Quality of RH Medicines: Update from WHO Prequalification of Medicines Programme and beyond.

4 October 2012, Paris

Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies World Health Organization Geneva [email protected]

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Content

• Context and links with other WHO activities • What is prequalification programme (PQP): • Overview of the programme activities • Specifics of RH medicines Challenges and a way forward • What it can offer to the regulators and industries?

• Conclusions

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• The

Millennium Development Goals

(MDGs): • Eight international

development goals

that 192 United Nations member states and at least 23 international organizations have agreed to achieve by the year 2015

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Medicines work in WHO HQ

•

Department of Essential Medicines and Health Products (EMP)

– Three teams for medicines work • •

Quality Assurance and Safety: Medicines (QSM)

Medicines Access and Rational Use (MAR) • Medicine Programme Coordination (MPC) • Collaboration with other clusters/departments/programmes/units in HQ – Vaccines and biologicals (IVB/QSS) –

Vaccines prequalification programme

– EMP –

Diagnostics prequalification programme

– Disease oriented programs (HIV/AIDS, malaria, TB, neglected diseases) • Collaboration with WHO regional and country offices

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QSM Technical Programmes

• International Nonproprietary Names (INNs) • Quality Assurance • Safety/Pharmacovigilance • Regulatory support •

Prequalification Programme for Medicines

• Quality Assurance and Safety of Blood Products and Related Biologicals • Anti SFFC (anticounterfeiting)

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Active collaboration with other international, regional and national organizations

• UN family, international organizations and donors: – UNICEF, UNFPA, UNIDO etc.

– BMGF, Global Fund, UNITAID – Manufacturers associations – MSF • Regional – –

EMA/EU Council of Europe/EDQM

– NEPAD • • Professional and scientific – FIP, CIOMS, IUPHAR, ISPE

National level

–

National Medicines Regulatory Authorities

States) (from all WHO Member

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Prequalification of Medicines Programme

 The UN Prequalification Programme managed by WHO is ensuring that medicines procured with international funds are of assessed and inspected for

quality, efficacy and safety

, involves Prequalification programme for medicines (finished dosage forms) Prequalification of active pharmaceutical ingredients (APIs) Prequalification of quality control (QC) laboratories  The Prequalification Programme is an action plan for expanding access to priority essential medicines in the following four areas: - HIV/AIDS - Tuberculosis - Malaria - Reproductive Health - Selected individual products for other diseases (Flu, Zinc sulphate)

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Extensive collaboration with regulators

• Not duplicating work done be stringent regulatory authorities – SRA approval of new and generic products – abridged procedure – US FDA tentative approvals – based on confidentiality agreement including in the PQ products list – European Medicines Agency (EMA) – Art 58 … and beyond – Collaboration with EDQM, in particular in the area of APIs (confidentiality agreements with US FDA, EDQM, EMA …) • Active participation and involvement of – SRA experts – Regulatory authority experts from less resourced settings

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http://www.who.int/medicines/areas/quality_safety/en/ or http://apps.who.int/prequal/ 9

Steps in the process

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Medicines Prequalification Process

Expression of Interest Assessment Product dossier SMF Inspections Additional information and data Corrective actions Compliance Compliance Handling of complaints Prequalification Monitoring Dossier maintenance (variations) 11

Transparency

• Very comprehensive web site • Guidance for applicants – Technical guidelines – Guidance on specific issues (comparator products etc.) • List of products prequalified and in pipeline • WHO Public Assessment Reports (WHO-PARs) • WHO Public Inspection Reports (WHO-PIRs) • Notice of Concern (NOC) documents • News, announcements for public meetings etc.

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Transparency – dossiers and their status information on the web

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Transparency

–

WHO Public Assessment Reports (WHOPARs): a lot of information

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Transparency - WHOPIRs and NOCs

• • • These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions: –

"3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;"

A WHO Public Inspection Report (WHOPIR)

provides a summary of the inspection (where found to be GMP complaint)

A Notice of Concern (NOC)

is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or contract research organization.

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API prequalification developing

Note:

as per today 12 different Chinese API manufacturers with 14 applications for individual API Prequalification received. None yet prequalified as applications relatively recent

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Service Delivery: Assessors

4.0

3.0

2.0

7.0

6.0

5.0

Reliability

5.6

6.1* 5.0* Responsive 6.2

5.6

5.0

Desired and minimum level of service Assurance

6.0

6.3

5.3* Actual score Empathy

5.3

5.9* 4.7* Tangibles

5.7

5.5

4.4*

1.0

Reliability: ability to perform the promised service dependably and accurately Responsiveness: willingness to help applicants and provide prompt service Assurance: knowledge, courtesy and ability to convey trust and confidence Empathy: caring, individualized attention provided to applicants Tangibles: appearance of physical facilities, equipment, personnel, and communications materials Base: Manufacturers (Regulatory Affairs), n=18 [Q10-Q14]

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Why products do not get prequalified?

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Common deficiencies: quality

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Common deficiencies: Safety/Efficacy – bioequivalence 21

Prequalification programme in 2011

• During 2011 35 products (finished dosage forms) prequalified • At the end of 2011, the WHO list of prequalified medicines 269 products manufactured in 25 countries • By the end of the year 8 active pharmaceutical ingredients (APIs) (6 for antimalarials and 2 for anti-TB medicines) prequalified • 6 more medicines Quality Control Laboratories (QCL) prequalified (Belgium, Brazil, India, the Netherlands, Portugal and Tanzania). At the end of 2011, a total of 23 QCLs had been prequalified, covering all WHO 6 regions (further 32 were working towards becoming prequalified).

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Training activities as a core

• PQP also organized, co-organized or supported 32 training courses, for nearly 1400 participants.

• Training on general or specific technical issues was given to manufacturers, and to NMRA and QCL staff. • Courses generally also include an introduction or update on PQP requirements and services.

• PQP has a 3 months rotational post for developing country assessors – many regulators from China, Ghana, Tanzania, Kenya, Uganda, Botswana, Zambia, Zimbabwe, Ukraine etc. have been in this post – current fellow on post is from Kenya

Drug Information Association www.diahome.org

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Technical assistance

• In 2011, PQP organized 17 technical assistance missions to 13 pharmaceutical manufacturers in 5 countries (Bangladesh, China, Kenya, Nigeria and Pakistan), • Technical assistance for 5 CROs in China, • Technical assistance for 2 QCLs in China, and 1 QCL each in Benin, Cameroon, Madagascar and Thailand. • Assistance took the form of an audit, followed by development of an improvement plan. Training in specific technical regulatory areas was made available where needed.

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Technical assistances organized by PQP in individual countries

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Quality monitoring projects

(1)

•

Quality survey of antimalarials Africa

– – Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania ACTs and sulfadoxine-pyrimethamine – 935 samples collected and screened by Minilab, 306 tested in laboratory

ACTs SPs 70 60 50 40 % 30

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20

44 27

10 0 Ca me ro on

0 0

Eth iop ia Gh an a

56

Ke ny a

8 0 63 67 0

Ni ge ria Ta nza nia

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Non-compliant 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 80 PQ total 3 111 73 Non-PQ total 68 Compliant 12 12 12 7 17 AL PQ 2 1 AL non-PQ A&A co-p PQ A&A co-p non-PQ 27

Quality monitoring projects

(2)

•

Quality survey of anti-TB medicines in NIS

– – – Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin 291 samples collected and tested 25 23 20 % 15 10 10 10 7 5 4 0 Ar me nia Az erb aij an Be lar us Ka zak hs tan Uk rai ne Uz be kis tan 13 •

None of 38 samples of WHO prequalified products failed 28

WHO Projects Organized in Cooperation with SFDA in China

Focus on quality and safety of medicines, sponsored by • Bill and Melinda Gates Foundation (BMGF) – To improve TB control in China by increasing national capacity to produce fixed-dose combination (FDC) anti TB medicines of assured quality and to regulate TB FDC drugs • Global Fund to Fight HIV/AIDS, TB and Malaria (GFATM) – To improve the quality of anti-TB, HIV/AIDS and malaria medicine produced in China to ensure improved accessibility and patient outcome

s TBS, Nov 3, 2011 29 29

Status of RH: PQ and ERP

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Why RH manufacturers do not apply for PQ?

And when they apply why slow progress?

       No "market" for international standard quality products, enough market for products "as it is" The need to make human and financial investments A lack of technical and regulatory skills Not yet ready to participate internationally/globally – national/subregional markets unsaturated Differences between PQP and national regulatory requirements and their implementation Varying requirements and standards of procurers Risk of losing traditional markets once defined as sub-standard – PQ programme NOCs etc.

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What PQ can offer to the regulators and industries in the regions?

• Regulators – Capacity building/training – improved technical knowledge and skills – Practice and experience for collaboration and cooperation – Offers a lot of practical tools and guidelines – Helps to build more credible regulatory systems – Save resources • Industries – Free of charge capacity building – Better quality production/products/regulatory knowledge – better access to markets – Access to international funds

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Conclusions

• PQP is a powerful and effective mechanism to promote access to quality medicines • PQP has saved lives • PQP is not a replacement for national regulatory systems but a (time limited) mechanism to promote access to quality medicines • Major proactive contributor to capacity building • Promotes collaboration and cooperation among regulators, including relying on each others work and reducing duplications

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Selection of articles and publications about PQP

• •

The biowaiver procedure: its application to antituberculosis products in the WHO prequalification programme. Strauch S, Jantratid E, Stahl M, Rägo L, Dressman JB. In J Pharm Sci. 2011 Mar;100(3):822-30. Epub 2010 Oct 6.

Ensuring quality medicines: a decade of prequalification ”. In WHO Drug Information, 25(3):231 −239. Available at:

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http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-/en/index.html

“WHO Prequalification of Medicines Programme: facts and figures for 2010.” In WHO Drug Information, 25(2):101 −103. Available at:

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http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-2/en/index.html

“Inspection of API manufacturing sites.” In: WHO Drug Information, 25(1):24−27 and in WHO Pharmaceuticals Newsletter, No. 1, 2011, pp. 12 −18. Available at: http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2011_Vol25-1/en/index.html

•

http://www.who.int/medicines/publications/PharmNewsletter1_11/en/index.html

Survey of the quality of anti-tuberculosis medicines circulating in selected newly

independent states of the former Soviet Union. Available at:

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http://www.who.int/prequal/info_applicants/qclabs/quality_monitoring.htm

“Best medicines. Good-quality active pharmaceutical ingredients are vital to the product of good-quality medicines.

” In: World Pharmaceutical Frontiers, September 2011. Available at: http://edition.pagesuiteprofessional.co.uk/launch.aspx?referral=other&pnum=77&refresh=5Wp1z0E20B4c&EID =daba9217-c7a4-4529-a687-a6fb6437e4c5&skip=&p=77 www.diahome.org

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