WHO Sampling and Testing Programmes Jitka Sabartova WHO Prequalification Programme: Priority Essential Medicines HSS/EMP/QSM Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, September

Sampling and testing for Quality Control Laboratories, Nairobi, September |2 | WHO Prequalification Programme monitoring of medicines quality Policy –To monitor quality of medicines procured by UN agencies/ prequalified products –To contribute to quality control of medicines, if requested by Member States –To contribute to capacity building by cooperation with NDRAs Sampling and testing projects –A tool for fulfilling the policy

Sampling and testing for Quality Control Laboratories, Nairobi, September |3 | Sampling and testing projects Conduct of projects Plan +updates P1 P2 P3 Actions Reports Inspections Assessment PhV Entry information Quality concerns, complaints/defects, signals, inspections PQ procedures …

Sampling and testing for Quality Control Laboratories, Nairobi, September |4 | Planning of projects Commitments Signals Evaluation, discussion with experts, if needed Draft plan Discussion with experts Plan Action needed? Conduct of projects NO YES Entry information Urgent action? End YES NO

Sampling and testing for Quality Control Laboratories, Nairobi, September |5 | Conduct of a project (1) Setting OBJECTIVES of the project Drafting protocol, its commenting and approval Selection of the testing laboratory/ies and sampling organizations Agreements, incl. financial arrangements Collection of samples Storage and dispatch of samples 1

Sampling and testing for Quality Control Laboratories, Nairobi, September |6 | Conduct of a project (2) Receipt and check-in of samples by the laboratory Testing of samples Monitoring of quality of labels and package inserts, if required Evaluation of reported data and discussion with involved parties Project report Actions 1 Conclusions and recommendations Laboratory report Report

Sampling and testing for Quality Control Laboratories, Nairobi, September |7 | Project protocol (1) Background information Objectives (limitations) Selection of countries and medicines –Procured volumes, existing regulation, stability of medicines Selection of sample collection sites – cooperation with NDRAs –Levels of distribution, regions, transport and storage conditions Instructions for sample collection - the more detailed the better –Definition of sample –Number of dosage units or multidose packages to be collected –Time period –Sample collection form (incl. monitoring storage conditions at collection sites) –Handling and storage of samples –Training of collectors

Sampling and testing for Quality Control Laboratories, Nairobi, September |8 | Project protocol (2) Selection of tests to be conducted –Closely related to the project objectives –In principle Appearance Identity and content of active ingredient/s, related substances Uniformity of dosage units, dissolution/disintegration, pH Sterility, bacterial endotoxins/ pyrogens Selection of specifications –If products from more manufacturers collected – pharmacopoeial specs easier, but it has to be taken into account when making conclusions –Differences in pharmacopoeial monographs to be considered Procaine Benzylpenicillin injection - PhInt spectrophotometry for total penicillins and titration for procain, no related substances; USP iodometric assay for antibiotics, no related substances; BP(Vet) HPLC for related substance and assay –Laboratory validated method

Sampling and testing for Quality Control Laboratories, Nairobi, September |9 | Project protocol (3) Content of the laboratory report Monitoring of quality of labels and package inserts –Evaluation of the compliance with the national requirements –Assessment of quality and completeness of essential information in package inserts Handling of results –Non-compliant results pre-discussed with the respective NDRA and manufacturer –All results provided to NDRAs involved in the project and discussed –Corrective actions recommended –Adoption of the relevant measures in the responsibility of the respective NDRA –Agreed outcomes and report from the project published

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality control laboratories used Importance of reliability WHO Prequalified laboratories used, if available If not, laboratories for which the evidence of reliability is available –European OMCL network –Inspection report

Sampling and testing for Quality Control Laboratories, Nairobi, September | WHO QCLs Prequalification Procedure (1) September 2009 Prequalified QCLs:  South Africa, RIIP+CENQAM (2005)  Algeria, LNCPP (2005)  South Africa, Adcock Ingram (2007)  Morocco, LNCM (2008)  Kenya, NQCL (2008)  India, Vimta Labs (2008)  France, CHMP (2008)  Vietnam, NIDQC (2008)  Kenya, MEDS (2009)  Singapore, HSA (2009)  Singapore, TÜV (2009)

Sampling and testing for Quality Control Laboratories, Nairobi, September | WHO QCLs Prequalification Procedure (2) September 2009

Sampling and testing for Quality Control Laboratories, Nairobi, September |

Sampling and testing for Quality Control Laboratories, Nairobi, September |

Sampling and testing for Quality Control Laboratories, Nairobi, September | WHO-PQ Capacity building Capacity building focuses on national QC laboratories Organization of trainings –Trainings in Quality Assurance, Quality Control and Ph.Int. (2007) Morocco, 44 participants from 16 Francophone countries (AFRO, EMRO), cooperation with EDQM and AFSSAPS Tanzania, 46 participants from 23 Anglophone countries (AFRO, EMRO, PAHO/AMRO) –Training on rational sampling and testing in quality control of medicines (2009) Nairobi, 48 participants from 22 countries (AFRO, EMRO, WPRO) –Participation in EDQM Quality Assurance training for OMCLs 2005, 5 participants from AFRO and EMRO; 2007, 12 participants from AFRO, EMRO and EURO Technical assistance provided to 8 national medicines QC laboratories –Focus on implementation of quality system and microbiological testing, inventory audits Organization of proficiency testing for national quality control laboratories –WHO External Quality Assurance Scheme - free of charge

Sampling and testing for Quality Control Laboratories, Nairobi, September | Survey of the quality of antiretroviral medicines circulating in selected African countries (1) Carried out in 2005, report published – 42 collection sites in 7 countries, cooperation with NDRAs –Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia 394 samples of monocomponent products and FDCs –didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine –lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine

Sampling and testing for Quality Control Laboratories, Nairobi, September | Survey of the quality of antiretroviral medicines circulating in selected African countries (2) Testing in Swissmedic –Ph.Int., USP, Indian Pharmacopoeia, validated in-house Swissmedic methods –Appearance, identity and content of active ingredient/s, related substances, uniformity of mass, dissolution/disintegration, pH Very low failure of 1.8%, no critical deficiencies –1 sample higher API content, 1 sample failed to disintegrate in 30', 2 samples lower dissolution Sampling limited to official procurement and treatment centres and capital cities Positive effect of common efforts of NDRAs, WHO and others involved in prequalification and purchase policies

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality monitoring of medicines funded by UNITAID (1) Strengthening quality control in close cooperation with NDRAs –Evaluation of the quality of medicines close to patients –Evaluation of compliance with national requirements for information on external and primary packaging and in package inserts –Capacity building of NDRAs by involving them in organization of the project Framework protocol supplemented by country specific sampling plans prepared by NDRAs Pilot phase –Paediatric and second line ARVs + co-trimoxazole –Kenya, Tanzania, Uganda and Zambia –Samples collected mostly in treatment centres, throughout regions –383 samples from 24 manufacturers –Majority of collected medicines registered in the country (for some information missing)

Sampling and testing for Quality Control Laboratories, Nairobi, September | No of countries No of manufacturers No of samplesProduct 3324Lamivudine - Oral solution/ Tablets 3234Nevirapine - Oral suspension/ Tablets 3224Stavudine - Capsules/ Powder for oral solution 3332Zidovudine - Capsules/ Tablets/ Oral Solution 128Lamivudine + Stavudine - Tablets 112Lamivudine + Zidovudine - Tablets 3358 Lamivudine + Stavudine + Nevirapine Dispersible tablets/ Tablets/ Tablets for oral suspension 3321Abacavir - Oral solution/ Tablets 1213 Didanosine - Dispersible tablet/ Enteric coated capsules/ Powder for oral solution 2224Efavirenz - Capsules/ Tablets 1110Tenofovir - Tablets 2229Emtricitabine + Tenofovir - Tablets 3134Lopinavir + Ritonavir - Tablets 41470Trimethoprim + Sulphamethoxazole - Oral suspension/ Tablets

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality monitoring of medicines funded by UNITAID (2) Pilot phase - testing –Testing in MHRA (UK), AFSSAPS (France), NICPBP (China) –Tests performed Appearance Identity Content of active ingredient/s Related substances Uniformity of mass Dissolution pH –Specifications

Sampling and testing for Quality Control Laboratories, Nairobi, September | SpecificationsProduct Ph.Int. Ph.Int., dissolution manufacturer Lamivudine - Oral solution/ Tablets USPNevirapine - Oral suspension/ Tablets Ph.Int., dissolution USP USP Stavudine - Capsules/ Powder for oral solution Ph.Int., dissolution USP Ph.Int. Zidovudine - Capsules/ Tablets/ Oral Solution Indian Ph.Lamivudine + Stavudine - Tablets Ph.Int., dissolution manufacturerLamivudine + Zidovudine - Tablets Indian Ph. Lamivudine + Stavudine + Nevirapine Dispersible tablets/ Tablets/ Tablets for oral suspension Ph.Int., dissolution manufacturerAbacavir - Oral solution/ Tablets Manufacturer Ph.Int., dissolution manufacturer Ph.Int. Didanosine - Enteric coated capsules/ Dispersible tablet/ Powder for oral solution Indian Ph.Efavirenz - Capsules/ Tablets ManufacturerTenofovir - Tablets ManufacturerEmtricitabine + Tenofovir - Tablets LaboratoryLopinavir + Ritonavir - Tablets USPTrimethoprim + Sulphamethoxazole - Oral suspension/ Tablets

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality monitoring of medicines funded by UNITAID (3) Pilot phase - results –Non-compliance 2 samples LAM+STA+NEV dispersible tablets collected in Zambia low stavudine content (83%) (4 samples from the same batch OK, complaint to the manufacturer) 1 sample Trimethoprim+Sulfamethoxazol collected in Kenya higher trimethoprim impurity –Problems solved All Didanosine dispersible tablets samples (2 manufacturers) additional peaks in related substances test, placebo requested from manufacturers  peaks due to excipients All Nevirapine oral suspension samples (2 manufacturers) additional peaks in related substances test, placebo requested from manufacturers  peaks due to excipients All LAM+STA+NEV tablets showed low nevirapine dissolution when tested according to Indian Ph. Conditions, dissolution method requested from both manufacturers  compliant results –Majority of collected medicines WHO prequalified

Sampling and testing for Quality Control Laboratories, Nairobi, September | WHO Prequalified priority essential medicines (September 2009)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Countries where WHO prequalified medicines are manufactured (July 2009)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antimalarial medicines in selected African countries (1) ACTs ( most sold and recommended by national guidelines), sulfadoxine- pyrimethamine, oral dosage forms –Artemether/lumefantrine, artesunate/amodiaquine (both co-blistered and FDCs), sulfadoxine/pyrimethamine, sulfamethoxypyrazine/pyrimethamine Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania Collection of samples –At all levels of distribution chain (private and public) and informal market, throughout the countries –In cooperation of NDRAs with WHO country offices –936 samples collected Testing –Screening of all collected samples by Minilab –305 samples then tested in RIIP, South Africa (296 samples) and USP laboratory, USA (9 samples)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antimalarial medicines in selected African countries (2)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antimalarial medicines in selected African countries (3) No of manufacturers No of samples tested No of manufacturers No of samples tested No of manufacturers No of samples tested Artesunate + Amodiaquine FDC Artesunate + Amodiaquine co-blistered Artemether / Lumefantrine Cameroon Ethiopia Ghana Kenya Nigeria Tanzania

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antimalarial medicines in selected African countries (4) No of manufacturersNo of samplesNo of manufacturers No of samples Sulfamethoxypyrazine / PyrimethamineSulfadoxine / Pyrimethamine 00716Cameroon 00525Ethiopia Ghana 11519Kenya Nigeria 47323Tanzania

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antimalarial medicines in selected African countries (5) Tests performed –Appearance –Identity and content of active ingredient/s –Artemether related substances –Uniformity of mass, dissolution, pH Specifications Results are currently evaluated Assessment of quality of product information (Labelling and PIL) Ph.Int., dissolution manufacturer Artemether / Lumefantrine - Tablets Artesunate - Ph.Int., dissolution laboratory Amodiaquine - USP Artesunate + Amodiaquine - Co-blistered tablets Laboratory Artesunate / Amodiaquine - FDC tablets USP Sulfadoxine / Pyrimethamine - Tablets Manufacturer Sulfamethoxypyrazine / Pyrimethamine - Tablets

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antituberculosis medicines (1) First- and second-line anti-TB medicines to be collected close to patients –Rifampicin capsules, Isoniazid tablets and injection, Rifampicin/Isoniazid tablets –Kanamycin powder for injection, Ofloxacin tablets and solution for infusion Eastern Europe and NIS –Countries with high multidrug-resistant TB and extensively drug-resistant TB –Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan Close cooperation with NDRAs and WHO EURO regional office 360 samples planned to be collected Testing –OMCLs of Austria and Luxembourg, in EDQM, SGS (Belgium) –Comparative dissolution study of Rifampicin capsules and Rifampicin/Isoniazid tablets at Goethe University, Germany (both conditions from Ph.Int. and USP)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Quality survey of antituberculosis medicines (2) Tests performed –Appearance –Identity and content of active ingredient/s –Related substances (for rifampicin and ofloxacin only) –For tablets and capsules uniformity of mass, dissolution –For parenteral products volume in container, pH, sterility, bacterial endotoxins (for infusion only) Specifications SpecificationProduct USP Isoniazid - Tablets Injection Ph.Int.Rifampicin - Capsules Ph.Int. Isoniazid / Rifampicin - Tablets USPKanamycin - Powder for injection USP USP monograph for tablets Ofloxacin - Tablets / Capsules Solution for infusion

Sampling and testing for Quality Control Laboratories, Nairobi, September | Specific quality monitoring projects Comparative dissolution study of Coartem tablets (2007) –Artemether / lumefantrine innovator - problems with dissolution reported –5 batches manufactured in different manufacturing sites and collected in Tanzania, tested in RIIP, South Africa –Dissolution profiles compared to the mean of all data  SIMILAR Generic products containing nelfinavir (2007) –Triggered by Roche worldwide withdrawal of Viracept –Test on EMS/MMS impurity using Roche method –Samples of finished product from Cipla, Hetero, GPO Thailand and of API from Matrix, Hetero collected from manufacturers, as well as from markets, tested in Swissmedic –All samples ≤ 0.5 ppm –For the purposes of Ph.Int. monograph dissolution tested

Sampling and testing for Quality Control Laboratories, Nairobi, September | Testing on request from countries/UN agencies Artesunate+Amodiaquine tablets (co-blistered), Guilin Pharmaceuticals, China – request from NGO in Indonesia Diethylcarbamazine citrate tablets, Asian Pharmaceutical Company, Nepal – request from Ministry of Health in Nepal Praziquantel tablets, Merck, Mexico – cooperation with WHO procurement and Neglected Tropical Diseases - Schistosomiasis control project Artesunate tablets, Guilin Pharmaceuticals, China – request from WPRO Miltefosin capsules, Popular Pharmaceuticals, Bangladesh - request from Ministry of Health in Bangladesh Rifampicin capsules and Clofazimine capsules, Sandoz, India - cooperation with WHO procurement and Neglected Tropical Diseases – Leprosis elimination project

Sampling and testing for Quality Control Laboratories, Nairobi, September | Thanks for your attention