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Update from WHO Prequalification of Medicines

Programme and beyond.

IPC, December 2012, Washington DC

Dr Lembit Rägo

Coordinator

Quality Assurance and Safety: Medicines

Essential Medicines and Pharmaceutical Policies

World Health Organization

Geneva

ragol@who.int

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Content

• Context and links with other WHO activities

• Overview of the programme activities

• News from 2012

• Short timelines for variations

• API prequalification taking off

• First Zn product prequalified

• RH medicines – first ERP

• Number of important publications incl. concept paper for future

• Scientific output

• Joint UNICEF/WHO PQP manufacturers meeting

• Advocacy

• Opportunities

• Challenges

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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)

• Two teams dealing with medical devices • Incl Diagnostics prequalification programme

• One - Quality, Safety and Standards (QSS) team for vaccines and biologicals

• Incl Vaccines prequalification programme– Disease oriented programs (HIV/AIDS, malaria, TB, neglected

diseases)– Collaboration with WHO programmes/departments, regional and

COs– Collaboration with numerous core- and operational partners

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QSM Technical Programmes

• International Nonproprietary Names (INNs)

• Quality Assurance (Expert Committee on SPP, International

Pharmacopoeia)

• Safety/Pharmacovigilance

• Regulatory support

• Prequalification Programme for Medicines

• Quality Assurance and Safety of Blood Products and

Related Biologicals

• Anti SFFC (anticounterfeiting)

• All coloured (and even the last) support directly and

indirectly PQP!

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Active collaboration with other international, regional and national organizations

• UN family, international organizations and donors:

– UNICEF, UNFPA, UNDP, 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 (from all WHO Member States)

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Prequalification of Medicines ProgrammePrequalification 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, and involves today three-in-one

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 sulfate)

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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 EDQM)

– New collaborative procedure (2012) with regulators to facilitate national registration – around 10 countries starting pilot, more extensive information exchange/collaboration in anticipation of less duplication

• Active participation and involvement of

– SRA experts, regulatory authority experts from less resourced settings

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• 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.

• Advocacy documents

• Scientific publications …

Transparency needs constant efforts

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

http://apps.who.int/prequal/ : constant flow of important news

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Expressionof Interest

Compliance

Additional informationand data

Correctiveactions

Compliance

Assessment Inspections

Medicines Prequalification Process: dossier maintenance taking more resources as number of PQP products grow

Prequalification

Monitoring

Product dossierSMF

Dossier maintenance(variations)

Handling of complaints

PQP handling today

variations

with short timelines,

much shorter than many

regulators incl. US FDA

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New – API prequal taking off. Steps in the process

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API prequalification developing

Note: 25 APIs prequalified, all from India, but including 1st from China. As per today

more than 12 different Chinese API manufacturers with 14 applications for individual API

prequalification received and several start making progress towards PQ

First Zn product prequalified recently

• Opens way for following products as a lot of technical

issues were solved

• Also new specific for Zn product applicants regulatory

guidance was issued (web posted)

– Can help to get further good quality effective products prequalified

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Reproductive health products

• Limited progress in terms of new PQ-d products

• Progress in working together with many counterparts to

facilitate RH PQ

• Still, some technically very sophisticated key products

making progress – implant

• Major brake through – successful eventually External

Review Panel (ERP). Gave 12 more products eligible

temporarily for procurement. ERP can be repeated in

2013

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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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Why products do not get prequalified?

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Number of important publications

• Publication in WHO Drug Information and/or web

posted in PQP web site

– Paper on ERP

– Paper on PQP rotational fellows

– Paper on API prequalification

– Concept paper on future of PQP (and opportunity to

cover all EML medicines)

• Discussed in 15th ICDRA together with vaccines PQ concept

paper, complimentary and need to be emerged in one for all

PQs

– …

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Scientific publications

• PQP has been and will continue issuing

scientific papers on actual topics

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Common deficiencies: quality

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Common deficiencies: Safety/Efficacy – bioequivalence

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PQP – upfront of innovative science

• Conclusion: from a clinical viewpoint,

not only are prequalified generic

antimalarials bioequivalent and

interchangeable with the reference

product (Coartem, Novartis), but also

the existing indirect evidence makes

it possible to conclude that these

WHO prequalified products are bioequivalent between themselveswith respect to the AUC.

• This means that these generics are

also interchangeable not only with

comparator but also between

themselves

(Note. The lack of the necessary precision to demonstrate bioequivalence between generics with respect to the Cmax within the conventional acceptance range does not preclude considering them as interchangeable, as Cmax is considered to be of less clinical relevance) 24

New advocacy booklet: http://www.who.int/medicines/publications/prequal_advocacy_booklet.pdf

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Joint UNICEF/WHO PQP manufacturers meeting

• This year first time joint UNICEF/WHO meeting

for manufacturers

– Involved also one-to-one technical meeting

opportunities for manufacturers (from 8.00 to 23.00

…)

– Overall positive feedback on the meeting and PQP

• … even the most problematic and "difficult" companies

agreed with other in one – PQP is technically very competent

and solid programme

– Worth to repeat in 2013?

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• During 2011 35 products (finished dosage forms) prequalified – 2012 ending with 40+?

• At the end of 2011, the WHO list of prequalified medicines - 269 products manufactured in 25 countries – today 320+

• By the end of the year 8 active pharmaceutical ingredients (APIs) (6 for antimalarials and 2 for anti-TB medicines) prequalified – today 25

• 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). Thailand and China have been added by today!

Prequalification programme in 2011, and up today

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• 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. Several added in 2012 …

Training activities remain a core

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• 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.

Technical assistance

TBS, Nov 3, 2011 31

WHO Projects Organized in Cooperation with CO and SFDA in China

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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 outcomes

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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 applications (so far)

– Free capacity building

– Better quality production/products/regulatory knowledge – better access to markets and international funds

– Better image

Opportunities

• Working together with all three PQ programmes for

potential synergies

• Better advocacy and promotion

• Establishing fee system in early 2013

• Contributions from old and new partners who benefit

from PQP

• Looking for new effciencies – webinars for trainings etc.

• Implementing new IT tool for PQP

• …

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Challenges

• New unpaid activities increasing – often with no

opportunity to say "NO" – "more for less" increasing to

the limits

• Financial insecurity (long term)

• Working together with all three PQ programs not for

political "demand" but for true benefits

• Keeping up staff moral – constantly reviewed,

pressurised, technical work not appreciated, arguments

not listened etc.

• Preparing for the long-term future – regulatory networks

taking over?

• …

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• 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

Conclusions