1. UN / WHO Prequalification Programme for Priority Medicines
Milan Smid, MD, PhD
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

2. UN Prequalification Programme for Priority Essential Medicines
Action plan of UN from 2001 for expanding access of priority medicines to patients with
HIV/AIDS
Malaria
Tuberculosis
Reproductive health
Influenza
Acute diarrhoea
Potentially other categories of products, if there is the need

3. Elements of Prequalification Programme
Objective:
To ensure quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID)
Components:
Evaluation of Quality, Safety and Efficacy of prioritised Essential medicines, inspections of manufacturers and monitoring of the products after their prequalification.
Prequalification of quality control laboratories.
Building capacity of regulators, manufacturers and quality control laboratories.

4. How prequalification is organized?
WHO manages and organizes the programme on behalf of the United Nations:
provides technical and scientific support to assessment, inspections (GMP, GCP, GLP) and quality control (GPCL)
involvement of qualified assessors and inspectors mostly from NRAs of ICH and associated countries and PIC/S inspectorates
guarantees that international norms and standards are applied all through the process
supports capacity of NRA in developing countries to evaluate, inspect and control the quality of medicines
involvement of qualified assessors and inspectors from NRAs in developing countries
by involvement of manufacturers from development countries into the project supports their capacity to produce according to international norms and standards

5. How prequalification is organized?
WHO PQT working in co-operation with partners
UNICEF
The Global Fund to Fight AIDS, Tuberculosis and Malaria
UN Population Fund (UNFPA)
UNAIDS
World Bank
Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department

6. Essential steps of PQ evaluation procedure
Need is specified and agreed by WHO treatment programmes
Invitation for Expression of interest (EOI) is published
Interested parties submit dossiers
Dossiers receive initial screening
Full dossiers are assessed
Inspections are conducted at manufacturing sites and at CROs
Samples are tested, if needed
If outcome is positive, pharmaceutical product is listed on the website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR)

7. Essential steps of monitoring of PQ product
Variations to the dossier of prequalified product
Sampling and Testing
Reinspections
Reevaluation
De-listing or suspension (if and when appropriate)

8. Standards
WHO standards as defined in WHO guidelines and International Pharmacopoeia are applied in prequalification process
If these not exist, ICH guidelines are applied
In case of need, guidelines of stringent regulatory authorities, which are involved in ICH process

9. World Health Organization
24 April, 2017
Steps in prequalification
Expression
of Interest
Product dossier
SMF
Assessment
Inspections
Additional information
and data
Corrective
actions
Compliance
Compliance
Prequalification
Maintenance and monitoring

10. 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 is sent first by to the applicant followed by surface mail

11. Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions)
In total 603 participations

12. Assessors participating in PQ assessment (all visits in 2001-2008, AFRO countries)
151 AFRO participations

13. 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

14. Co-inspectors to WHO PQ inspections (plan I-VIII 2009)

15. Prequalification assessment
Innovator products
Accepted, if approved by stringent authorities like US FDA and EMEA
Based on availability of assessment reports, WHO Certificate of Pharmaceutical Product (CPP), batch certificate
Continuous update on product changes after prequalification
Confidence in scientific expertise of well-established RAs

16. 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

17. Prequalification assessment
Multisource products
Assessment
Quality: information on starting materials and finished product, (API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc.)
Interchangeability with reference product (efficacy and safety): Report of bio-equivalence, biovaiwer or clinical study demonstrating interchangeability with reference product
Inspection of manufacturers and CROs
Laboratory analysis in case of need
Monitoring after prequalification

18. Prequalification assessment
Combined products, new dosage forms, new indications
Assessment
May require safety and efficacy data
Monitoring after prequalification

19. Outcomes of PQ procedure
Information in public domain (homepage)
Lists of PQ medicinal products
WHOPAR (SPC, PIL, labelling)
WHOPIR (both FPP and API)
Information on progress of assessment procedure and inspections
Supportive documents: WHO guidelines, description of PQ procedure

20. Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities
Benefits prevail the risks at a time of regulatory approval and nothing indicates that benefits will not prevail also during use of product in normal medical practice
Available data about quality (Dossier)
Available data about efficacy and safety or interchangeability (Dossier)
Available data are credible and were eticaly obtained
Good practices (GLP, GCP, GPhVP, …)
Existing reassurance about production in stable quality and quality assurance mechanisms
GMP
Way of use of medicine characterized for physicians and patients
Data sheets, SPCs, PILs, package labeling
Lack of knowledge is be properly manged
Pharmacovigilance, risk management programmes
Evaluations and inspections follow WHO and/or ICH standards

21. Difference between PQP and national approval procedures
Only certain categories of products are accepted
Voluntary - no direct legal implications
Free of charge (yet)
Assessment and inspections done by multinational teams
Assessment and inspection outcomes are publicly available, no negative conclusions and findings published (yet)
Issues of IPP fully in responsibility of applicant / manufacturer
Definitive negative conclusions exceptional
Technical assistance and regulatory support possible

23. Prequalified Priority Products (November 2008)

25. Countries, in which PQ products are manufactured (August 2008)

26. Invitations to manufacturers to submit EOIs /1
In August 2008 the 6st Invitation for submissions of antimalarial medicines was launched:
1.Artemisinin-based fixed dose oral combination formulations
- Artemether + Lumefantrine,
tablet 20 mg mg;
tablet 40 mg mg
tablet 60 mg mg;
tablet 80 mg mg

27. Invitations to manufacturers to submit EOIs /2
2. Artemisinin-based fixed dose combination or co-blistered oral formulations
- Artesunate + Amodiaquine,
tablet 25mg mg;
tablet 50mg + 153mg
tablet 100mg + 306mg
- Artesunate + Mefloquine,
tablet 25mg + 250mg;
tablet 50mg + 250mg
tablet 100mg + 250mg
- Artesunate + Sulfadoxine + Pyrimethamine,
tablet 25mg + 500mg + 25mg
tablet 50mg + 500mg + 25mg;
tablet 100mg + 500mg + 25mg

28. Invitations to manufacturers to submit EOIs /3
3. Artemisinin-based fixed dose combination or co-blistered oral paediatric formulations, preferably dispersible
- Artemether + Lumefantrine
- Artesunate + Amodiaquine
- Artesunate + Mefloquine
- Artesunate + Sulfadoxine + Pyrimethamine

29. Invitations to manufacturers to submit EOIs /4
4. Artemisinin-based single-ingredient formulations
- Artemether, oily injection 20 mg/ml; 40 mg/ml; 80 mg/ml
- Artesunate, powder for injection 60 mg (vial)
- Artesunate, suppositories 50 mg; 100 mg; 200 mg; 400 mg
- Artesunate, tablet* 25 mg; 50 mg; 100 mg

30. Invitations to manufacturers to submit EOIs /5
5. Other antimalarial medicines
- Amodiaquine, tablet 153 mg (or 200 mg as hydrochloride)
- Mefloquine, tablet 250 mg
- Sulfadoxine + Pyrimethamine, tablet 500 mg + 25 mg
____________
* Artesunate tablets to be used only in combination with either Amodiaquine, Mefloquine or Sulphadoxine + Pyrimethamine

31. Prequalified Artemisinin based products 18 February 2009

32. ACT products under evaluation, February 20091
Artemether
injection 2
Artemether + lumefantrin
oral powder 3
tablet 4
Artesunate
Powder 5
Injection 6
Artesunate +mefloquine
Tablet 7
Granule 8
Artesunate + amodiaquine 9
Artesunate + pyrimethamine + sulfadoxine

33. Prequalification of Quality Control Laboratories
Invitation for expression of interest issued by WHO
Laboratory Information File submitted by interested QCLs
If needed, technical assistance is provided
Inspection is organised
Currently 7 QCLs prequalified, 18 in process of prequalification (mostly from Africa)
More information PQP website

34. Quality control laboratories participating in WHO PQP (January 2009)

35. Contribution of PQ to capacity building
Organization of trainings
general and problem specific (HIV/AIDS, TB and antimalarial products, pediatric dosage forms, BE, BE/BCS, GMP)
Trainings of NRA staff and manufacturers frequently combined
Involvement of assessors from NRAs into PQ assessment
Involvement of inspectors from NRAs into PQ inspections
3 months rotations of experts from NRAs in WHO HQ – PQT

37. Topics of training workshops 2006-2008

39. Rotation positions at WHO PQP
2006-January (including ongoing stays)
Zimbabwe 2
Uganda 2
Tanzania 2
Ethiopia 1
Kenya expected
EAC: 57,1%

40. Technical Assistance Provision of expert consultants to
Manufacturers
Quality control laboratories
Regulators
Assistance focuses on
GMP, GCP or GLP compliance
Regulatory guidance
Assistance is separated from the assessment / inspections and may be followed by specific trainings

41. Technical assistances organized by WHO PQP 2006-2008

42. Conditions for provision of technical assistance
Manufacturers:
Participation in the prequalification programme,
Found to be capable and willing to improve
Location in a developing country
Products:
Inclusion in the list of expression of interest
High value for Public Health purpose
Poor representation on the Prequalification list.

43. Thank you for attention