUALIFICATION
EXPERIENCE
ILLUSTRATIVE EXAMPLES
OF DEFICIENCIES
Chemical synthesis
 Detailed information on the synthesis of non-
compendial APIs —or a flow chart and textbooklevel narrative on official APIs— was not provided.
 The final purification, crystallization and subsequent
operations were not described in details.
 Existence/absence of polymorphs, hydrates/solvates,
solubility in water and organic solvents at 25oC, pKa,
hygroscopicity data were not submitted.
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Stability testing
 Stress stability (forced degradation) testing
was limited to analytical method validation
studies and were conducted under harsh
conditions to produce degradants that may
not be observed under the accelerated stress
studies .
 “Room temperature and accelerated stability
tests are in progress.”
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Specifications of API
 The melting point is 143-145oC (p.4) as
opposed to 131-134oC ± 1.5oC in the DMF.
 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%).
 Residual solvents were included in the in-house
monograph but not in the DMF.
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Specifications of API
 No adequate information was provided on the
preparation and quality specification of primary
(absolute) and secondary (working) standards.
(For instance, lack of complete CoA, assay by
two different validated methods, detailed
information on storage, etc.).
 HPLC method is described as an alternative
assay to titration but acceptance limits are 97103% as opposed to 98-102% in the DMF.
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Development pharmaceutics
 A report was not submitted to identify and
describe the formulation and process attributes
that can influence batch reproducibility, product
performance and FPP quality, including stability.
 A tabulated summary of the compositions of the
FPP used in clinical trials or stability studies and
a presentation of dissolution profiles was not
provided.. Dissolution time was not studied at all.
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Stability of FPP and SmPC
 Degradants, dissolution rate and profile,
water content, hardness, microbiological
attributes, etc. were not tested or
quantified.
 A national DRA-approved Summary of
Product Characteristics (SmPC) type
information for health professionals was
not submitted.
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Correspondence with manufacturers
 The stress data show that the blister pack
does not protect the tablets even if
overwrapped by additional protective
packing. Supplier reduced expiry date.
 Analysis of the tests for microbiological
purity on „two (2) batches showed
contamination with an invading yeast.”
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PREQUALIFICATION
QUALITY
REQUIREMENTS
STANDARDS, GUIDELINES
and TEMPLATES
International Pharmacopoeia







Artemether
Artemisinin
Artemotil
Artenimol
Artesunate
Mefloquine Hydrochloride
Proguanil Hydrochloride BP
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International quality standards





Amodiaquine USP
Amodiaquine Hydrochloride USP
Lumefantrine
Pyrimethamine BP, PhEur, PhInt, USP
Sulphadoxine BP, PhEur, PhInt, USP
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Prequalification quality guidelines
1.
Guide on Submission of Documentation for
Prequalification of innovator Finished
Pharmaceutical Products (FPPs) used in the treatment
of HIV/AIDS, malaria and tuberculosis and approved
by Drug Regulatory Authorities (DRAs) in the
International Conference on Harmonization (ICH)
region and associated countries, including among
others the EU, Japan and USA
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Prequalification quality guidelines
2. Guideline on Submission of Documentation
for Prequalification of Multi-source
(Generic) Finished Pharmaceutical Products
(FPPs) Used in the Treatment of
HIV/AIDS, Malaria and Tuberculosis,
together with eight (8) annexes.
3. Guidance on Variations to a Prequalified
Dossier
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Prequalification quality guidelines
4. Supplement 1 [for use from July 2005
(CPH25)] - Dissolution testing
5. Supplement 2 – Revision 1[for use from
May 2006 (CPH31)] - Extension of the
WHO List of Stable (not easily
degradable ARV) APIs1
1World
Health Organization, WHO Technical Report Series, No. 863,
1996. Annex 5 Guidelines for stability testing of pharmaceutical products
containing well-established drug substances in conventional dosage forms.
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Annex 8 to the Generic Guideline
Pharmaceutical Quality Information Form
The PQIF contains summary information provided
by the applicant on critical pharmaceutical quality
attributes –chemistry, pharmaceutical formulation,
manufacturing process and product performance–
and their relevance to safety and efficacy, following
the structure of the Generic Guideline and
frequently in tabulated forms.
Focus on analytical and stability issues,
development pharmaceutics and specifications.
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Main points again
1.
2.
3.
WHO provides information to African regulators
and pharmaceutical manufacturers about the
ongoing activities of the PQ program and discuss
how countries could further benefit from
cooperation in the area of dossier assessment and
GMP inspection.
The EoI limits the number of FPPs.
Many DRAs did not assess generic FPPs –used in
the treatment of HIV/AIDS, malaria and
tuberculosis– and most manufacurers did not have
dossiers for MA, at the beginning of PQ.
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Main points again
4.
5.
Artemisinin-derived APIs and FPPs were marketed at
global level for decades without meeting basic
standards of quality.
It takes time to get into prequalification compliance



6.
Develop new formulation
Data to be generated, tests carried out
GMP upgrade needed
Increase in the number of prequalified Artesunate
Tablets is expected because there has been an official
comparator since 2005.
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PLEASE MAKE USE OF
THE OPPORTUNITY
TO PARTICIPATE IN THE
PREQUALIFICATION
PROJECT
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