1 WH O Technical Briefing | September 2010 Safe quality medicines

1 WHO Technical Briefing | September 2010

Safe quality medicines

Medicines quality assurance:WHO normative functions in the field of pharmaceuticals

Sabine Kopp, PhD Quality Assurance and Safety: Medicines

Department of Medicines Policy and Standards


Main points addressed

WHO standard setting process WHO international guidelines,

standards and norms in the area of quality assurance

What's new ?


WHO does the work?

193 Member States Two governing bodies: - World Health Assembly

- Executive Board

WHO Secretariat: - Headquarters

- six Regional Offices and Country offices- WHO Expert Panels and Expert Committees(e.g... on the International Pharmacopoeia

and Pharmaceutical Preparations) Constitution 1946, in force since 7 April 1948(World Health Day)


How to become a "WHO Expert"?

Official nomination process Upon proposal to WHO in consultation with:

Member State/national government (citizenship)+ WHO Regional Office (in accordance with

Member State) + WHO Headquarters

Period of maximum 4 years Possibility to renew


What is the WHO Expert Committee?

Official Advisory Body to Director-General of WHO Governed though rules and procedures (Ref. WHO Manual) Participation in Expert Committee (EC) meetings:

Members ("Expert") selected from WHO Panel of Experts

Technical advisers Observers: - international organizations,

- NGOs, - professional associations…


Outcome of the WHO Expert Committee?

Report of the WHO Expert Committee:

- Summarizes discussion- Gives recommendations to WHO + Member States- Includes newly adopted guidelines; - Is presented to WHO Governing Bodies for final

comments, endorsement and implementation by Member States

constitutes WHO technical guidance


Examples of WHO Expert Committees ?

WHO Expert Committee on Specifications for Pharmaceutical Preparations

WHO Expert Committee on the Selection and Use of Essential Medicines

WHO Expert Committee on Drug Dependence WHO Expert Committee on Biological Standardization Joint FAO/WHO Expert Committee on Food Additives ….


When does the WHO Expert Committee start development of a guideline/guidance?

Based on recommendations by :

World Health Assembly resolutions (e.g. WHA 20.34, GMP - Good manufacturing practices)

Executive Board resolutions (e.g. EB37.R9 delegating certain functions of INN Programme to DG based on advice from Experts)

International Conference of Drug Regulatory Authorities (e.g. 10th +11th ICDRA – FDC guidelines + Certification Scheme for pharmaceutical starting materials moving into international commerce)

Other WHO programmes and clusters (e.g. necessity for quality control specifications for specific medicines of major public health interest)

Expert Committee (e.g. revision of general methods included in The International Pharmacopoeia)


How does the WHO consultation process work?

Step 1. Preliminary consultation and drafting Step 2. Draft guidelines Step 3. Circulation for comments Step 4. Revision process .......... (back to step 2 and 3 as often as needed) WHO Expert Committee (EC) meeting

if guideline adopted, published in EC report as Annex -> WHO Governing bodies -> Recommendation to Member States for implementation


WHO Partners

National and regional authorities International organizations (UNAIDS, UNFPA, UNICEF, World Bank,

WIPO, WTO, WCO, etc) International professional and other associations, NGOs (including

consumer associations, MSF, industry: IFPMA-IGPA- WSMI, FIP, WMA, etc)

WHO Expert Panels (official nomination process) Specialists from all areas, regulatory, university, industry……… WHO Collaborating Centres (official nomination process) Pharmacopoeia Commissions and Secretariats, national institutions

and institutes .. Regional and inter-regional groups (ICH…)


Why need for stringent standards for medicines?

"… drugs are a public good and not simply just another commodity: first for their high social value, and then because consumers and prescribers are unable to assess their quality, safety and efficacy" (Dr Gro Harlem Brundtland, former Director General of the World Health Organization)

medicines belong to one of the most regulated group of products


Medicines Quality Assurance in WHO

Historical overview

1874 Discussion on Unification of terminology and composition of drugs 1902 First Conference organized by Belgian Government 1906 Agreement on Unification of the Formulae of Potent Drugs ratified

by 19 states 1925 Brussels agreement (signed 1929)

League of Nations: “international pharmacopoeia”


Medicines Quality Assurance in WHO

Historical overview (2)

1937 First meeting (experts from B, DK, F, NL, CH, UK, USA) - League of Nations

1947 Interim Commission of WHO takes up health related work of League of Nations

1948 First World Health Assembly established Expert Committee on Unification of Pharmacopoeia


Quality of medicines remains a problem in many countries


Challenges: past and present…

Past: Manufacture direct from API -> finished product Manufacture of API in sites close to or same as product Experience and long-standing knowledge of

production, product and manufacture of parties involved

Few intermediates in sales chain Usually stable trade and sales connections


Challenges: past and present…

Present: Rationalization of drug production Contracting-out of many steps in manufacture Many intermediates in trade and sales chain Trade, shipping, long distances involved Increase of risks… Increase of requirements and documentation Increase of national control mechanisms


Global challenges …

National vs international requirements Number of requirements Application and interpretation of requirements Import vs export control on national level Quality assurance systems applied Knowledge of product by parties involved in

manufacture Cross-border promotion and sale - Internet Free trade zones


Global challenges…

Number of national and international inspections by same party

Number of inspections in same site by different parties Applicability of new technologies in different settings Contracts, agreements, eg Mutual Recognition Agreements Risks of mistakes, accidents, human errors etc Counterfeit drugs …...


WHO’s global guidelines and strategies

Requirements for drug registration and model legislation

Networking among and with regulatory authorities International alerts Counterfeit network Global norms and international standards and

nomenclature


INNs


WHO’s medicines quality assurance guidelines

Cover: Development Production Quality Control Quality related regulatory guidelines Inspection Distribution from manufacture (and before) to delivery to

patient


Adopted WHO guidance texts and guidelinesin medicines quality assurance (without PhInt)

Maintain to keep up to date:Total of :

56 CURRENT official WHO guidance texts and guidelines to date, including 7 (4 updates, 3 new, adopted 2009)


Quality Control

http://www.who.int/medicines/areas/quality_safety/quality_assurance/control/

12 guidance documents and guidelines, including - Good laboratory practices + training materials- Guidelines for establishment of chemical reference standards- Model certificate of analysis- International Pharmacopoeia + Basic tests


WHO’s global guidelines - quality control -

International specifications (Ph. Int., screening tests..) WHO Model Certificate of Analysis (COA) Considerations for requesting analysis of samples Quality control laboratories:

Good practices for national control labsList of equipmentExternal qc assessment scheme for labs


International PharmacopoeiaPh.Int.

current: 4th edition! Supplement 1, no 2 in prep. implementation: “ready for use” by Member States Scope since 1975:

Model List of Essential Medicines and Drugs recommended by WHO Specific disease

programmes, e.g. Malaria, TB, HIV/AIDS, medicines for children



External Quality Assessment Scheme for National Drug Quality Control Laboratories

Phase 5 (01/2010 - 12/2012)

- 60 laboratories participate- Studies: - Assay by titration: 1 April 2010 - Water content by Karl-Fischer: 1 September 2010 - Dissolution test: 1 February 2011 - Related substances by HPLC: 15 July 2011 - Related substances by TLC: 15 January 2012 - Assay by HPLC: 15 June 2012 - Dissolution test: 15 October 2012


Distribution

http://www.who.int/medicines/areas/quality_safety/quality_assurance/distribution

More than 9 guidance documents and guidelines, e.g.: - Certification schemes (CPP and SMACS)- Quality system for Procurement- Good distribution practices for starting materials and finished

products- Good storage practices


Production

- http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/

18 guidance documents and guidelines, including: - Good Manufacturing Practices (GMP)

…..Consisting of 12 major "guideline" texts (regularly updated, new texts added as needs are identified)

- ….. Training materials (slides, video, GMP text)- Risk analysis (HACCP)


WHO’s global guidelines -production

Good Manufacturing Practices (GMP) ….. 1. Main principles for pharmaceutical products

Requirement for the sampling of starting materials (amendment) Water for pharmaceutical use Heating, ventilation and air-conditioning (HVAC) systems Validation

2. … for starting materials, including Active pharmaceutical ingredients Pharmaceutical excipients


WHO’s global guidelines -production (2)

3. … for specific pharmaceutical products: Sterile pharmaceutical products Biological products (rev in progress) Investigational pharmaceutical products for clinical

trials in humans Herbal medicines Radiopharmaceuticals Blood establishments


Inspection

http://www.who.int/medicines/areas/quality_safety/quality_assurance/inspections/en/index.html

6 guidance documents and guidelines


WHO’s global guidelines - inspection

Inspection of….. pharmaceutical manufacturers drug distribution channels (products)

Guidelines for pre-approval inspection Quality systems requirements for national GMP

inspectorates Model GMP certificate Model report for inspections


Quality related regulatory standards

http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/

17 guidance documents and guidelines, including : - Stability testing requirements - Interchangeability of generic medicines- Fixed-dose combination- All prequalification procedures


WHO’s guidance on interchangeability of medicines

WHO guideline on registration requirements to established interchangeability for multisource pharmaceutical products (revised in 2006)

Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (under revision)


WHO’s guidance on interchangeability of medicines (2)

Proposal to waive in vivo bioequivalence requirements for the WHO model List of Essential Medicines (immediate release, solid dosage forms)

Guidelines for organizations performing in vivo bioequivalence studies


Related WHO’s guidances …

All guidelines for Prequalification of medicines, laboratories …..

Model Quality Assurance System for Assessment of Procurement Agencies Guideline for sampling of pharmaceuticals Guidelines for registration of fixed-dose combination medicinal products....


New WHO guidelines adopted during 45th Expert Committee held 18-22 October 2010

Good Pharmacy Practice (joint FIP/WHO, revised) Guidance for Pharmaceutical Microbiology

laboratories (new) Procedure for prequalification of laboratories

(revised) Preparing a Laboratory Information File (update) GMP: main principles (revised) GMP for blood establishments (jointly with ECBS) GMP for HVAC (revised)


New WHO guidelines adopted during 45th Expert Committee held 18-22 October 2010 (2)

GMP for sterile pharmaceutical products (revised) Guiding principles on transfer of technology (new) Guidelines for preparing a Site Master File (new) Model guidance for the storage and transport of

time- and temperature sensitive pharmaceutical products (new, jointly with ECBS)

Guidance on submission of documentation for prequalification of innovator FPPs approved by stringent regulatory authorities (new)


New WHO guidelines adopted during 45th Expert Committee held 18-22 October 2010 (3)

Procedure for prequalification of medicines (revised)

Guideline for submission of documentation for a multisource (generic) finished product (new)

Special guidance for artemisinin as a starting materials for production of antimalarials (subject to confirmation of impurity profile, new)

Definition of substandard medicines (new) Procedure for adoption of ICRS (revised)


New Specifications adopted during 45th Expert Committee held 18-22 October 2010 (3)

27 new specifications and general texts, including :

Antiretrovirals Anti-TB medicines Antimalarials Anti-infectives Paediatrics


What is in the QA pipeline?

Guidelines/guidance :Paediatrics development (new)Development of generics (new)Risk analysis (update)Guideline on submission of

documentation for a multisource (generic) product – quality part (new)


What is in the QA pipeline? - 2 -

Guidelines/guidance:

Update of Comparator List Update of stability requirements in Member States Advice to NMRAs on Diethylene glycol intoxication Tools and framework for monitoring of market

situation


Advantages of WHO's Expert Committee standard-setting process

1. Guidelines and specifications validated internationally, through an independent scientific process, adoption by members of WHO Expert Advisory Panels

2. Collaboration with standard-setting organizations and parties, including regional and national pharmacopoeias

3. Networking and close collaboration with WHO Member States, Drug Regulatory Authorities, national medicines quality control laboratories


Advantages of WHO's Expert Committee standard-setting process (2)

4. Links with other WHO activities

5. Reality check: Input from manufacturers (including international associations of research, generic and self-medication associations) around the world

6. Consideration of costs, e.g. keeping need for reference standards at a minimum

7. Service FREE FOR USE by all Member States


As health professionals, in public and private sector, as an international community...we have a lot left to do

…all of us, together, things that do matter,in right time and in right order!


WHO Medicines Quality Assurance website:

http://www.who.int/medicines/areas/quality_safety/quality_assurance

Documents

1 WH O Technical Briefing | September 2010 Safe quality medicines