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.

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

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.

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

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

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)

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)

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

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

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 e-mail to the applicant followed by surface mail

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

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

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

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

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

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

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

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

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

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

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

http://who.int/prequal/

Prequalified Priority Products (November 2008)

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

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 + 120 mg; tablet 40 mg + 240 mg tablet 60 mg + 360 mg; tablet 80 mg + 480 mg

Invitations to manufacturers to submit EOIs /2 2. Artemisinin-based fixed dose combination or co-blistered oral formulations - Artesunate + Amodiaquine, tablet 25mg + 76.5mg; 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

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

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

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

Prequalified Artemisinin based products 18 February 2009

ACT products under evaluation, February 2009 1 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

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

Quality control laboratories participating in WHO PQP (January 2009)

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

Topics of training workshops 2006-2008

Rotation positions at WHO PQP 2006-January 2009 (including ongoing stays) Zimbabwe 2 Uganda 2 Tanzania 2 Ethiopia 1 Kenya expected EAC: 57,1%

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

Technical assistances organized by WHO PQP 2006-2008

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.

Thank you for attention smidm@who.int