who training workshop on pharmaceutical quality, gmp and bioequivalence

2006.08.21. Pogány - Tanzania 1/36

WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence

János Pogány, pharmacist, PhD consultant to WHO

Tanzania, 21 August 2006E-mail: [email protected]

Expression of Interest andGuidelines on Assessment of

Applications for Prequalification

mailto:[email protected]






AbbreviationsAPI Active Pharmaceutical Ingredient DRA Drug Regulatory Authority EoI Expression of Interest FDC Fixed-Dose CombinationFPP Finished Pharmaceutical ProductGMP Good Manufacturing PracticesICH International Conference on HarmonizationMA Marketing AuthorizationPQ PrequalificationTRSTechnical Report SeriesYellow → emphasis Green → WHO Blue → ICH region


Objectives of the workshopWHO 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.


Subjects for discussion1. Interchangeability of multisource (generic)

FPPs2. EoI for Antimalarial Drugs3. Global quality issues4. Prequalification Experience – Illustrative

deficiencies5. Pharmaceutical Quality Information Form6. Main points again


Interchangeability (IC)Interchangeability (IC) of multisource FPPs =

(Essential similarity with innovator FPP) =

Pharmaceutical equivalence (PE) +

Bioequivalence (BE)

IC = PE + BE


INACTIVE INGREDIENT

S

ACTIVE INGREDIENT

S

PACKING MATERIALS

FPP Manufacturing process

Manufacturing

authorization

Marketingauthorization

GMP standards

Pharmacopeiastandards

NATIONAL DRA1

NATIONAL DRA2

CRITICAL VARIABLES OF FPP QUALITY


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


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


Low quality-risk APIs1. Certificate of suitability (CEP) is submitted (DRA)2. Drug Master File

Open part (APPLICANT) Closed part (DRA)

3. Pharmacopeia monograph is available Literature evidence of stability Synthesis impurities and degradants are controlled by

monograph Class1 solvents excluded; class2 / class 3 solvents controlled

4. FPP is registered in the ICH region (DRA)

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) FPPsAll oral FPPs include paediatric formulations.(EOI is included in the Notes Page of this and the subsequent slides)


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.


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

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.


Global regulatory issuesAPI 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


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)


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.

PREQUALIFICATION EXPERIENCE

ILLUSTRATIVE EXAMPLES OF DEFICIENCIES


Chemical synthesis Detailed information on the synthesis of non-

compendial APIs —or a flow chart and textbook-level 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.


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.”


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.


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 97-103% as opposed to 98-102% in the DMF.


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.


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.


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.”

PREQUALIFICATION QUALITY

REQUIREMENTSSTANDARDS, GUIDELINES

and TEMPLATES


International Pharmacopoeia Artemether Artemisinin Artemotil Artenimol Artesunate Mefloquine Hydrochloride Proguanil Hydrochloride BP


International quality standards Amodiaquine USP Amodiaquine Hydrochloride USP Lumefantrine Pyrimethamine BP, PhEur, PhInt, USP Sulphadoxine BP, PhEur, PhInt, USP


Prequalification quality guidelines1. 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


Prequalification quality guidelines2. 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


Prequalification quality guidelines4. Supplement 1 [for use from July 2005

(CPH25)] - Dissolution testing5. 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.


Annex 8 to the Generic GuidelinePharmaceutical 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.


Main points again1. 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.

2. The EoI limits the number of FPPs.3. 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.


Main points again4. Artemisinin-derived APIs and FPPs were marketed at

global level for decades without meeting basic standards of quality.

5. It takes time to get into prequalification compliance Develop new formulation Data to be generated, tests carried out GMP upgrade needed

6. Increase in the number of prequalified Artesunate Tablets is expected because there has been an official comparator since 2005.


PLEASE MAKE USE OF THE OPPORTUNITY

TO PARTICIPATE IN THE PREQUALIFICATION

PROJECT

who training workshop on pharmaceutical quality, gmp and bioequivalence

Documents

ich guidelines

bioequivalencejnos pogny

pogny tanzaniasubjects

gmp inspection

monograph class1 solvents

area of dossier assessment

innovator fpp

drapharmacopeia monograph