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Training Workshop on Pharmaceutical Quality and Bioequivalence, 17-19 January 2006

János Pogány, pharmacist, Ph.D. consultant to WHO

Hanoi, Vietnam, 17 January 2006E-mail: pogany@t-online.hu

Procedures for Participation in the Prequalification Project

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AbbreviationsAPIActive Pharmaceutical Ingredient DRA Drug Regulatory Authority EoI Expression of Interest FDC Fixed-Dose CombinationFPP Finished Pharmaceutical ProductGMP Good Manufacturing Practices of WHO ICH International Conference on HarmonizationMAMarketing AuthorizationPQ Prequalification

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Subjects for discussion1. Expectations of participants2. Interchangeability of FPPs3. EoI4. Global quality issues5. Illustrative PQ Requirements for Quality of

APIs and FPPs6. Pharmaceutical Quality Information Form7. Main points again

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Expectations of participants1. Procedures for participation in the PQ project2. Expression of Interest3. Documentation to be discussed

Guidelines for drafting a Site Master File (SMF) Guidelines on submission of documentation for multi-source

(generic) FPPs• Quality part• Bioequivalence part

4. The workshop should be interactive with questions and answers after each major point of the guidelines.

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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 of

specifications) 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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High-risk APIs and FPPs Reference standard/comparator is not available for:

Pharmaceutical (dissolution) 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 national DRA as regards assessment of applications for MA

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Low-risk APIs1. Certificate of suitability (DRA)2. Drug Master File

Open part (Applicant) Closed part (DRA)

3. Pharmacopeia monograph Literature evidence of stability Synthesis impurities are controlled by monograph

(toxicology of additional impurities) Class1 solvents excluded, class2 solvents controlled

4. FPP is registered in the ICH region

SIXTH EXPRESSION OF INTEREST

October 2005

HIV and related diseases

Illustrative examples

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EOI – Oral Preparations1. Antiretrovirals as single-ingredient formulations

for use in adults and adolescents2. Anti-retrovirals as fixed-dose combinations3. Anti-infective drugs

Antibacterial and antimycobacterial agents Antiprotozoal and antifungal agents Antiviral agents Anti-cancer drugs Palliative care drugs

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Antiretrovirals Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Abacavir Didanosine Lamivudine Stavudine Tenofovir Zidovudine Only FPPs listed in the EOI are assessed.

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Antiretrovirals Non-Nucleoside Reverse Transcriptase Inhibitors Efavirenz Nevirapine Protease Inhibitors Indinavir Nelfinavir Saquinavir Ritonavir

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Antiretrovirals - paediatric FPPs Reduced and/or scored solid dosage formulations of:

Abacavir

Efavirenz

Lamivudine

Nevirapine

Zidovudine

http://www.who.int/3by5/paediatric/en/

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Anti-retrovirals as FDCs Reverse Transcriptase Inhibitors Lamivudine + Stavudine Lamivudine + Zidovudine (Combivir) Lamivudine + Stavudine + Efavirenz Lamivudine + Stavudine + Nevirapine Lamivudine + Zidovudine + Efavirenz Lamivudine + Zidovudine + Nevirapine Lamivudine + Zidovudine + Abacavir (Trizivir) Tenofovir + EmtricitabineProtease Inhibitors Lopinavir + Ritonavir http://webitpreview.who.int/entity/3by5/publications/documents/arv_guidelines/en/

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Paediatric FDCs Reduced and/or scored solid dosage formulations of:

Reverse Transcriptase Inhibitors Lamivudine + Stavudine Lamivudine + Zidovudine Lamivudine + Stavudine + Nevirapine Lamivudine + Zidovudine + Nevirapine Lamivudine + Zidovudine + Abacavir Protease Inhibitors Lopinavir + Ritonavir

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Co-packaged FPPsCo-packaged preparations of the standard ARV

combinations, for adult, adolescent and paediatric use are also sought

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EOI requirements The medicines listed in this Invitation for

Expression of Interest are those for which a need has been identified by the HIV/AIDS department, WHO. The submitted products should be of assured pharmaceutical quality and relevant data to support efficacy should be provided. Procedure for submission of EOI:

1. Submit a covering letter expressing the interest to participate in the project, confirming that the information submitted in the product dossiers is correct.

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EOI requirements2. Submit a product dossier in the recommended format

as specified in the „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.” The dossier should be accompanied by a sample of the product to enable analysis (e.g. 1 x 100 Tablets).

3. Submit a Site Master File for each manufacturing site as listed in the product dossier, in the recommended format.

http://mednet3.who.int/prequal/

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EOI – assessment criteria Valid manufacturer’s license for production Product registered or licensed in accordance with national

requirements Products manufactured in compliance with GMP as certified by

the national regulatory authority and/or certified GMP inspectors Product certificates exist in accordance with the WHO

certification scheme on the quality of pharmaceutical products moving in international commerce

Product dossiers of acceptable quality submitted and outcome of the assessment in respect of the pre-qualification procedure

Outcome of the inspection performed by or on behalf of the above-mentioned agencies

Manufacturer demonstrates sound financial standing

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History and current status First EOI published and assessment of

dossiers started in 2001 ARV FPPs [316 applications (15 cancelled) -

many approvals as at January 2006] Generic ARV FPPs were scarcely available

at the beginning of the project, while there are many suppliers today

Problems delaying prequalification

GLOBAL QUALITY ISSUES

FPPs in general

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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 DRA

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Global regulatory issues

Formal stability studies were not required for MA

Biostudies were not required for MA National Good Manufacturing Practices

(GMP) do not comply with WHO-GMP requirements

Illustrative Prequalification Requirements for Quality

of APIs and FPPs

ILLUSTRATIVE EXAMPLES

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WHO general requirements If the product has been locally developed

and manufactured, the NDRA must evaluate the data set itself (p. 23).

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).

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General evaluation issues 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. This is still the situation today for example: Efavirenz Emtricitabine Tenofovir

and new monographs are continuously improved New evaluation issues surfaced with FDC.

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Synthesis deficiencies

Potential synthesis impurities (e.g., by-products, solvents) were not tested and representative batch scale were not provided

The final purification, crystallization and subsequent operations were not described in details.

Existence/absence of polymorphs, particle size, bulk and tapped density and hygroscopicity were not submitted

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Specifications Stress stability (forced degradation) tests were not

submitted to identify existence or absence degradants and to substantiate specificity of the impurity test method.

Degradants, dissolution rate and profile, water content, hardness, microbiological attributes, etc. of FPPs were not tested or quantified.

No adequate information was provided on the preparation and quality specification of primary (absolute) and secondary (working) analytical standards. (For instance, lack of complete CoA, assay by two different validated methods, detailed information on storage, etc.).

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Development pharmaceutics A report was not submitted to identify and

describe the critical product 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 (bioequivalence), stability and validation studies was not presented and, in case of formulation changes, dissolution profiles was not provided..

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Concurrent validation The progress from pre-formulation → formulation →

pilot manufacture → production scale manufacture was not shown in the submission.

There was no validation report on not less the than first three (3) production scale batches to establish the nature and specifications of subsequent in-process acceptance criteria and final tests as well as provide assurance that the manufacturing process met expected results.

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Retrospective validationAnnual quality review data and analysis were not submitted to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.

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SmPC and PIL A national DRA-approved Summary of

Product Characteristics (SmPC) type information for health professionals was not submitted or it was not based on documented facts and figures.

Patient Information Leaflet (PIL) was not based on the SmPC

PREQUALIFICATION QUALITY REQUIREMENTS

FPPs in general

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Prequalification guidelines (1)

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 guidelines (2)2. WHO/DMP/RGS/98.5 Marketing Authorization of

Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities (The Blue Book)

3. 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.

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Annexes to Generic Guide1. Model Certificate of a Pharmaceutical Product2. Model Batch Certificate of a Pharmaceutical Product3. Model Stability Report of Active Pharmaceutical

Ingredient (API)4. Model Stability Report of Capsules/Tablets5. Suggested Structure of the Summary of Product

Characteristics6. Suggested Structure of the Package Information Leaflet7. Presentation of bioequivalence trial information 8. Presentation of pharmaceutical quality information

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Prequalification guidelines (3)4. Supplement 1 [for use from July 2005

(CPH25)] - Dissolution testing5. Supplement 2 [for use from July 2005

(CPH25)] - 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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Prequalification guidelines (4)5. Guidance on Variations to a Prequalified Dossier 6. 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.

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MAIN POINTS AGAIN1. The workshop deals with selected aspects of procedures of

prequalification2. The EoI limits the number of FPPs to the list3. National DRA have not assessed generic FPPs –used in the

treatment of HIV/AIDS, malaria and tuberculosis– and most manufacurers have not had dossiers for MA, at the beginning of PQ.

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

5. Generic ARV FPPs are widely available as a result of PQ.

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THANK YOU