World Health Organization Activities Focus on Prequalification of Medicines André van Zyl (M. Pharm, Ph.D, Ph. D) Head of Inspections Quality Assurance and Safety: Medicines (QSM), Department of Essential Medicines and Pharmaceutical Policies (EMP), Health Systems and Services (HSS) WHO, Geneva vanzyla@who.int

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Essential Medicines and Pharmaceutical Policies www.who.int/medicines Essential Medicines and Pharmaceutical Policies Medicines information, access, rational use, traditional medicine, INN, quality and safety (norms and standards including Pharm. Int. and….

Prequalification

Prequalification of Medicines Programme The UN Prequalification Programme is ensuring that medicines procured with international funds are of assessed and inspected quality, efficacy and safety. The Prequalification Programme is an IMPLEMENTEED action plan for expanding access to priority essential medicines in the following four areas: - HIV/AIDS - Tuberculosis - Malaria - Avian Flu - Reproductive Health A UN Prequalification Program of Quality Control Laboratories exists to facilitate the quality control of the prequalified products.

Medicines Prequalification Process Additional information Expression of Interest Product dossier SMF Assessment Inspections Additional information and data Corrective actions Compliance Compliance Prequalification Monitoring

Prequalification of Priority Essential Medicines Organisation (1) Assessment of the product dossier i.e. quality specifications, pharmaceutical development, stability, bioequivalence… Copenhagen assessment week 15 to 20 assessors during one week at least every two months Every dossier is assessed by at least four assessors including one senior assessor for the second assessment An assessment report is issued Letter summarizing the findings and asking for clarification and additional data if necessary; sent first by e-mail to the applicant followed by surface mail Variations - Done in house and during Copenhagen-week

Prequalification of Priority Essential Medicines Organisation (2) Inspections of manufacturers: - Finished Products (FPP) - Active Pharmaceutical Ingredient (API) and also - Contract Research Organizations (CRO, which carry out clinical/bioequivalence studies) Team of inspectors - WHO representative (qualified GMP inspector) - Inspector from well-established inspectorate - National inspectors invited to be part of the team but have no decision making power (different GMP standards, potential conflict of interest) -Inspector of potential target countries (and other countries in need for capacity building) as observer, for capacity building purpose.

2.2.2 Parma. development TB 4FDC tablets Products B A FPPs (packed products) Unpacked tablets (control) After 5 days at 40°C/75% RH After 5 days at 40°C/75% RH + Light S. Singh, Int. J. Tuberc. Lung. Dis., 7, 298 (2003) Quality of the products not known “bleeding”

Assessment What is required? 1. Details of the product 2. Regulatory situation in other countries 3. Active pharmaceutical ingredient (s) (API) 3.1 Properties of the active pharmaceutical ingredient(s) 3.2 Sites of manufacture 3.3 Route(s) of synthesis 3.4 Specifications API described in a pharmacopoeia: API not described in a pharmacopoeia: 3.5 Stability testing

Assessment What will be required (2)? 4. Finished product 4.1. Formulation 4.2. Sites of manufacture 4.4. Manufacturing procedure 4.5 Specifications for excipients 4.6 Specifications for the finished product 4.7 Container/closure system(s) and other packaging 4.8 Stability testing

Assessment What will be required (3)? 4.9 Container labelling 4.10 Product information 4.11 Patient information and package inserts 4.12 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) 4.13 Interchange-ability (bio-equivalence studies) 4.14 Summary of pharmacology, toxicology and efficacy of the product

Assessment Key numbers for 2008 40 products prequalified (21 in 2007) 92 dossiers submitted (90 in 2007) 732 assessment reports (463 in 2007) 52 inspections (45 in 2007) For each prequalified product there were: 5-15 assessment reports 1 or more inspections 2 years total time on average to get prequalified (the clock stops for PQ when request for additional information/corrective actions is sent to the applicant)

Product dossiers accepted for evaluation 2005 2006 2007 2008 HIV 67 42 25 42 TB 17 9 17 12 Malaria 3 5 7 9 R Health - - 10 4 87 56 59 67

Currently under evaluation in WHO Prequalification Programme As of 31 January 2009 : 68 products for treatment of HIV/AIDS and related diseases 41 products for treatment of tuberculosis 17 products for treatment of malaria 11 reproductive health products Total 137

Transparency – dossier status information on the web

Inspections… .What about inspections? .Why do inspections? …"We are already approved by FDA, TGA, MHRA…"

Quality issues…. Quality concerns - India 96 samples (chloroquine and antibacterials) collected in Nigeria and Thailand - >36% failed pharmacopoeia standards (Shakoor O et al, 1997) Delhi - 53 samples, 86% were substandard or counterfeit (Iyengar J. A, Asia Times. 2002) One out of four tablets sold in the market in UP reported as fake Singh RK. Bitter pill: one out of four drugs in UP is fake. (HT Nation. Mumbai. 2006) Quality concerns - China Strict control on compliance implemented and enforced 07/07: "former head was executed for accepting bribes to approve untested medicine" Little information available in public domain Fake artesunate: 38% ('01); 53% ('03) - in Myanmar 89% - Laos Wellcome trust: 22 of 27 locations (in 15 - only fakes) (Lancaster IM 2006)

Quality issues…. Poor quality has an impact on the patient Also a problem in industrialized countries 1999 to 2000, Schering Plough USA had to recall about 59 million metered dose asthma inhalers 17 children died - no active ingredient 2003, TGA (Australia) recalled products of Pan Pharmaceuticals Ltd 219 products (local market) and 1650 for exports recalled and cancelled 2007, Roche recalled all batches of ARV Viracept contamination with genotoxic substance

GMP issues…. GMP compliance – Majority of generic products world wide sourced from India Review of 30 inspection reports for GMP Focus on manufacturers for international supply Assessed against WHO GMP Period 2001 to 2004 Included the "top 45" group of companies

GMP issues…. GMP compliance – India Review of 30 inspection reports for GMP Focus on manufacturers for international supply Assessed against WHO GMP Period 2001 to 2004 Included the "45" group of companies

GMP issues…. Top 5 (all) Top 2 (major) First inspections - Number of non-compliances in each area Top 5 (all) Top 2 (major)

China India PICS WHO 20 Validation and Process validation 4. Qualification and validation 4.1 In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. (defined in Annex 15 – not included here) 4.2 The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan. 57 Validation of manufacturing processes included 4.3 Qualification and validation should establish and provide documentary evidence that: (a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ);

Inspections - statistics in 2008 vs 2007 A total of 52 inspections were carried out in 2008: (45 in 2007) 27 (26) FPP manufacturers 11 (6) active pharmaceutical ingredient (API) manufacturers 14 (13) contract research organizations (CROs) In 2008 three inspectors in-house (plus manager)

GMP issues... Deviations, changes In process controls Product quality review Contamination, cross contamination and mix ups Validation and qualification work was often incomplete Process validation lacking or unreliable results Qualification e.g. HVAC, water (not to current standards)

New York Times 2007

WHO Prequalification and Bio-equivalence studies Example Two of the ECGs shown to the inspectors, bearing different subject numbers and initials, were found to be identical. Other ECGs bearing different subject numbers and initials appear to have been recorded from a single subject. Out of 95 ECGs copied by the inspectors, 43 appear to have been recorded from the same and single subject during a single session E.g. Project XXX: screening, subjects #01, 02, 04, 06, 07, 08, 11, 14, 19, 22, 23, 24, 25; follow-up, subjects #02, 03, 04, 05, 06, 07, 08, 09, 10, 11, 12, 13, 15, 16, 19, 20, 21, 22, 24; E.g. Project YYY: screening, subjects #01, 02, 06, 07, 08, 09, 10, 11, 12, 19, 20. follow-up, subjects #01 to 07, 10, 12 to 16, 18, 19, 21, 23 to 27

WHO Prequalification and Bio-equivalence studies Authenticity of chromatograms and peak areas? Identical chromatograms with different identities Integration reports of identical chromatograms showed different peak areas, even though peak integration parameters were identical Identical chromatograms had different peak areas but the same area percent

WHO Prequalification and Bio-equivalence studies Examples Half of the CRFs "missing" Source data destroyed accidently by fire or "monsoon" Sponsor claims the data were kept by the CRO, and the CRO claims the data were kept by the sponsor All data and retention samples destroyed as the product "expired" – even though the submission is still under evaluation

Prequalification Programme: 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 Assessment and Inspection Report (WHOPAR and WHOPIR) reflects a positive outcomes 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 research organization.

Transparency – Inspection outcomes on the web

CRO inspection findings World Health Organization 18 September, 2018

Not only bad news or problems…

List of WHO Prequalified Medicinal Products Currently prequalifed products (31 January 2009): 164 for treatment of HIV/AIDS and related diseases 18 for treatment of tuberculosis (10 prequalified in 2007-08) 14 for treatment of malaria (9 prequalified in 2007-08) Total 196

Training activities in 2008 In Brazil, China, Ghana, India, Indonesia, Iran, Jordan, Morocco, Nicaragua, Pakistan, Tanzania … More than 500 participants - staff of regulatory authorities and pharmaceutical manufacturers Topics: Development of dossiers for submission Assessment of bioequivalence (interchangeability) of medicines Pharmaceutical Development of Paediatric Formulations GMP, Quality and Bioequivalence of malaria ATC products GMP, Quality and Bioequivalence of RHPs

QCL Prequalification trends

Sampling and testing projects in 2008 Quality survey of antimalarials (ACTs and sulfadoxine-pyrimethamine) Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Nigeria, Senegal, Tanzania, Uganda 936 samples collected and screened by Minilab, 299 selected for full testing in laboratory (testing ongoing) Assessment of quality of product information (Labelling and PIL) Quality monitoring of products funded by UNITAID Pilot phase (paediatric and second-line antiretrovirals) in cooperation with NDRAs in Kenya, Tanzania, Uganda, Zambia 378 samples collected and tested in laboratory (testing ongoing) Quality survey of anti-TB medicines in Eastern Europe Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan; Focused on Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin (360 samples planned)

Technical Assistance - Policy Criteria for the products in relation to which technical assistance is considered: Inclusion in the list of expression of interest High value for Public Health purposes Poor representation on the Prequalification list Manufacture has applied for PQ (exemptions can be made upon justified requests for technical assistance from regional offices) danger Criteria for the experts: Excellent qualifications and long standing experience in the area where expertise is required Absence of conflict of interest Total intellectual independence from the prequalification programme, no participation in inspections or assessments.

New PQ procedure for APIs in 2009 Until now - evaluation of API source and manufacturer mostly the responsibility of finished product manufacturer Not all NDRAs inspect API manufacturers, and seldom a full evaluation of API dossier Often - API source considered "confidential" information Oct 2008 WHO Expert Committee on Specifications for Pharmaceutical Preparations adopted PQ procedure for active pharmaceutical ingredients (APIs) New approach similar to CEP (EDQM) – assessment of API Master File and site inspection for GMP compliance (ICH Q7)

The purpose of the prequalification programme is to list medicinal products of good quality - that are safe and effective – in the interest of public health in resource-limited countries. The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy (quality submissions in demand) WHO wishes to gratefully acknowledge the assistance and help provided in 2008 by our many partners in and outside WHO, donors and many other individuals and organizations Especially grateful to the staff from National Drug Regulatory Authorities of: Australia, Austria, Brazil, Canada, China, Estonia, Ethiopia, France, Germany, Ghana, Hungary, Italy, Kenya, Netherlands, Poland, Singapore, South Africa, Spain, Sweden, Switzerland, Tanzania, Uganda, Ukraine, United Kingdom, and Zimbabwe …

Thank you for your attention