1 department of medicines policy and standards, health technology and pharmaceuticals...

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Prequalification of Essential Medicines

Dr Lembit RägoCoordinator

Quality Assurance and Safety: Medicines (QSM)Medicines Policy and Standards (PSM)

WHO Headquarters, Geneva, [email protected]

WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies

8 – 12 October, Geneva

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WHO Today

Hosts three prequalification programs

1. Prequalification of vaccines (QSS/IVB/FCH)

2. Prequalification of diagnostics (EHT/HTP)

3. Prequalification for priority essential medicines (QSM/PSM/HTP)

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VACCINEShttp://www.who.int/immunization_standards/vaccine_quality/pq_system/en/

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DIAGNOSTICS http://www.who.int/hiv/amds/diagnostics/en/

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

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Prequalification of essential medicines

The UN prequalification program is an action plan for expanding access

for patients with

HIV/AIDS

Tuberculosis

Malaria

Reproductive health

by ensuring quality, efficacy and safety of medicines procured using

international funds (e.g. GFTAM, UNITAID)

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How prequalification is organized? (I)

Role of WHO: Managing and organizing the project on behalf of the United Nations. • provides technical and scientific support and guarantee

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 (IPC group); WHO disease oriented programs

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How prequalification is organized? (II)

Stakeholders: • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB

(Global Drug Facility); HIV/AIDS Department; other disease oriented programs

• Interested Governments• Funding partners: Governments (Belgium, France, China etc.),

Gates Foundation, UNITAID Beneficiaries:

• UN Procurement, Global Fund and UNITAID procurement, NGOs (e.g. MSF)

• National Regulatory Agencies• Developing country industries

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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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• What if not covered by these options?

Multisource products • Full dossier with all 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• 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)

Commercial sample Requested, but not always analysed before prequalification.

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Prequalification: generics and not generics

Prequalification requirements for generics – fully in line with major regulatory agencies. A multisource (generic) medicine must:

1. contain the same active ingredients as the innovator drug

2. be identical in strength, dosage form, and route of administration

3. have the same use indications

4. be bio-equivalent (as a marker for therapeutic interchangeability)

5. meet the same batch requirements for identity, strength, purity and quality

6. be manufactured under the same strict standards of GMP required for innovator products.

What if not generics – full data set to prove the 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

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Guidance for applicants

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Prequalification: the technical documents are WHO normative documents.

When these are "silent" other guidelines such as selected ICH guidelines may be used

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Which medicines and why PQ Programme deals with?

Application to include a product on Expression of Interest (EOI) Lists published comes from WHO disease oriented programs

Products should be of high public health value Products must be in line with WHO treatment guidelines Products must be in line with Essential Medicines List Rare exceptions from these principles, if justified

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New Product Group from 2006: Selected Reproductive Health Products

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Current status

Started with HIV/AIDS products in 2001 – malaria and TB products joined later

Prequalified products (May 2007) "Active" dossiers in pipeline (2006)• 164 HIV related medicines 60+ • 12 anti-tuberculosis medicines 25+• 8 anti-malarial medicines 30+• 184 115+

Ongoing assessments and follow-up• Products• Manufacturing sites (both for APIs and finished dosage forms) • CROs

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News example

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Transparency: WHO Pubilc Inspection Reports

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Increased transparency about the "pipeline"

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Problems encountered with products containing artemisinin derivatives

General Very few innovator products Many not typical generics as well Very few antimalarials recommended by treatment guidelines approved in ICH

and associated countries Limited DRAs and regulatory experts having experience with antimalarials Fixed dose combinations more complicated than single component products

Quality related issues Manufacturers do not comply with GMP (even if located in the EU or EFTA

countries – products not registered and produced only for export)

Many dossiers have outstanding deficiencies in proving the quality of the product – non-compliance with established specifications or poorly defined manufacturers specifications; stability data either 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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Since 2005 annual reports; 2006 annual report on the web

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Outcome of 2006

44 products listed (32 in 2005) - 38% more than in 2005

But … No new antimalarials No new TB drugs (but 4 new ones added in early 2007) No new QC labs

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Year 2006: statistics (1)

INSPECTIONSINSPECTIONS

A total of 49 (2005 – 52) inspections were carried out:

17 (20) inspections of the manufacturing sites of finished product manufacturers

10 (10) inspections of the manufacturing sites of active pharmaceutical ingredients (APIs)

15 (14) inspections of contract research organizations (CROs)

7 (8) inspections of national pharmaceutical quality control laboratories (NPQCLs) in Africa.

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Inspections: where?

India – 28 China – 6 Belgium - 1 Canada – 1 Malaysia - 1 France - 1 South Africa – 3 Switzerland - 1 United States – 1 Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda – all 1

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Year 2006: statistics (2)

AssessmentsAssessments

During the 6 (9 - 2005) dossier assessment sessions,

334 (222 – 2005) assessment reports linked to 334 HIV/AIDS-related products were written.

A total of 78 (52) assessment reports — linked to 70 (50) TB products were written

A total of 29 (73) assessment reports were written, linked to than 31 (40) malaria products All together 75% increase in the number of assessment

reports!

More facts will be soon in Annual Report 2006 on the web

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Publications 2005/2006

New, more user friendly prequalification web site launched in November 2006, updated and improved also later: http://mednet3.who.int/prequal/

Articles:

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 Prequalification Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

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Measures taken to get more products prequalified

General Formerly very limited resources vs huge obligations and scope PQ programme started with only ONE professional, by the end of 2007 it

may have up to 15 (three will be secondments from Governments) Business plan and funding proposals created, funds received (Gates;

UNITAID) Specific

Internal SOPs and work procedures to facilitate process created Specific for antimalarials "Note for Applicants" prepared New regulatory guidance documents created and started Specific guidance on comparator products More direct discussions with manufacturers started Regulatory advise on complicated cases Additional work that could help manufacturers under way

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Capacity building of NRAs and Manufacturers

Both remain important components and need strengthening

Both need improvement and new approaches

From 2006 one rotational post in PQ program for developing country regulators

From 2007 second will be opened

NB! In 2006 programme started to deliver in addition to general training focused to selected manufacturers technical assistance (beneficiaries in countries such as China, Ukraine, Zimbabwe …)

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Training and related activities in 2007

In June two days workshop in cooperation with WHO EMRO about prequalification

In June three days workshop on BE/BCS and dissolution testing (new course) in cooperation with EURO and FIP in Ukraine

In October repetition of Cape Town course on paediatric medicines development in WHO EURO

In November TBS on Medicines Quality and Prequalification In November upon request from Chinese Gov on week training

in China Training of assessors in AFRO (planning stage) … Training for QC lab personnel – EDQM Septmeber in Vienna

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Prequalification of Quality Control Laboratories (1)

So far only for AFRO region, potential expansion 3 QC Labs prequalified

South Africa, CENQAM - 6/2005 South Africa, RIIP - 7/2005 Algeria, LNCPP - 10/2005

3 QC Lab near to PQ?? South Africa, Kenya, Tanzania

11 QC Labs audited, corrective measures proposed Cameroon, Mali, Madagascar, Niger, Senegal Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania

4 QC Labs expressed interest, but not send LIF yet Benin, Burkina Faso, Cote d'Ivoire, Guinea

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Prequalification of Quality Control Laboratories (2)

Technical assistance Experts provided to 2 QC Labs : Ethiopia and Tanzania Several in AFRO have received free of charge International

Pharmacopoeia and other docs, pluss chemical reference substances for ARVs

10 of the QC Labs were involved in Proficiency testing (Phase 3, 07/2004 - 06/2006) Algeria, South Africa CENQAM, South Africa RIIP Mali, Niger, Senegal Ghana, Kenya MEDS, Tanzania, Uganda

3 other African QC Labs took part in Proficiency testing (Phase 3, 07/2004 - 06/2006) Morocco, Tunisia, Zimbabwe

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Are there alternative regulatory pathwaysfor products of public health needs?

EU Article 58

US FDA tentative approvals linked to PEPFAR

Canadian Access to medicines scheme WHO cooperation with the above mentioned Confidentiality agreement with US FDA in place and working; CA with

Health Canada expected by March 2007

How better use the synergies?

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Summary and conclusion

Quality can not be assessed, tested or inspected on the product, BUT It has to be built into it!

We have the obligation to ensure it with all the means we have in the best way we can.

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