Prequalification Programme: Priority Essential Medicines Dr A J van Zyl Technical Officer HTP/PSM/QSM World Health Organization (WHO) Geneva, Switzerland

Prequalification Programme: Priority Essential Medicines

Dr A J van ZylTechnical OfficerHTP/PSM/QSM

World Health Organization (WHO)Geneva, Switzerland

[email protected]

Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations

15 October 2007

Tallinn, Estonia

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Quality of medicines remains a problem in many countries

Oct 2006. Panama: More than 30 died - cough syrup containing diethylene glycol – industrial solvent (in antifreeze) – kidney failure

1999. Belgium: Two babies died. Injected KCl (supposed to be glucose)

2000. USA: 17 children died. No active ingredient in inhalers

Picture. New York Times 2007 Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006

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What is WHO doing to help the countries?

Normative functions – setting norms and standards Including GMP

Capacity building

Prequalification Programme: Priority Essential Medicines

"Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency

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In this presentation…

What is "prequalification" and how does it work Steps in prequalification Norms and standards used Evaluations (dossiers and site inspections) Outcome of assessment Capacity building and improvements

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Prequalification of essential medicines

The UN prequalification program:

Is an action plan for expanding access to medicines for patients with:

HIV/AIDS

Tuberculosis

Malaria

And access to Reproductive Health Products

Ensures quality, efficacy and safety of medicines procured using

international funds (e.g. GFTAM)

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How prequalification is organized?

Role of WHO: Managing and organizing the project on behalf of the United Nations.

• Provides technical and scientific support• Ensures that international norms and standards are applied all

through the process including assessment, inspection (GMP, GCP, GLP) and quality control

Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS and with the

support of the World Bank• Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB

(Global Drug Facility); HIV/AIDS Department Actors:

Mainly qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S

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I Expression of InterestProduct dossier

SMF

Compliance

Additional informationand data Corrective actions

Compliance

Assessment Inspections

Steps in prequalification

Prequalification Monitoring

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Quality Assurance (QA) of WHO prequalification process

PQ team has its own Quality Assurance system:

Quality Assurance and Safety: Medicines (QSM) Standard Operating Procedures (SOPs) Manuals and guidelines General Procedure for Prequalification Norms and standards (product dossiers,

manufacturers etc)

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Product dossier assessment

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Reproductive Health Products

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Evaluation procedure

Assessment of product dossiers (Quality specifications, pharmaceutical development, production, control,

stability, bioequivalence etc). Teams of professionals from national Drug Regulatory Authorities

(DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ...

Copenhagen assessment week• 8 to 20 assessors together during one week at least every two months at

UNICEF in Denmark• Every dossier is assessed by at least four assessors. • An assessment report is issued - signed by assessors• Letter summarizing the findings and asking for clarification and additional

data if necessary• Letter is sent first by e-mail to the applicant followed by surface mail

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Assessment procedure- Product dossiers

Innovator products• Abridged procedure if approved by stringent authorities like EMEA and US FDA• Assessment reports from Drug Regulatory Authorities (DRSs), WHO Certificate of

Pharmaceutical Product (CPP), batch certificate, update on changes• Trusting scientific expertise of well-established DRAs

Multisource (generic) products Full dossier with all the data and information requested• Quality:

• Information on starting materials and finished product, including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc

• Efficacy and safety:• Bio-equivalence study or clinical study report

Commercial sample Requested, but not always analysed before prequalification.

US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure)

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Prequalification: generics and not generics

Generic medicines: 1. To contain the same active ingredients as the innovator drugs as the innovator drug2. To be identical in strength, dosage form, and route of administration3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality5. To be manufactured under the same strict standards of GMP required for innovator products.6. To be bio-equivalent

Prequalification requirements for generics Fully in line with major regulatory agencies

What if not generics Full data to prove safety (including preclinical toxicology) and efficacy has to

be presented Not all non-innovator products in prequalification pipeline can be

defined as generics – no innovator may be available

See also FDA requirements for generic drugs (www.fda.gov/cder/ogd)

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Norms and standards used

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Prequalification: where the technical documents come from?

International consultation process

The WHO Expert Committee – review and adopts

Executive Board World Health Assembly

Printed in respective TRS and WHO web site

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Publications 2005/2006

New, user friendly prequalification web site launched in November 2006: http://who.int/prequal/

Articles: 1. Prequalifi cation of medicines. WHO Drug Information, 2005, 19:1.

2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2.

3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

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Problems encountered with product dossiers

General HIV/AIDS: Initially – few monographs (Official Pharmacopoeia) Malaria - very few innovator products, many not typical generics as well

Very few antimalarials approved in ICH and associated countries Limited DRAs and regulatory experts having experience Fixed dose combinations more complicated than single component products TB: Old products, low profits – lack of data meeting current requirements

General Quality related issues Manufacturers do not comply with GMP Products not controlled - registered and produced only for export Lack of specifications or poorly defined manufacturers specifications Stability data missing or not meeting requirements No method validation etc.

Mostly manufacturers can overcome these problems if motivated. However, it may take a lot of time

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Problems encountered with product dossiers

Lack of reference products for bioequivalence studies For generic products: Bioequivalence studies to show the same blood

concentrations (assume same safety and efficacy profile) Often unclear which comparator product to be used BE not a requirement in all countries

Safety and efficacy related issues Insufficient data submitted

Incomplete protocols and trial reports Incomplete evaluation of published literature

No characterisation of pharmacokinetic properties of the product General statements made: No interaction known (clearly not true); No (or minimal)

adverse events (literature survey if no original data) Too broad efficacy claims Galenical development history not provided

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Inspection of sites

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Inspections:

Team of inspectors for each inspection WHO PQ inspector plus PIC/S member country plus local

country inspector (observer) Some cases – capacity building (recipient country)

Preparation includes SMF, product information, inspection reports, complaints etc

APIs, Finished products Clinical studies: Mostly Bioequivalence studies (generic

products

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Inspections:

Assess compliance with

WHO norms and standards: GMP GCP GLP GSP GDP…

Organizations conducting clinical trials WHO training materials

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Where are the inspections performed?

India, Bangladesh, Pakistan China Belgium Canada Malaysia France South Africa Switzerland United States Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda

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Inspections:

Production and control activities:

Normally over 3 days Covers all aspects of GMP

Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel, Utilities (e.g. HVAC, water) . . .

Also data verification (dossier) including stability data, validation (process), development batches and bio batches

Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification . . .

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Inspections:

Bio-equivalence studies GCP and GLP

About 2 days per study including

Clinical part Clinic, Pharmacy and related areas, data verification

Bio-analytical part Laboratory and data verification

Statistical analysis

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Problems identified in GMP inspections:

Various including validation, ventilation, equipment, quality risk management…

Validation and qualification work was often incomplete

Validation Master Plans (VMP) lacked details Validation policies as defined in the VMPs were

not implemented Process validation was lacking Validated procedures (e.g. environmental

monitoring) were lacking

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No URS for HVAC, water and computer systems Incomplete (not detailed) or "no" qualification of HVAC / water /

computers Insufficient filtration of air to production areas No prevention of possible cross-contamination and contamination. No authorized schematic drawings "As built" AHUs lacked components reflected in the schematic

drawings, including filters Temperature and RH mapping studies incomplete, or results not

applied HVAC systems not controlled or monitored Filters:

not planned, classified, tested (including installed filter leakage test), monitored

Pressure differential gauges not controlled, including calibration and zero checks

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Wrong sequence of components (e.g. after filtration)

Inappropriate AHU for equipment e.g. coaters, FBD Claim "wet scrubbers" – but not

functional

Inappropriate change control

No quality risk management documented

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Problems identified in GCP inspections:

Volunteers Number of volunteers in a study No control for participating in several studies in a short period Supportive documentation – DOB, identification, ECGs Screening ICF

Ethics committee Independence Supportive documentation

Clinic Archives Pharmacy

Documentation, randomization, dispensing CRFs Analytical method validation Stability (stock solutions, samples) Source data including chromatograms

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Outcome

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Outcome

List of prequalified products New and revised guidelines, norms and standards

MonographsInternational Chemical Reference standards

Sampling and testing of products on the marketTraining

Capacity building. . .

See also Annual Report

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List of prequalified products

Disease 2001 2002 2003 2004 2005 2006 2007

HIV/

AIDS

… … … … … 25(excluding US FDA, Canada)

19 (excluding US FDA)

TB … (5) 2 1 0 4

Malaria 0 2 3 0 3

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Examples of Antimalarials prequalified so far

Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12

Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24lumefantrine 120mg

Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml

Artesunate 50mg Tablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12

Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification

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Monitoring…

Ongoing assessments and follow-up

• Products• Manufacturing sites (both for APIs and finished dosage forms) • CROs• Sampling and testing

• Data verification inspections

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Since 2005: PQ Annual report

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Capacity building and improvement

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Capacity building of DRAs and Manufacturers

Both remain important components and need strengthening

Both need improvement and new approaches

From 2006 - in addition - provide (to selected manufacturers):

Technical Assistance

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Measures taken to get more products prequalified

Action taken. . . Formerly very limited resources vs huge obligations and scope

Initially only ONE professional - today at least 15 (including 4 secondments from Governments such as France and China)

Business plan and funding proposals – now funds received (Gates) and (UNITAID)

Internal SOPs and work procedures "Note for Applicants" (anti-malaria products) New regulatory guidance documents created and started Specific guidance on comparator products More direct discussions with manufacturers started Regulatory advice on complicated cases including BE Pharmaceutical development, technology transfer, paediatric

formulations "Notes to consider"

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Measures taken to get more products prequalified Action taken (2) . . .

Additional funding (e.g. Gates, UNITAID) Additional training workshops Additional staff to be recruited Communication to be improved

Regulators Manufacturers Donors and partners

More proactive approach towards potential suppliers – new elements Regulatory advice Technical assistance

Strengthening links with WHO regions Taylor made approach to different regions Building capacity in countries

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Alternative regulatory pathways

USA FDA tentative approvals linked to PEPFAR Included in WHO PQ List Confidentiality agreement with US FDA in place

EU Article 58 For products exclusively to be used outside EU

Canadian Access to medicines scheme WHO cooperation with the above mentioned Confidentiality agreement in preparation

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Thank you

Documents

Prequalification Programme: Priority Essential Medicines Dr A J van Zyl Technical Officer HTP/PSM/QSM World Health Organization (WHO) Geneva, Switzerland