Survey of the quality of antiretroviral medicines circulating in selected African countries

Publication date: 2007

World Health Organization 2007 All rights reserved. The document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of WHO. The document should not be displayed on any website. Please send any request for permission to: Prequalification Programme, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mail: prequal@who.int. The designations employed and the presentation of the material in the document do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. 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Acknowledgements This report is a result of the study carried out by the World Health Organization (WHO) in cooperation with the National Drug Regulatory Authorities of Cameroon, the Democratic Republic of Congo, Kenya, Nigeria, United Republic of Tanzania, Uganda and Zambia. WHO would like to thank these National Drug Regulatory Authorities for their cooperation and assistance. Medicines National Professional Officers and HIV/AIDS National Professional Officers from the WHO country offices worked together with senior inspectors from National Drug Regulatory Authorities to collect samples. Special acknowledgements go to the country teams, led by the following persons: Dr David Singhe, Head of Technical Division, National Quality Control Laboratory, Cameroon Ms Thérèse Tshitende, Chief of Division, Department of Pharmacy, Democratic Republic of Congo Dr Nicholas Mwaura, Deputy Director, National Quality Control Laboratory, Kenya Mrs Ngozi Uzoamaka Onuorah, Deputy Director Ports Inspection, National Agency for Food and Drug Administration and Control, Nigeria Mr Youze G. W. Mlavwasi, Pharmacist in charge, Muhimbili National Hospital, United Republic of Tanzania Mr Deus Mubangizi, Chief Inspector of Drugs, National Drug Authority, Uganda Ms Esnat Mwape, Director General, Pharmaceutical Regulatory Authority, Zambia Mrs Helen Tata (WHO Department of Technical Cooperation for Essential Drugs and Traditional Medicine - TCM) developed and coordinated the survey sampling and Mrs Seija Hannula (WHO Department of Medicines Policies and Standards - PSM) coordinated testing of the collected samples with the Official Medicines Control Laboratory of Swissmedic, Berne, Switzerland, which carried out the laboratory tests. Special thanks are due to Dr Lembit Rägo, Dr Sabine Kopp and Mr Eshetu Wondemagegnehu (WHO Department of Medicines Policies and Standards - PSM) for support from the WHO Team of Quality Assurance and Safety: Medicines - QSM, Dr Gilles Forte (WHO Department of Technical Cooperation for Essential Drugs and Traditional Medicine) for support from the WHO Team of Medicines Policy and Supply Management - MPM and to Dr Jean-Marie Trapsida (WHO/AFRO) for support from the WHO Regional Office for Africa. Mr Paul Sidhu from Australia prepared the initial draft report and Mrs Monika Zweygarth finalized the report and provided editorial services. The contribution of the following people who reviewed and commented on the drafts of the report is gratefully acknowledged: Dr Theo Dekker, Dr Janos Pogany, Dr Adriaan van Zyl and Dr Jitka Sabartova (WHO Department of Medicines Policies and Standards - PSM). Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) i CONTENTS Abbreviations. ii Summary. iii 1. Background. 1 2. Methodology . 3 2.1 Participating countries and study period . 3 2.2 Selection of sample collection sites. 3 2.3 Antiretroviral products surveyed. 4 2.4 Sample collection . 4 2.5 Testing laboratory. 5 2.6 Tests conducted . 5 2.7 Test methods. 5 2.8 Specifications . 6 2.8.1 Appearance. 6 2.8.2 Labelling . 6 2.8.3 Identity . 6 2.8.4 Disintegration. 6 2.8.5 Dissolution . 7 2.8.6 Content of active ingredient . 7 2.8.7 pH. 7 2.8.8 Related substances. 7 2.8.9 Uniformity of mass. 8 2.9 Conformity of samples with standards . 8 3. Results . 9 3.1 Overview of samples tested. 9 3.2 Compliance with quality standards . 13 3.2.1 Appearance. 13 3.2.2 Labelling . 13 3.2.3 Disintegration. 14 3.2.4 Dissolution . 14 3.2.5 Content of active ingredient . 15 3.2.6 Impurities (related substances). 17 3.2.7 Uniformity of mass. 17 3.2.8 Samples from identical batches. 18 3.3 Summary of quality failures . 18 4. Discussion. 19 5. Conclusion and recommendations. 21 6. References . 22 Appendix 1: Test results . 23 Appendix 2: Batches with multiple samples tested . 51 Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) ii Abbreviations AIDS Acquired Immune Deficiency Syndrome AFRO WHO Regional Office for Africa API Active pharmaceutical ingredient ART Antiretroviral therapy ARV Antiretroviral BP British Pharmacopoeia DRA Drug regulatory authority DRC Democratic Republic of Congo FDC Fixed-dose combination FPP Finished pharmaceutical product GMP Good Manufacturing Practice HIV Human Immunodeficiency Virus INN International Nonproprietary Names for pharmaceutical substances IP Indian Pharmacopoeia NGO Nongovernmental Organization NPO National Professional Officer OMCL Official Medicines Control Laboratory Ph.Eur. European Pharmacopoeia Ph.Int. The International Pharmacopoeia RSD Relative standard deviation USP United States Pharmacopeia WHO World Health Organization Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) iii Summary Background Provision of antiretroviral therapy has expanded in Sub-Saharan Africa and quality assurance of antiretrovirals is of crucial importance for the success of treatment programmes. Therefore WHO, in co-operation with national authorities, organized a quality survey of antiretrovirals in selected African countries. Methods The survey was performed in Cameroon, the Democratic Republic of Congo, Kenya, Nigeria, United Republic of Tanzania, Uganda and Zambia. Country teams made up of WHO country officers and national authority representatives collected samples at public and private sector antiretroviral procurement organizations and treatment centres around the capital cities. Samples included monocomponent products of didanosine, efavirenz, lamivudine, nevirapine, stavudine and zidovudine, and fixed-dose combinations of lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine. All samples were tested by the Official Medicines Control Laboratory of Switzerland, Swissmedic, for appearance, labelling, identity, related substances, and content of each active ingredient. In addition, capsules and tablets were tested for uniformity of mass and either dissolution or disintegration; oral solutions were tested for pH if appropriate. Methods of the International Pharmacopoeia, United States Pharmacopoeia, Indian Pharmacopoeia or manufacturers’ methods with method transfer were used as appropriate. Sampling and testing were carried out over a period of six months from 13 June to 15 December 2005. Findings None of the antiretrovirals sampled had any critical quality deficiencies which would pose a serious risk to patients. In 394 samples collected, the overall failure rate was 1.8%. One sample contained a broken tablet and tablets with chipped coating. Two samples were insufficiently labelled on the immediate packaging. The content of active ingredient of one sample exceeded the upper limit. One of 163 samples tested for disintegration failed to disintegrate completely within 30 minutes, and two of 153 samples tested for dissolution showed lower results than required. Fifty-three percent of sampled products were WHO-prequalified. Information on registration by National Drug Regulatory Authorities was available for 285 products; of these, 84% were registered. Products not registered at the time of sampling were found in three countries, mostly at private sector facilities, and constituted 12% of the total of 394 sampled products. Conclusions The generally good quality and safety of products sampled indicate the positive effect of common efforts of National Drug Regulatory Authorities, WHO and other organizations involved in prequalification and purchase policies. Market control was still incomplete in at least three countries. Since the survey was limited to official distribution points and treatment centres around the capital cities, these results cannot be generalized to the entire territories of the countries surveyed. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 1 1. Background In 2006, almost two thirds of all persons infected with HIV were living in Sub-Saharan Africa 1 . Provision of antiretroviral treatment in Sub-Saharan Africa increased tenfold between December 2003 and June 2006, with significant national scale-up efforts in Botswana, Kenya, Namibia, Malawi, Rwanda, South Africa, Uganda and Zambia 1 . Antiretroviral treatment (ART) is provided by both public and private sector facilities. Although public facilities increasingly deliver free or subsidized ART, the engagement of NGOs, health care provided by international and national corporations, faith-based organizations, individual medical providers and pharmacies will continue to be critical in a number of national settings 2 . Of 16 faith-based non-governmental drug supply organizations in Africa surveyed by WHO in 2003, twelve distributed HIV diagnostic tests, four also distributed antiretrovirals 3 . Many issues in the delivery of antiretroviral treatment in resource-poor settings have been identified, including the selection of beneficiaries, strengthening of health systems, clinical management, demand and adherence, community involvement, financing, and monitoring and evaluation 4 . However, the first requirement for any treatment programme is the availability of antiretrovirals of acceptable quality, safety and efficacy. Quality assurance of antiretrovirals is of crucial importance for the success of treatment programmes. Antiretrovirals manufactured below established standards of quality can lead to therapeutic failure, development of drug resistance and toxic or adverse reactions. The HI virus develops resistance readily, and resistant strains can be transmitted, making sub-standard medicines a public health problem 5 . The problem of sub-standard and counterfeit medicines in developing countries is well documented. A survey on the quality of antimalarials in eight African countries found failure rates at all levels of the distribution chain, including public-sector hospitals and medical stores, with content failure rates ranging from 20-67% for chloroquine tablets and dissolution failure rates of 75-100% for sulfadoxine/pyrimethamine tablets 6 . In quality tests for a mixed sample of tracer medicines in six countries, including Tanzania and Ghana, failure rates above 10% were common, and studies in ten countries found great variation in compliance with Good Manufacturing Practices 7 . Counterfeiting is particularly prevalent where regulatory and legal oversight is weak, where prices of medicines are high, where price differentials between identical products exist, and where the official supply chain fails to reach some communities, especially in rural areas 8 . All these criteria apply to antiretrovirals in Africa. Only 23% of the people in need of ART in sub-Saharan Africa had access to it at the end of 2006 1 . Differential pricing is in place for antiretrovirals, with discounts being offered to eligible countries and organizations 9 . Regulatory capacity is often inadequate: in a WHO survey of regulatory authorities in 38 African countries, 63% stated that they were unable to evaluate the quality, efficacy and safety of new medicines for lack of resources, and about half did not carry out medicines inspections 10 . Laboratories are not adequately equipped to do quality analysis of ARVs, especially of new multi-source products 11 . In November 2003, the WHO issued an alert about the availability of a counterfeit version of a triple antiretroviral combination product, Ginovir 3D, in Côte d'Ivoire. The label stated that the product was manufactured by Selchi Pharmaceuticals, Namibia, and contained zidovudine (200mg), lamivudine (150mg), and indinavir (40mg) per capsule. The recommended dosage of indinavir is 800mg/day, boosted with 100mg ritonavir 12 . Analysis by the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) upon request from the Association of AIDS Patients (AIDES) showed that the samples contained zidovudine 201mg, stavudine 40mg, and an unidentified substance 13 . Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 2 A literature survey on drug quality in USAID-assisted countries from 2001 to 2007, including 16 African countries 14 , contains a reference to this incident, and to other reports on counterfeit or substandard antiretrovirals in the Democratic Republic of Congo, Ethiopia, Kenya, Uganda , and Zimbabwe. Most of these reports relate to antiretrovirals circulating in the informal market. The WHO alert on a counterfeit ARV in Côte d’Ivoire raised concerns from various member states on the quality of medicines circulating in the WHO African region. During the 54 th session of the WHO Regional Committee for Africa, held in Brazzaville from 30 August to 3 September 2004, delegates from countries echoed this concern. To facilitate global access to medicines of acceptable quality, the WHO prequalification programme evaluates pharmaceutical products according to WHO-recommended standards of safety, efficacy and quality, and compliance with good manufacturing practices and good clinical practices (GCP). It prequalifies medicines which are acceptable, in principle, for procurement by UN procurement agencies 15 . In 2004, WHO started its programme to prequalify quality control laboratories for the analysis of HIV-, malaria- and tuberculosis-related products in Africa. Three laboratories were prequalified as at January 2007 16 , two in South Africa and one in Algeria. The implementation of a harmonized quality assurance system by procurement agencies will be a further step towards assuring the quality, safety and efficacy of medicines. Although prequalification is an invaluable tool for procurement of quality antiretrovirals, the process does not guarantee the quality of the products procured from the suppliers listed. Neither does the absence of a product from the list mean that it is sub-standard. Ongoing quality control of antiretrovirals remains essential at all stages of the supply cycle. Aim of this study The aim of this project was to assess the quality of antiretroviral medicines obtained at accredited public and private sector antiretroviral procurement and treatment sites in selected African countries, using a variety of assessment methods. The following questions were addressed: • What proportion of antiretroviral samples collected at approved procurement and treatment centres fails quality testing? • Are any of the deficiencies critical, i.e. could they affect treatment efficiency and/or cause harm to the patient? • Which specific quality tests do the samples fail, if any? The results of this study are expected to assist responsible authorities in the countries surveyed to develop appropriate quality assurance strategies for antiretrovirals. They also provide information for WHO to adapt its prequalification procedures. Finally, they will be of use in awareness and advocacy programmes on quality issues in antiretroviral treatment in general. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 3 2. Methodology 2.1 Participating countries and study period The survey was performed in Cameroon, the Democratic Republic of Congo, Kenya, Nigeria, United Republic of Tanzania, Uganda and Zambia. Sampling and testing were carried out over a period of six months from 13 June to 15 December 2005. A follow-up survey will consider other countries including Chad, Ethiopia, Mali, Rwanda and Senegal. 2.2 Selection of sample collection sites The survey was undertaken in and around the capital city of each country. Four separate lists of public and private sector antiretroviral procurement organizations and treatment centres were prepared. Only officially approved treatment centres were considered. Sites were selected from the lists, aiming at the following composition of sites in each country: a) Two public-sector antiretroviral treatment centres b) Two private-sector antiretroviral treatment centres c) One public-sector antiretroviral procurement centre d) One private-sector antiretroviral procurement centre or distribution outlet Sample collection sites were selected from the lists in such a manner to cover both urban and sub-urban areas of the capital city, and a variety of facilities at different levels of the health care system, including procurement centres, hospitals, health centres and pharmacies. The above target composition of sample collection sites was modified in a number of countries, depending on the presence of each type of site on the lists, and the availability of antiretrovirals at the sites. A total of 42 collection sites were included in the final selection. The types of collection sites selected in each country are listed below. • Nigeria – 7 sites: one public-sector State procurement centre, one private-sector procurement company, two manufacturers, one importer/wholesaler of pharmaceuticals, one public-sector national research institute and one public-sector teaching hospital • Cameroon – 2 sites: two public-sector procurement centres • Uganda – 6 sites: one public-sector procurement centre (national medical stores), one private-sector pharmacy, two public-sector treatment centres and two private treatment centres (one hospital, one clinic) • United Republic of Tanzania – 6 sites: one public-sector procurement centre, one private-sector procurement centre, one public-sector hospital, one public-sector cancer institute, one private-sector hospital and one private-sector maternity home Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 4 • Democratic Republic of Congo – 6 sites: One private-sector local manufacturer, one private-sector procurement centre, one private-sector distribution centre, two public-sector hospitals and one private-sector hospital • Zambia – 8 sites: Five pharmaceutical companies (wholesalers/importers), one university teaching hospital and two public-sector treatment centres • Kenya – 7 sites: One public-sector procurement agency, one faith-based NGO procurement agency, two public-sector hospitals (one tertiary hospital, one district hospital) and two private-sector hospitals 2.3 Antiretroviral products surveyed Finished dosage forms of capsules, tablets and oral solutions or suspensions containing the following active ingredients were included in the survey: Monocomponent products: • didanosine • efavirenz • lamivudine • nevirapine • stavudine • zidovudine Fixed-dose combinations (FDCs): • lamivudine/zidovudine • stavudine/lamivudine • stavudine/lamivudine/nevirapine A total of 394 samples were collected and analysed. Of these, 209 were WHO- prequalified products. More details are shown in Chapter 3. 2.4 Sample collection In each country, a team made up of the Medicines National Professional Officer (NPO), HIV/AIDS-NPO and a senior inspector from the National Drug Regulatory Authority was established to manage the project and collect samples. Where there was no NPO, preferably, the chief analyst of the Drug Quality Control Laboratory joined the team. If there was no analyst, then the head of Drug Registration or an inspector from the drug regulatory authority was invited to join the team. A Sample Information Collection Form was designed for this survey. The team completed one Sample Information Collection Form for each sample collected. The following details were recorded: Commercial name/brand/trade name, name of active ingredient(s), dosage form, strength per unit dose, packaging material of primary container and description of secondary container, quantity collected, description of the product, date of manufacture, batch number, expiry date, name and country of manufacturer, registration status and country, site and date of sample collection. These details were considered essential not only for final data analysis, but also to identify each sample. Each sample was given a unique code number, prefixed by the country code as assigned by AFRO. This code number was also marked on the sample pack with indelible ink. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 5 Each Sample Information Collection Form was signed by all the team members. 2.5 Testing laboratory All samples were sent to the Official Medicines Control Laboratory (OMCL) of Switzerland, Swissmedic, for testing. Each sample was assigned an OMCL number. 2.6 Tests conducted Depending upon the formulation, each sample was tested for the following: • Appearance • Labelling • Identity • Uniformity of mass (capsules/tablets) • Dissolution if appropriate, otherwise disintegration (capsules/tablets) • pH if appropriate, depending upon the matrix (oral solutions) • Related substances • Content of each active ingredient Uniformity of content was only tested in one case to confirm other results. 2.7 Test methods Appearance, uniformity of mass and disintegration were tested using procedures of the International Pharmacopoeia 17 . Dissolution tests were performed using either the methods specified in USP monographs or manufacturers’ methods with method transfer. Related substances and content of each active ingredient were tested according to the following methods, depending on the prequalification status of the products: • For WHO-pre-qualified products, validated in-house Swissmedic methods as described for comparable product compositions were used if available. If not, manufacturers’ methods were used. For combination products containing stavudine/ lamivudine/nevirapine without documented manufacturer’s methods, Swissmedic methods for the corresponding monocomponent products were used. • For products not prequalified by WHO with unknown compositions, the use of official Ph.Int., BP, USP or IP methods (in this order) was preferred. If no official method existed for a product, Swissmedic methods with appropriate method validation and transfer were used. All methods used were subjected to appropriate method transfer procedures and were verified before use. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 6 2.8 Specifications The following specifications were used for the different tests. 2.8.1 Appearance Tablets should be undamaged, smooth, and usually of uniform colour. Capsules should be smooth and undamaged. Oral solutions should be clear with no visible particulate matter. Suspensions should be homogenous on shaking. 2.8.2 Labelling Each label on the immediate container was checked for the following information: (1) The name of the pharmaceutical product (2) The name(s) of the active ingredient(s); INNs (International Nonproprietary Names) should be used wherever possible (3) The amount of the active ingredient(s) in each tablet/capsule and the number of tablets/capsules in the container (4) The batch (lot) number assigned by the manufacturer (5) The expiry date (6) Any special storage conditions or handling precautions that may be necessary (7) Directions for use, warnings, and precautions that may be necessary (8) The name and address of the manufacturer or the sponsor responsible for placing the product on the market 2.8.3 Identity Identity was confirmed by matching the retention time of active peak in the standard and sample HPLC chromatograms obtained in the assay. 2.8.4 Disintegration Acceptable time for complete disintegration was specified as follows: Uncoated tablets ≤ 15 minutes Film-coated tablets ≤ 30 minutes Capsules ≤ 30 minutes Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 7 2.8.5 Dissolution The USP method 18 was used for dissolution tests. According to this method, dissolution is tested in three stages, with the following acceptance criteria: Stage Number of units tested Acceptance Criteria S1 6 units Each unit is not less than Q* + 5% S2 Another 6 units Average of 12 units (S1 + S2) is equal to or greater than Q, and no unit is less than Q − 15% S3 Another 12 units Average of 24 units (S1 + S2 + S3) is equal to or greater than Q, and not more than 2 units are less than Q − 15%, and no unit is less than Q − 25% * Q is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the content stated on the label. The testing is continued through the three stages unless the results conform at either stage 1 or stage 2. Specifications applied in terms of Q values and testing time limits are shown above the tables of test results in Appendix 1 where applicable. 2.8.6 Content of active ingredient The limits for content of the active ingredient(s) applied to the individual products are shown above each table of results in Appendix 1. The limits vary, depending on the source of the specifications. The pharmacopoeial limits are typically 90.0-110.0%, but manufacturer’s limits may be narrower, e.g. 95.0-105.0%. Non-symmetric limits, like 92.5-105.0%, indicate that the active ingredient is prone to degradation during storage of the product. 2.8.7 pH Acceptable ranges of pH of oral solutions, where tested, are shown above the respective tables in Appendix 1. 2.8.8 Related substances Related substances are impurities arising in pharmaceutical products during synthesis of the active ingredient or as a result of degradation. Specifications for testing of related substances applied to the individual products are shown above each table of results in Appendix 1. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 8 2.8.9 Uniformity of mass Specifications of the International Pharmacopoeia 17 as shown below were applied. Pharmaceutical form Average mass Acceptable deviation in % Number of units (of 20 units tested) less than 80 mg ± 10.0 minimum 18 ± 20.0 maximum 2 80 mg to 250 mg ± 7.5 minimum 18 ± 15.0 maximum 2 more than 250 mg ± 5.0 minimum 18 Tablets (uncoated and film-coated) ± 10.0 maximum 2 less than 300 mg ± 10.0 minimum 18 ± 20.0 maximum 2 300mg or over ± 7.5 minimum 18 Capsules ± 15.0 maximum 2 2.9 Conformity of samples with standards The samples were considered to be in conformity with standards if they met the specifications as set out in Section 2.8 above and/or listed above each table of results in Appendix 1. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 9 3. Results A total of 394 samples from 42 sample collection sites in seven African countries were collected and tested. Details and test results of the samples are listed in Appendix 1, grouped by active ingredients and specifications used. Samples in each table are sorted in ascending order of OMCL numbers, reflecting the sequence in which samples from the seven countries were received and tested at the laboratory. An overview of the samples tested is given in Section 3.1 below. The main findings of the different quality tests are summarized in Section 3.2. OMCL numbers are used to refer to samples in the text. 3.1 Overview of samples tested The samples collected in each country are listed in Table 1 according to the APIs contained. Table 1: Numbers of samples of FPPs/FDCs collected in each country Active ingredient(s) Number of samples Total Cameroon DRC Kenya Nigeria Tanzania Uganda Zambia didanosine - - - - - - 1 1 efavirenz 9 3 13 3 7 5 6 46 lamivudine 5 7 14 15 15 6 4 66 nevirapine 8 21 14 15 7 7 72 stavudine 3 5 18 10 12 5 7 60 zidovudine 4 7 5 7 9 4 8 44 lamivudine / zidovudine 5 4 6 4 8 6 4 37 stavudine / lamivudine - - 14 - - - 2 16 stavudine / lamivudine / nevirapine 8 7 18 1 6 4 8 52 Total 34 41 109 54 72 37 47 394 The registration status of the sampled products in each country except Kenya was recorded on the Sample Collection Forms. All samples collected in Cameroon, Tanzania and Uganda were registered in these countries. A more complex situation was found in DRC, Nigeria and Zambia. Tables 2 - 4 show the numbers of registered and non-registered samples in these three countries differentiated according to active ingredients and sites of sample collection. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 10 Table 2: Registration status of products sampled in DRC DRC Registered Not registered Active ingredient(s) Number of samples Manu- facturer Private procure- ment Private hospital Public hospital Manu- facturer Private procure- ment Private hospital Public hospital didanosine - - - - - - - - efavirenz 3 - - - 1 - 1 1 - lamivudine 7 - 2 - 1 1 1 2 - nevirapine 8 - 3 - 3 - - 2 - stavudine 5 - 1 - 2 1 - 1 - zidovudine 7 - 4 - 1 - 1 1 - lamivudine / zidovudine 4 - 2 1 1 - - - - stavudine / lamivudine - - - - - - - - - stavudine / lamivudine / nevirapine 7 1 3 1 2 - - - - Total 41 29 12 In DRC, 10 sampled products which were not registered at the time of sample collection were registered for one year in 2000-2002, but the registration was not renewed. Dossiers of two further non-registered products were submitted to WHO for the prequalification procedure. Table 3: Registration status of products sampled in Nigeria Nigeria Registered Not registered* Active ingredient(s) Number of samples Manu- facturer Private procure- ment Public procure- ment Public treatment centre Manufac turer Private procure- ment Public procure- ment Public treatment centre didanosine - - - - - - - - efavirenz 3 - - 1 - - 1 - 1 lamivudine 15 3 - 5 6 - 1 - - nevirapine 14 3 - 5 4 - 1 - 1 stavudine 10 - - 3 3 - 2 - 2 zidovudine 7 3 - 2 - - 2 - - lamivudine / zidovudine 4 2 - - 1 - 1 - - stavudine / lamivudine - - - - - - - - - stavudine / lamivudine / nevirapine 1 - - - - - - 1 - Total 54 41 13 *The registration status in Nigeria was evaluated according to the information on the package label. Although no evidence of registration on the package does not necessarily mean that products are not registered, these products were included in Table 3 as non-registered. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 11 Table 4: Registration status of products sampled in Zambia Zambia Registered Registration pending Not registered Active ingredient(s) Number of samples Whole- saler Uni- versity hospital Public treatment centre Whole- saler/ importer Teaching hospital Public treatment centre Whole- saler/ importer Teaching hospital Public treatment centre didanosine 1 - - - 1 - - - - - efavirenz 6 1 1 2 2 - - - - - lamivudine 4 - - - 2 2 - - - - nevirapine 7 2 1 1 3 - - - - - stavudine 7 1 2 1 2 - - 1 - - zidovudine 8 1 2 2 2 1 - - - - lamivudine / zidovudine 4 2 - - 1 - 1 - - - stavudine / lamivudine 2 - - - 1 - - 1 - - stavudine / lamivudine / nevirapine 8 4 2 1 1 - - - - - Total 47 26 19 2 In the Sample Collection Forms from Zambia the information on pending registration applications was also provided. Table 5 indicates the number of prequalified and non-prequalified products for the different active ingredients and Table 6 indicates the number for individual countries where samples were collected. The percentage of products prequalified by WHO appears in brackets. WHO- prequalification status reflects the situation at the time of sampling. Table 5: WHO-prequalification status of samples tested (percentage of products prequalified by WHO in brackets) Number of samples Active ingredient(s) WHO- prequalified Not WHO- prequalified Total didanosine - 1 1 efavirenz - 46 46 lamivudine 43 (65%) 23 66 nevirapine 44 (61%) 28 72 stavudine 26 (43%) 34 60 zidovudine 36 (81%) 8 44 lamivudine / zidovudine 29 (78%) 8 37 stavudine / lamivudine - 16 16 stavudine / lamivudine / nevirapine 31 (60%) 21 52 Total 209 185 394 Table 6: WHO-prequalification status of samples collected in individual countries (percentage of products prequalified by WHO in brackets) Number of samples Active ingredient(s) WHO- prequalified Not WHO- prequalified Total Cameroon 23 (68%) 11 34 DRC 25 (61%) 16 41 Kenya 49 (45%) 60 109 Nigeria 18 (33%) 36 54 Tanzania 55 (76%) 17 72 Uganda 23 (32%) 14 37 Zambia 16 (34%) 31 47 Total 209 185 394 Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 12 Table 7 shows number of samples of different dosage forms and strengths collected and tested for each FPP/FDC. Table 7: Active ingredient(s), dosage forms and strengths of samples tested Active ingredient(s) Dosage form Strength(s) and number(s) of samples Total didanosine Tablets 100mg: 1 1 efavirenz Capsules 50mg: 6, 200mg: 11 17 Tablets 600mg: 26 26 Oral solutions 30mg/ml: 3 3 lamivudine Tablets 150mg: 43 43 Oral solutions 50mg/5ml: 23 23 nevirapine Tablets 200mg: 44 44 Oral suspensions 50mg/5ml: 28 28 stavudine Capsules 15mg: 4, 20mg: 2, 30mg: 24, 40mg: 28 58 Powder for oral solution 200mg: 2 2 zidovudine Capsules 100mg: 7 7 Tablets 300mg: 15 15 Oral solutions 50mg/5ml: 22 22 lamivudine/zidovudine Tablets 150/300mg: 37 37 stavudine/lamivudine Tablets 30/150mg: 8, 40/150mg: 8 16 stavudine/lamivudine/ nevirapine Tablets 30/150/200mg: 34, 40/150/200mg: 18 52 Total 394 Expiry dates of samples collected in this survey ranged from June 2006 to September 2009. Two samples from Nigeria, the first country to start sampling on 13 June 2005, had the earliest expiry dates. Figure 1 shows percentages of expired samples over time, for samples from each country. Countries are listed in the legend in the order in which their samples were tested at the laboratory. No expired samples were found in this survey. Some products were close to their expiry dates when they underwent testing. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 13 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Jun-05 Dec-05 Jun-06 Dec-06 Jun-07 Dec-07 Jun-08 Dec-08 Jun-09 Nigeria (n=54) Cameroon (n=34) Uganda (n=37) Tanzania (n=72) DRC (n=41) Kenya (n=109) Zambia (n=47) Time of survey Figure 1: Percentages of expired samples over time, by country 3.2 Compliance with quality standards Overall, only seven of 394 samples tested failed to comply with specifications of any of the quality tests performed. Several samples were not classified as failures, although they were slightly out-of-specification. Other samples were just inside the acceptable limits, and potential quality problems were noted. The findings of the different tests are summarized in Sections 3.2.1 to 3.2.7 below. 3.2.1 Appearance Not all the products were WHO-prequalified and the manufacturers' specifications for appearance were not available for some products. Therefore the appearance was evaluated against the general specifications for dosage forms only. Of the 394 samples assessed, one was found to be of unsatisfactory appearance in terms of the specifications: efavirenz 600mg tablets (OMCL No 4.41, page 26): The sample of a non-WHO-prequalified product, collected at wholesaler/importer in Zambia, contained a broken tablet and a number of tablets with chipped coating. 3.2.2 Labelling Two of 394 samples failed to comply with labelling requirements: Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 14 stavudine 200mg powder for oral solution (OMCL Nos. 1.13 and 1.24, page 35): These two samples of a non-WHO-prequalified product, collected at a public-sector procurement centre in Cameroon and at a public-sector treatment centre in Tanzania respectively, were produced by the same manufacturer. The following information was missing from the label of the primary container: − Any special storage conditions or handling precautions that may be necessary − Directions for use, warnings and precautions that may be necessary − The name and address of the local sponsor 3.2.3 Disintegration One of 163 samples tested was unsatisfactory with regard to disintegration: lamivudine / zidovudine 150/300mg tablets (OMCL No. 7.04, page 41): This sample of a non-WHO-prequalified product was collected at a manufacturer in Nigeria. In repeated tests, two to four out of six tablets failed to disintegrate completely within 30 minutes. 3.2.4 Dissolution A total of 153 samples were tested for dissolution. All except two samples complied with specifications. In the samples which complied, the minimum amounts of active ingredient dissolved for monocomponent products, in percent of the label claim, were 93% for lamivudine (number of products tested - n=25), 80% for nevirapine (n=29), 94% for stavudine (n=26), and 80% for zidovudine (n=12, an additional sample did not comply). In fixed-dose combinations, the respective minimum amounts dissolved were 92% and 89% for lamivudine/zidovudine (n=28, an additional sample did not comply), and 85%, 92% and 92% for stavudine/lamivudine/nevirapine (n=31). Details for the two samples which failed dissolution testing were as follows: zidovudine 300mg tablets (OMCL No. 5.19, page 37): This sample of a non-WHO-prequalified product, collected at a public-sector procurement centre in Tanzania, did not meet the USP specification for dissolution (Q value of 75% at 30 minutes). The test was performed according to the USP monograph using apparatus 2 (paddle). At Stage 1, three tablets had results of 69%, 70% and 74%, i.e. below 80% (Q+5%). At Stage 2, the average of the 12 tablets was 76%, which met the specification, but one tablet (58%) was below 65% (Q–15%). At Stage 3, not more than two tablets were less than Q–15%, and none was less than Q–25%, but the average of the 24 tablets was determined to be 74%, which was less than Q (75%). Consequently, the sample was found to be unsatisfactory with respect to dissolution. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 15 lamivudine/zidovudine 150/300mg tablets (OMCL No. 7.24, page 43): This sample of a WHO-prequalified product, collected at a private-sector hospital in the DRC, failed to meet the USP Stage 3 requirements for dissolution. The lowest amounts of lamivudine and zidovudine dissolved were determined to be 51.6% and 50.6% respectively. These results were below the Stage 3 specification of not less than 55% (Q–25%). This batch was very close to expiry (09/05) at the time of dissolution testing, which took place on 20/09/05. Another sample of the same product from a different batch (OMCL No. 7.25, expiry 12/05), collected at a private-sector distribution centre in the DRC, was found to be of satisfactory quality with respect to dissolution. 3.2.5 Content of active ingredient All 289 samples of monocomponent products and 104 of 105 samples of fixed-dose combinations complied with content specifications. Mean content and ranges for the different active ingredients and dosage forms are illustrated in Figures 2 and 3. Figure 2: Monocomponent antiretrovirals (n=289): Content of active ingredient (in % of stated amount): average, minimum and maximum Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 16 Figure 3: Fixed-dose antiretroviral combination tablets (n=105): Content of active ingredient (in % of stated amount): average, minimum and maximum The sample which failed the specifications in terms of content was a “high failure”, with a content above the acceptance criteria: stavudine/lamivudine/nevirapine 30/150/200mg tablets (OMCL No. 6.16, page 49): In this sample of a WHO-prequalified product, collected at a public-sector treatment centre in Tanzania, the content of stavudine was 117%, which was above the specified range of 90.0 to 110.0%. This result was consistent with the results of dissolution testing, where the amount of stavudine dissolved ranged from 120-135% of the stated amount. In order to confirm this high result, 20 tablets were tested for uniformity of content of stavudine. For the first set of 10 tablets, the content of stavudine ranged from 101.2 to 138.4% with a mean of 117.5% (RSD=12.7%) and for the second set, it ranged from 95.4-131.7% with a mean of 108.1% (RSD =10.6%). The three different tests confirmed that this sample did not meet the specification for the content of stavudine. One sample of non-WHO-prequalified stavudine 40mg capsules from a private-sector procurement company in Nigeria (OMCL No. 1.09, page 34) contained 107.9% of the stated amount of active ingredient, which is slightly above the specification of 90.0- 105.0%. Given the uncertainty of measurement of the method, this result is considered satisfactory. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 17 In four samples of fixed-dose combination tablets, the content of one or more active ingredients was at the lower limit of the specifications (90.0-110.0%): • Three samples of WHO-prequalified stavudine/lamivudine/nevirapine tablets – two from public procurement centres in Cameroon (OMCL Nos. 6.05 and 6.06) and one from a public treatment centre in Uganda (OMCL No. 6.11), contained 90.2%, 91.3% and 90.3% of the stated amount of stavudine respectively (see page 48). • One sample of stavudine/lamivudine 40/150mg from a wholesaler/importer in Zambia (OMCL No. 8.16, page 45, non-WHO-prequalified product) contained 90.5% and 92.1% of the stated amounts. In the remaining 15 samples tested, the content of stavudine ranged from 97.5-104.5% and that of lamivudine from 98.0- 101.8%. One sample of zidovudine 50mg/5ml oral solution (OMCL No. 5.07, page 39), not WHO-prequalified, collected at a manufacturer in Nigeria, had a low content of 90.7% of the label claim. Given that all the above-mentioned samples met the requirements for related substances, the results suggest that correct amounts of active ingredients might have not been added at the time of manufacture. There was another sample of non-WHO-prequalified oral suspension containing nevirapine (OMCL No. 3.14, from a manufacturer in Nigeria, page 33) with a relatively low content of active ingredient (93.4% of the stated amount of nevirapine). This sample had a lower pH value than all the other nevirapine oral suspensions tested (3.4 compared to 5.5 - 6.0) and also different appearance (orange compared to white to pale off-white). However as this product was not WHO-prequalified and the manufacturers' specifications for pH value and appearance were not available, it was considered to be compliant. 3.2.6 Impurities (related substances) All 394 samples were tested for related substances. Two samples showed apparent out- of-specification results as discussed below. zidovudine 300mg tablets (OMCL Nos. 5.05 and 5.36, page 40): Both samples, collected at a manufacturer in Nigeria and at a public-sector treatment centre in Kenya respectively, were from the same batch. They contained 0.3% of an impurity identified as 3’-chloro-3’-deoxythymidine. This result does not meet the USP specification of ≤0.2% for any other individual unidentified impurity. However, as the acceptable limit for this impurity in the active ingredient is 1.0% according to USP, as well as the European Pharmacopoeia, it has not been concluded as a failure. In the only sample of didanosine tested, total impurities were determined to be 0.5%. This result is at the upper limit of the specification for this product. At the time of testing (14/12/05), the sample was well within its expiry date (12/06). 3.2.7 Uniformity of mass 316 samples were tested for uniformity of mass and all complied with USP (28) 2005 specifications. In 308 samples, all 20 units were within the required range for at least 18 units. Eight samples had one unit outside this range, but within the limits allowed for the remaining two units. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 18 3.2.8 Samples from identical batches Two or more samples were tested from each of twenty-nine batches (see Appendix 2), with comparable results. Two samples shared a batch number coincidentally but these samples were manufactured at different manufacturing sites. 3.3 Summary of quality failures In total, seven samples out of a total of 394 failed to meet specifications of different tests. This represents a failure rate of 1.8%. A summary of failures is shown in Table 8. Table 8: Overview of failures Test Sample description WHO- pre- qualified OMCL No. Page Country and type of sampling site Reason Appearance (1) efavirenz 600mg tablets No 4.41 26 Zambia, a wholesaler / importer One broken tablet and chipped coating of other tablets Label (2) stavudine 200mg powder for oral solution No 1.13 35 Cameroon, public procurement centre Information items 6, 7 and 8 missing from immediate container Label (3) stavudine 200mg powder for oral solution No 1.24 35 Tanzania, public treatment centre Information items 6, 7 and 8 missing from immediate container Disintegration (4) lamivudine/ zidovudine 150/300mg tablets No 7.04 41 Nigeria, manufacturer Exceeded 30- minute limit Dissolution (5) zidovudine 300mg tablets Yes 5.19 37 Tanzania, public procurement centre Failed stage 3 specification of the USP Dissolution (6) lamivudine/ zidovudine 150/300mg tablets Yes 7.24 43 DRC, private hospital Failed stage 3 specification of the USP Content (7) stavudine/ lamivudine/ nevirapine 30/150/200mg tablets Yes 6.16 49 Tanzania, public treatment centre Content of stavudine exceeded specification As Table 8 shows, failures were not particularly frequent for any specific country, type of collection site, product, dosage form or type of test. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 19 4. Discussion This extensive survey, which covered seven African countries and used various types of antiretroviral procurement and treatment centres as sampling sites, achieved its objective of determining quality failure rates of antiretroviral products. The antiretrovirals tested were generally of good quality, with a low failure rate of 1.8%, and no serious failures, i.e. no critical deficiencies which would pose a serious risk to patients. The sampling sites were generally fairly large, official treatment centres or wholesalers. No samples were collected from any unofficial sources of antiretrovirals. The logistic organization of the survey was good. Samples were gathered by the WHO country officers and national authority representatives within a reasonably short period. Packaging and documenting of sampling was generally adequate and consistent. Uniform Sample Information Collection Forms were used, and the samples were sent to the laboratory without delay. Involvement of WHO Medicines National Professional Officers and inspectors or analysts from National Drug Regulatory Authorities in sampling ensured the proper handling and labelling of samples and no deterioration of the quality of samples. In this survey, a single laboratory analysed all the samples. As the number of samples was high, a large laboratory was needed. In total, 394 samples were collected for testing; 209 (53%) of these were WHO-prequalified at the time of sample collection. The highest percentage of prequalified products was for products containing zidovudine (81%), followed by the fixed-dose combination lamivudine/zidovudine (78%) and lamivudine (65%), whilst no prequalified product was amongst samples containing didanosine, efavirenz and the combination stavudine/lamivudine/nevirapine. This reflected the availability of prequalified products at the time of collecting samples, when no products containing efavirenz or didanosine were prequalified, and the FDC stavudine/lamivudine/ nevirapine had just been added to the prequalification list. With respect to the individual countries, the highest percentages of prequalified products were found among samples collected in Tanzania (76%) and Cameroon (68%), whilst in Uganda, Nigeria and Zambia the percentages of prequalified products were much lower (32%, 33% and 34%, respectively). Information on the registration status of the sampled products was provided from all selected countries except Kenya. Of the 285 sampled products for which the information was provided, 84% were registered nationally, among them all samples collected in Cameroon, Tanzania and Uganda. A more complex situation was found in DRC, Nigeria and Zambia. In DRC 29% of sampled products were not registered at the time of sample collection, however 83% of these had either been registered previously, or applications had been submitted to WHO for prequalification. In Nigeria, no evidence of registration was found on the package labels of 24% of sampled products, which does however not confirm that products were unregistered. In Zambia, 45% of sampled products were not registered at the time of sample collection; for 90% of these, registration by the National Drug Regulatory Authority was pending. From these results it can be concluded that the majority of sampled products were in principle under the control of National Drug Regulatory Authorities. However, at least 12% of all sampled products were not registered at the time of sampling, indicating that market control was still incomplete in at least three countries. Non-registered products were collected mostly from the private sector. The proportions of WHO-prequalified products were 60% among nationally registered products, and 35% among non-registered products. The appearance of samples was evaluated against the general specifications for dosage forms and only one of 394 samples did not comply. Only two of 394 samples (collected in two countries but belonging to the identical pharmaceutical product from one manufacturer) were insufficiently labelled. All 316 samples tested for uniformity of mass were compliant with the specifications. 163 samples were tested for disintegration and one only failed to disintegrate completely within 30 minutes. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 20 Two of 153 samples tested for dissolution (one monocomponent product and one FDC) were found non-compliant due to lower dissolution results than required. One of these, a fixed-dose combination of lamivudine/zidovudine, failed in dissolution of both active ingredients. With regard to related impurities tested for the active ingredients, all 394 samples were found to be compliant with the specifications, indicating that the APIs used in the manufacturing were of acceptable quality and/or stability did not pose a major problem. Only one of 394 samples did not comply in the terms of active ingredient content. It concerned WHO-prequalified stavudine/lamivudine/nevirapine FDC tablets, with the stavudine content beyond the upper limit. The result was confirmed through repeat analysis and was consistent with the results of dissolution testing. The manufacturer, which was contacted, provided results at the time of release and results of analysis of retention samples, which all were compliant. This will be reviewed during the next inspection of this manufacturer within the prequalification programme. The low failure rates found in this survey are encouraging, as they indicate that the purchase policies for the antiretrovirals supplied to the distribution points sampled were valid. More than half of the samples were of WHO-prequalified products. Considering that in January 2005, less than a third of all dossiers submitted (85 of 285) were approved for prequalification 19 and that many other manufacturers never sought prequalification for their products, it appears that preference is given to WHO-prequalified products in procurement. Even if non-WHO- prequalified products were procured, they were of acceptable quality. However it should be borne in mind that the quality control methods used were designed for well defined products in the regulated area, where they are used in parallel to the assessment of a dossier and inspections. These methods may have some limitations in a less regulated environment. Limitations The survey did not cover any remote treatment sites, or any informal sources of antiretroviral medication. Antiretrovirals in these settings may have higher failure rates than that observed in this survey, for various reasons: Transport, storage and control of medicines are more challenging in remote areas, and the presence of counterfeit products is reported more frequently from informal markets than from the formal, regulated environment 14 . Performing a similar survey in more rural settings would pose significant challenges. Particular care would have to be taken to achieve adequate sampling coverage, coordination of logistics and transport of samples with accompanying information. In terms of sample analysis, the task could be divided among several smaller laboratories, but careful planning of sampling and logistics would again be required. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 21 5. Conclusion and recommendations The quality of antiretrovirals supplied at official distribution points around the capital cities of seven African countries was found to be good, with only 1.8% failures and no critical deficiencies. It indicates that the efforts made by the WHO and other organizations on prequalification and purchase policies of the antiretrovirals have a positive effect. However, at least 12% of sampled products were not registered at the time of sampling indicating that market control in some countries is still incomplete. No samples of antiretroviral products were collected at non-official sources, where higher failure rates than observed in this survey, or even counterfeit products, could be expected. Therefore, the positive outcome of this study does not necessarily reflect the quality of all antiretroviral products available to the public in these countries. The organization of the survey was satisfactory, with no major limitations encountered. The following recommendations are made: � The findings of this survey should be made available to medicines regulatory authorities in African countries to assist them to develop appropriate quality assurance strategies. � The findings of this survey should be used in awareness and advocacy programmes, reinforcing the need for quality assurance in procurement. � The quality of antiretroviral products at user points should continue to be monitored. Various settings should be included in future surveys. � The findings are of general public interest and should be published in a suitable journal. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 22 6. References 1 UNAIDS AIDS Epidemic Update: Special Report on HIV/AIDS. December 2006. Geneva, Switzerland: UNAIDS/WHO, 2006. 2 UNAIDS/WHO. Progress on global access to HIV antiretroviral therapy : an update on «3 by 5». Geneva, Switzerland: WHO, 2005. 3 Banda M, Ombaka E, Logez S, Everard M. Multi-Country Study of Medicine Supply and Distribution Activities of Faith-Based Organizations in Sub-Saharan African Countries. WHO/PSM/PAR/2006.2. World Health Organization / Ecumenical Pharmaceutical Network, 2006. 4 Attawell K, Mundy J. Provision of antiretroviral therapy in resource-limited settings: A review of experience up to August 2003. WHO and the UK’s Department for International Development. 2003. URL: http://www.who.int/3by5/publications/documents/en/ARTpaper_DFID_WHO.pdf 5 UNAIDS/WHO. Guidance Modules on Antiretroviral Treatments. Module 8: Antiretrovirals: Regulation, Distribution and Control. Geneva. WHO, 1998. URL: http://www.paho.org/english/hcp/hca/ModulosARV.htm 6 Ondari C, Maponga C. The quality of antimalarials. A study in selected African countries. WHO/EDM/PAR/2003.4. Geneva, Switzerland: WHO, 2003. 7 WHO. The World Medicines Situation. WHO/EDM/PAR/2004.5. Geneva, Switzerland: World Health Organization, 2004. 8 WHO. Counterfeit medicines. Fact sheet revised. 14 November 2006. URL: http://www.who.int/mediacentre/factsheets/fs275/en/ 9 Médecins sans Frontières (MSF). Untangling the Web of Price Reductions. June 2005 10 World Health Organization Regional Office for Africa. Medicines regulatory authorities: Current status and the way forward. Report of the Regional Director. ARF/RC/56/11, 17 June 2006. 11 Ratanawijitrasin S, Wondemagegnehu E. Effective drug regulation. A multicountry study. Geneva, Switzerland: World Health Organization, 2002. 12 WHO. Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines for a public health approach. Geneva, Switzerland: WHO, 2003. 13 Counterfeit triple antiretroviral combination product (Ginovir 3D) detected in Cote d’Ivoire. WHO QSM/MC/IEA.110, November 28, 2003. Bulletin d’Analyse N° 2003/U/NX/20391/M/ NC, Direction des Laboratoires et des Contrôles, (date de notification 11 juillet 2003) AFSSAPS. 14 Primo-Carpenter J, McGinnis M. Matrix of Drug Quality Reports in USAID-assisted Countries by the U.S. Pharmacopeia Drug Quality and Information Program. January 2007. Rockville, MD, USA: The United States Pharmacopeial Convention Inc., 2003-2007. URL: http://www.usp.org/pdf/EN/dqi/ghcDrugQualityMatrix.pdf 15 WHO. Fact Sheet No. 278. The WHO prequalification project. May 2004. Geneva, Switzerland: World Health Organization, 2004. URL: http://www.who.int/mediacentre/factsheets/fs278/en/index.html. 16 WHO. Prequalification Programme: Access to quality control laboratories that meet recommended international norms and standards for the analysis of products in the Prequalification Programme. HIV/AIDS, malaria and tuberculosis products Version: 5th Edition. 9 January 2007. URL: http://mednet3.who.int/prequal/lists/PQ_QCLabsList.pdf 17 World Health Organization. International pharmacopoeia. Third Edition. Volume 4. General requirement for dosage forms. Geneva, Switzerland: WHO, 1994. 18 The United Stated Pharmacopeia 28. The U. S. Pharmacopeial Convention, Inc., Board of Trustees, Webcom Limited, Toronto, Ontario, 2412-2414, 2005. 19 UNICEF/UNAIDS/WHO/MSF. Sources and prices of selected medicines and diagnostics for people living with HIV/AIDS. 6 th Edition. United Nations Children's Fund, Joint United Nations Programme on HIV/AIDS (UNAIDS), Médecins sans Frontières, 2005. Survey of the quality of antiretroviral medicines circulating in selected African countries (September 2007) 23 Appendix 1: Test results 1. Didanosine Tablets, not prequalified (1 sample) .24 2. Efavirenz Test Plan A: Capsules/tablets, not prequalified (43 samples) .25 Test Plan B: Oral solutions, not prequalified (3 samples).27 3. Lamivudine Test Plan A: Tablets, not prequalified (18 samples).28 Test Plan B: Tablets, prequalified (25 samples).29 Test Plan C: Oral solutions (23 samples) .30 4. Nevirapine Test Plan A: Tablets, not prequalified (15 samples).31 Test Plan B: Tablets, prequalified (29 samples).32 Test Plan C: Oral suspensions (28 samples) .33 5. Stavudine Test Plan A: Capsules, not prequalified (32 samples) .34 Test Plan B: Oral solutions, not prequalified (2 samples).35 Test Plan C: Capsules, prequalified (26 samples) .36 6. Zidovudine Test Plan A: Capsules and tablets, prequalified (17 samples) .37 Oral solutions, prequalified (3 samples) .38 Test Plan B: Oral solutions, not prequalified, and prequalified with different matrix (19 samples) .39 Test Plan C: Tablets, not prequalified and prequalified with unknown composition (5 samples).40 7. Lamivudine/zidovudine Test Plan A: Tablets, not prequalified (8 samples).41 Test Plan B: Tablets, prequalified (29 samples).42 8. Stavudine/lamivudine Tablets, not prequalified (16 samples).45 9. Stavudine/lamivudine/nevirapine Test Plan A: Tablets, not prequalified (21 samples).46 Test Plan B: Tablets, prequalified (31 samples).48 1. Didanosine Tablets, not prequalified (1 sample) SPECIFICATIONS: Content of didanosine: 92.5-105.0% of stated amount Related substances: Hypoxanthine (Ph.Eur. 5.2, 07/2005:2200 Impurity A): ≤ 2.0% Impurities, other (individual): ≤ 0.2% Impurities total, other: ≤ 0.5% � = Complies 24 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- integra- tion Uniformity of mass 9.01 Dinor 100mg tablets 01A05001 HDPE bottle 2 × 60 12/2006 Zambia � � � 99.6 (a) � mean: 1195.59mg -1.1% to + 0.8% (a) Complies; total impurities=0.5% (at the limit of the specification) 2. Efavirenz Test Plan A: Capsules/tablets, not prequalified (43 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content of efavirenz: 90.0-110.0% of stated amount Related substances: Any individual impurity: ≤ 1.0% Total impurities: ≤ 2.0% � = Complies 25 OMCL No. Trade name, strength and dosage form Batch number Primary Pack Sample and pack size Ex- piry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- integra- tion Uniformity of mass 4.01 Aviranz 600mg tab 1513769 Plastic bottle 2×30 03/07 Nigeria � � � 96.2 � � mean: 1212.9mg -0.9% to +0.7% 4.02 Stocrin 600mg tab NB14210 Plastic bottle 2×30 12/06 Nigeria � � � 100.9 � � mean: 1231.4mg -0.6% to +0.5% 4.03 Polodipin 200mg cap G46198 Plastic bottle 2×30 01/06 Nigeria � � � 99.3 � � mean: 445.9mg -6.1% to +6.3% 4.04 Efavir 200mg cap G56486 Plastic bottle 2×90 02/07 Cameroon � � � 99.2 � � mean: 447.0mg -4.6% to +4.0% 4.05 Efavir 600mg tab G56252 Plastic bottle 4×30 01/07 Cameroon � � � 96.7 � � mean: 1359.9mg -2.2% to +1.7% 4.06 Efavir 600mg tab G56499 Plastic bottle 4×30 03/07 Cameroon � � � 96.1 � � mean: 1363.1mg -3.0% to +2.9% 4.09 Stocrin 200mg cap NB22820 Plastic bottle 2×90 01/08 Cameroon � � � 102.6 � � mean: 516.2mg -1.0% to +1.2% 4.10 Stocrin 200mg cap NB32540 Plastic bottle 2×90 02/08 Cameroon � � � 102.4 � � mean: 509.5mg -1.3% to +1.5% 4.11 Stocrin 200mg cap NB35720 Plastic bottle 2×90 02/08 Cameroon � � � 100.1 � � mean: 514.6mg -1.6% to +1.7% 4.12 Stocrin 600mg tab NB32530 Plastic bottle 4×30 02/07 Cameroon � � � 102.4 � � mean: 1226.4mg -0.5% to +0.7% 4.13 Sustivir 600mg tab Y41684 Plastic bottle 2×30 09/07 Uganda � � � 98.2 � � mean: 1375.8mg -1.9% to 2.2% 4.14 Efavir 600mg tab Y42035 Plastic bottle 2×30 11/06 Uganda � � � 96.6 � � mean: 1370.1mg -1.7% to +2.0% 4.15 Stocrin 600mg tab NB35330 As 4.17 Plastic bottle 2×30 02/07 Uganda � � � 102.5 � � mean: 1223.3mg -0.6% to +0.9% 4.16 Stocrin 50mg cap NA24340 Plastic bottle 2×30 05/07 Uganda � � � 103.2 � � mean: 129.0mg -3.4% to +3.7% 4.17 Stocrin 600mg tab NB35330 As 4.15 Plastic bottle 2×30 02/07 Uganda � � � 101.3 � � mean: 1223.4mg -1.5% to +2.5% 4.18 Stocrin 600mg tab NB35320 Plastic bottle 2×30 02/07 Tanzania � � � 102.3 � � mean: 1223.8mg -1.4% to +0.8% 4.19 Stocrin 600mg tab NB26700 Plastic bottle 2×30 01/07 Tanzania � � � 101.2 � � mean: 1228.1mg -0.8% % to0.7% 4.21 Stocrin 600mg tab HV77220 As 4.24 Plastic bottle 2×30 02/06 Tanzania � � � 102.2 � � mean: 1241.4mg -1.4% to +1.0% 4.22 Stocrin 600mg tab HV77230 Plastic bottle 2×30 02/06 Tanzania � � � 102.6 � � mean: 1238.5mg -1.5% to +1.1% 4.23 Stocrin 600mg tab NB26690 Plastic bottle 2×30 01/07 Tanzania � � � 103.1 � � mean: 1229.6mg -1.3% to +0.7% 4.24 Stocrin 600mg tab HV77220 As 4.21 Plastic bottle 2×30 02/06 Tanzania � � � 103.1 � � mean: 1240.5mg -1.1% to 1.2% 4.25 Stocrin 600mg tab NA30350 Plastic bottle 2×30 08/06 DRC � � � 103.2 � � mean: 1240.9mg -0.9% to 0.9% 4.20 Efavir 200mg cap Y41451 Plastic bottle 2×90 01/06 Tanzania � � � 98.4 � � mean: 442.9mg 19 capsules: -4.7% to +3.7% 1 capsule: +7.6% 4.26 Estiva 200mg cap EV40911 Plastic bottle 2×90 08/06 DRC � � � 97.4 � � mean: 401.9mg -5.7% to +4.5% 4.27 Stocrin 200mg cap HV60070 Plastic bottle 1×90 02/06 DRC � � � 103.2 � � mean: 514.9mg -2.3% to +2.5% 4.28 Efariv 600mg tab 050708 Plastic bottle 4×30 04/07 Kenya � � � 97.3 � � mean: 1139.3mg -2.5% to +3.0% 4.29 Aviranz 600mg tab 1390735 Plastic bottle 4×30 03/06 Kenya � � � 98.1 � � mean: 1239.0mg -1.4% to +1.9% 4.30 Aviranz 600mg tab 1386917 Plastic bottle 4×30 03/06 Kenya � � � 99.2 � � mean: 1231.6mg -1.2% to +1.8% 2. Efavirenz Test Plan A: Capsules/tablets, not prequalified (43 samples) – methods of the Indian Pharmacopoeia (continued) SPECIFICATIONS: Content of efavirenz: 90.0-110.0% of stated amount Related substances: Any individual impurity: ≤ 1.0% Total impurities: ≤ 2.0% � = Complies 26 OMCL No. Trade name, strength and dosage form Batch number Primary Pack Sample and pack size Ex- piry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- integra- tion Uniformity of mass 4.31 Aviranz 600mg tab 1390752 Plastic bottle 4×30 03/06 Kenya � � � 96.6 � � mean: 1195.4mg -2.5% to +1.6% 4.33 Stocrin 50mg cap NA37970 Plastic bottle 4×30 05/07 Kenya � � � 99.9 � � mean: 127.4mg -6.8% to +5.3% 4.34 Stocrin 50mg cap NB00350 Plastic bottle 4×30 07/07 Kenya � � � 110.0 � � mean: 132.2mg -1.6% to +1.5% 4.35 Stocrin 50mg cap NA42780 Plastic bottle 4×30 08/07 Kenya � � � 102.6 � � mean: 127.3mg -5.9% to +6.4% 4.36 Stocrin 200mg cap NA17240 Plastic bottle 2×90 05/07 Kenya � � � 102.7 � � mean: 516.9mg -1.9% to +0.9% 4.37 Stocrin 200mg cap NB10760 Plastic bottle 2×90 12/07 Kenya � � � 106.3 � � mean: 517.4mg -2.3% to +2.7% 4.41 Efcure 600mg tab 01A04003 Plastic bottle 2×30 10/06 Zambia � (1) � 101.3 � � mean: 1228.7mg -1.2% to +1.1% 4.42 Aviranz 600mg tab 1520830 Plastic bottle 2×30 04/07 Zambia � � � 100.5 � � mean: 1228.6mg -1.1% to +0.9% 4.43 Efavir 200mg cap G47289 Plastic bottle 2×30 09/06 Zambia � � � 99.8 � � mean: 441.0mg -6.5% to +4.9% 4.44 Stocrin 50mg cap L030600 Plastic bottle 3×30 06/07 Zambia � � � 99.9 � � mean: 129.7mg -3.4% to +3.6% 4.45 Stocrin 50mg cap L030420 Plastic bottle 1×30 05/07 Zambia � � � 105.3 � � mean: 131.2mg -2.6% to +4.1% 4.38 Stocrin 600mg tab HV31700 Plastic bottle 4×30 12/05 Kenya � � � 99.9 � � mean: 1234.5mg -1.5% to 1.0% 4.39 Stocrin 600mg tab NB52450 Plastic bottle 4×30 02/07 Kenya � � � 102.3 � � mean: 1222.2mg -0.8% to 0.9% 4.40 Stocrin 600mg tab NB02550 Plastic bottle 4×30 11/06 Kenya � � � 102.1 � � mean: 1228.1mg -0.9% to 0.7% 4.46 Stocrin 600mg tab NB14200 Plastic bottle 2×30 12/06 Zambia � � � 102.2 � � mean: 1228.0mg -1.4% to 0.8% (1) Does not comply: Sample contained one broken tablet and several with chipped coating. (WHO sampling number: PW/PI/010/004) 2. Efavirenz Test Plan B: Oral solutions, not prequalified (3 samples) – Swissmedic methods SPECIFICATIONS: Related substances: Impurity 1 (potential impurity from synthesis of efavirenz): ≤ 0.25% Any other individual impurity: ≤ 0.2% Sum of all impurities: ≤ 0.5% � = Complies 27 OMCL No. Trade name, strength and dosage form Batch number Pri- mary pack Sample size Ex- piry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related substances 4.07 Stocrin 30mg/ml oral solution NB17260 As 4.32 Plastic bottle 2×180ml 12/07 Cameroon � � � 100.1 � 4.08 Stocrin 30mg/ml oral solution NB17250 Plastic bottle 2×180ml 12/07 Cameroon � � � 101.6 � 4.32 Stocrin 30mg/ml oral solution NB17260 As 4.07 Plastic bottle 2×180ml 12/07 Kenya � � � 100.6 � 3. Lamivudine Test Plan A: Tablets, not prequalified (18 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content of lamivudine: 90.0-110.0% of stated amount Related substances: Any individual impurity: ≤1.0% Sum of all impurities: ≤2.0% � = Complies 28 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample & pack size Expiry date Country Label Ap- pear- ance Iden- tity Dis- integra- tion Content (% of stated amount) Related sub- stances Uniformity of mass 2.01 Heptavir 150mg tab HD50215 Plastic bottle 2 × 60 01/07 Nigeria � � � � 100.9 � mean: 286.5mg -2.9% to +1.7% 2.05 Avolam 150mg tab 1375882 As 2.06 Blister strips 2 × 6 × 10 01/06 Nigeria � � � � 104.8 � mean: 309.4mg -1.1% to +0.8% 2.06 Avolam 150mg tab 1375882 As 2.05 Blister strips 2 × 6 × 10 01/06 Nigeria � � � � 104.8 � mean: 309.3mg -1.3% to +0.8% 2.08 Avolam 150mg tab 1369991 Blister strips 2 × 6 × 10 01/06 Nigeria � � � � 104.9 � mean: 309.4mg -1.7% to +1.1% 2.09 Avolam 150mg tab 1365896 Blister strips 2 × 6 × 10 12/05 Nigeria � � � � 106.4 � mean: 309.1mg -0.8% to +1.0% 2.10 Avolam 150mg tab 1369945 Blister strips 2 × 6 × 10 01/06 Nigeria � � � � 106.5 � mean: 309.4mg -1.0% to +0.9% 2.11 Avolam 150mg Tab 1365906 Blister strips 2 × 6 × 10 12/05 Nigeria � � � � 107.7 � mean: 310.1mg -1.2% to +0.9% 2.40 Lavir 150mg tab 01A05002 As 2.63 Plastic bottle 2 × 60 02/07 Tanzania � � � � 102.7 � mean: 291.4mg -1.8% to +1.2% 2.41 Lavir 150mg tab 01A05001 Plastic bottle 2 × 60 02/07 Tanzania � � � � 100.4 � mean: 292.0mg -1.9% to +2.5% 2.42 Lamivudine 150mg, tab AL05- L9001 Plastic bottle 2 × 14 05/07 DRC � � � � 99.5 � mean: 313.0mg -1.7% to +1.6% 2.43 Avolam 150mg tab 1358116 Blister strips 2 × 60 11/05 DRC � � � � 100.5 � mean: 310.2mg -2.0% to +2.0% 2.49 Heptavir 150mg tab HD41010 Plastic bottle 2 × 60 09/06 Kenya � � � � 99.4 � mean: 285.6mg -2.8% to +2.2% 2.50 Lamiriv 150mg tab 031673 Blister strips 2 × 60 11/05 Kenya � � � � 100.1 � mean: 336.4mg -2.2% to +2.3% 2.51 Lamiriv 150mg tab 031674 As 2.62 Blister strips 2 × 60 11/05 Kenya � � � � 98.8 � mean: 334.5mg -2.0% to +2.3% 2.52 Lamiriv 150mg tab 040341 Blister strips 2 × 60 12/05 Kenya � � � � 100.6 � mean: 335.8mg -3.3% to +4.7% 2.62 Lamiriv 150mg tab 031674 As 2.51 Blister strips 2 × 60 11/05 Kenya � � � � 99.4 � mean: 337.1mg -2.7% to +4.7% 2.63 Lavir 150mg tab 01A05002 As 2.40 Plastic bottle 2 × 60 02/07 Zambia � � � � 98.8 � mean: 290.6mg 19 tablets: -2.4% to +2.4% 1 tablet: + 5.1% 2.64 Avolam 150mg tab 1499688 Blister strips 2 × 60 02/07 Zambia � � � � 101.6 � mean: 308.3mg -2.9% to +1.7% 3. Lamivudine Test Plan B: Tablets, prequalified (25 samples) – Swissmedic methods SPECIFICATIONS: Content of lamivudine: 95.0-105.0% of stated amount Related substances: Impurity A - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.3% Impurity B - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.2% Any other impurity: ≤ 0.1% Total impurities: ≤ 1.0% Dissolution: Not less than 80% (Q) of the stated amount of lamivudine dissolved in 30 minutes � = Complies *=WHO-prequalified 29 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample & pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- solution (% of stated amount) Uniformity of mass 2.02* Lamivudine 150mg tab 7200227 Plastic bottle 2 × 60 02/07 Nigeria � � � 102.5 � 94.8-100.7 mean: 279.2mg -1.9% to +2.7% 2.07* Epivir 150mg tab B144178 As 2.13 Plastic bottle 2 × 60 09/06 Nigeria � � � 100.3 � 94.4-101.4 mean: 304.5mg -1.1% to +1.3% 2.13* Epivir 150mg Tab B144178 As 2.07 Plastic bottle 2 × 60 09/06 Nigeria � � � 102.4 � 96.4-103.0 mean: 305.9mg -1.0% to +1.0% 2.20* Lamivir 150mg tab G32074 Plastic bottle 2 × 60 02/06 Cameroon � � � 100.1 � 96.5-99.7 mean: 307.7mg 19 tablets: -3.5% to + 1.8% 1 tablet: - 5.1% 2.22* Epivir 150mg tab R169400 As 2.26 and 2.57 Plastic bottle 2 × 60 03/07 Uganda � � � 102.1 � 97.1-101.5 mean: 304.9mg -2.3% to +3.2% 2.23* Epivir 150mg tab R171437 Plastic bottle 2 × 60 04/07 Uganda � � � 102.6 � 95.4-98.7 mean: 307.2mg -1.2% to +1.6% 2.24* Lamivir 150mg tab G54349 Plastic bottle 2 × 60 02/08 Uganda � � � 101.5 � 97.9-100.7 mean: 301.6mg -1.8% to +2.1% 2.26* Epivir 150mg tab R169400 As 2.22 and 2.57 Plastic bottle 2 × 60 03/07 Uganda � � � 100.1 � 93.8-102.8 mean: 306.0mg -2.5% to +2.5% 2.27* Lamivir 150mg tab Y50645 Plastic bottle 2 × 60 02/08 Tanzania � � � 103.0 � 99.8-102.8 mean: 303.0mg -1.6% to +1.7% 2.29* Lamivir 150mg tab Y41272 As 2.35 Plastic bottle 2 × 60 05/07 Tanzania � � � 102.0 � 98.6-100.0 mean: 309.3mg -1.7% to +2.5% 2.30* Lamivir 150mg tab G54328 Plastic bottle 2 × 60 02/08 Tanzania � � � 101.6 � 97.3-100.2 mean: 296.5mg -1.9% to +3.1% 2.31* Lamivir 150mg tab Y50743 Plastic bottle 2 × 60 02/08 Tanzania � � � 102.7 � 97.6-98.8 mean: 300.6mg -1.4% to +1.8% 2.32* Lamivir 150mg tab G54177 Plastic bottle 2 × 60 01/08 Tanzania � � � 98.3 � 94.5-98.6 mean: 300.9mg - 2.4% to +3.1% 2.35* Lamivir 150mg tab Y41272 As 2.29 Plastic bottle 2 × 60 05/07 Tanzania � � � 98.9 � 93.3-97.4 mean: 305.9mg - 1.9% to +1.7% 2.37* Lamivir 150mg tab G54329 As 2.39 Plastic bottle 2 × 60 02/08 Tanzania � � � 100.6 � 99.3-100.1 mean: 300.8mg -2.8% to +1.5% 2.39* Lamivir 150mg tab G54329 As 2.37 Plastic bottle 2 × 60 02/08 Tanzania � � � 100.2 � 96.3-101.5 mean: 300.5mg -3.3% to +2.1% 2.46* Lamivir 150mg tab G54268 Plastic bottle 2 × 60 02/08 DRC � � � 99.5 � 98.0-102.1 mean: 303.3mg -2.0% to +3.3% 2.47* Epivir 150mg tab B128377 Plastic bottle 1 × 60 03/06 DRC � � � 100.5 � 95.8-99.1 mean: 307.1mg -1.0% to +1.1% 2.56* Epivir 150mg tab B145845 Plastic bottle 2 × 60 09/06 Kenya � � � 100.4 � 95.1-97.0 mean: 302.5mg -1.5% to +1.4% 2.57* Epivir 150mg tab R169400 Plastic bottle 2 × 60 03/07 Kenya � � � 100.5 � 93.0-102.4 mean: 303.5mg -2.2% to +2.3% 2.58* Epivir 150mg tab B132605 Plastic bottle 2 × 60 05/06 Kenya � � � 100.0 � 96.5-103.3 mean: 305.2mg -1.4% to +1.1% 2.59* Epivir 150mg tab R154285 Plastic bottle 2 × 60 12/06 Kenya � � � 99.2 � 94.8-99.7 mean: 302.3mg -1.6% to +2.0% 2.60* Epivir 150mg tab B143470 Plastic bottle 2 × 60 09/06 Kenya � � � 101.1 � 96.9-101.5 mean: 304.7mg -1.2% to +1.7% 2.61* Epivir 150mg tab R152020 Plastic bottle 2 × 60 11/06 Kenya � � � 102.4 � 95.4-99.1 mean: 304.5mg -1.7% to +1.5% 2.65* Lamivir 150mg tab Y50435 Plastic bottle 2 × 60 12/06 Zambia � � � 98.6 � 101.5- 103.0 mean: 299.6mg -1.2% to +1.4% 3. Lamivudine Test Plan C: Oral solutions (23 samples) – Swissmedic methods SPECIFICATIONS: Content of lamivudine: 90.0-105.0% of stated amount Related substances: Cytosine (Ph.Eur. 5.3, 01/2006:2217 Impurity E): ≤ 0.3% Impurity G - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.3% Impurity H - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.7% Impurity J - Ph.Eur. 5.3, 01/2006:2217: ≤ 1.2% Other known single impurity: ≤ 0.3% Other single impurity (known): ≤ 0.2% Total impurities: ≤ 2.7% pH: 5.7 to 6.3 � = Complies *=WHO-prequalified 30 OMCL No. Trade name, strength and dosage form Primary pack Sample & pack size Expiry date Country Appearance Content (% of stated amount) Related substances pH 2.03 Avolam 50mg/5ml oral sol. Glass bottle 2 × 100 01/2006 Nigeria � 95.3 � 6.0 2.04 Avolam 50mg/5ml oral sol. Glass bottle 1 × 200 02/2007 Nigeria � 97.1 � 5.7 2.12* Lavudine 50mg/5ml oral sol. Plastic bottle 2 × 100 01/2007 Nigeria � 96.8 � 5.8 2.14* Epivir 10mg/ml oral sol. Plastic bottle 2 × 240 07/2005 Nigeria � 94.4 � 6.1 2.15 Virex-L 50mg/5ml oral sol. Glass bottle 2 × 100 02/2007 Nigeria � 99.0 � 5.0 2.16* Lamivir 50mg/5ml oral sol. Glass bottle 2 × 100 11/2006 Cameroon � 97.8 � 5.9 2.17* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 11/2006 Cameroon � 96.4 � 6.0 2.18* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 03/2007 Cameroon � 97.0 � 6.0 2.19* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 02/2007 Cameroon � 97.5 � 6.1 2.21* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 240 02/2007 Uganda � 95.6 � 6.0 2.25 Okavir 50mg/5ml oral sol. Glass bottle 2 × 100 07/2006 Uganda � 94.3 � 6.0 2.28* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 01/2007 Tanzania � 95.0 � 6.1 2.33* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 07/2006 Tanzania � 94.0 � 6.0 2.34 Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 07/2006 Tanzania � 96.4 � 6.0 2.36* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 02/2007 Tanzania � 96.3 � 5.9 2.38* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 02/2007 Tanzania � 98.9 � 6.0 2.44* Lamivir 50mg/5ml oral sol. Plastic flacon 2 × 100 08/2006 DRC � 99.9 � 6.0 2.45* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 05/2006 DRC � 95.6 � 5.9 2.48* Epivir 10mg/ml oral sol. Plastic bottle 2 × 140 11/2005 DRC � 96.8 � 6.1 2.53* Epivir 10mg/ml oral sol. Plastic bottle 2 × 240 02/2007 Kenya � 100.2 � 6.1 2.54* Epivir 10mg/ml oral sol. Plastic bottle 2 × 240 11/2006 Kenya � 98.3 � 6.1 2.55* Epivir 10mg/ml oral sol. Plastic bottle 2 × 240 10/2006 Kenya � 98.4 � 6.1 2.66* Lamivir 50mg/5ml oral sol. Plastic bottle 2 × 100 09/2006 Zambia � 95.1 � 6.1 4. Nevirapine Test Plan A: Tablets, not prequalified (15 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content of nevirapine: 90.0-110.0% of stated amount; Related substances: Any individual impurity: ≤ 1.0% Total impurities: ≤ 2.0% � = Complies 31 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample & pack size Expiry date Country Label Ap- pear- ance Iden- tity Dis- integra- tion Content (% of stated amount) Related substances Uniformity of mass 3.02 Nevran 200mg tab 1397711 Paper carton 2 × 5 × 12 04/06 Nigeria � � � � 97.7 � mean: 805.6mg -1.7% to +1.3% 3.07 Nevran 200mg tab 1394027 Blister strips 2 × 5 × 12 03/06 Nigeria � � � � 98.5 � mean: 802.7mg -3.6% to +1.9% 3.08 Nevran 200mg tab 1386313 Blister strips 2 × 5 × 12 02/06 Nigeria � � � � 97.4 � mean: 804.9mg -2.9% to +2.9% 3.09 Nevran 200mg tab 1386311 Blister strips 2 × 5 × 12 02/06 Nigeria � � � � 97.6 � mean: 805.4mg -1.8% to +1.8% 3.10 Nevran 200mg tab 1386265 Blister strips 2 × 5 × 12 02/06 Nigeria � � � � 97.9 � mean: 805.3mg -0.9% to +1.9% 3.25 Nevir 200mg tab OIA05007 Plastic bottle 2 × 60 02/07 Tanzania � � � � 98.5 � mean: 370.4mg -1.3% to +1.4% 3.49 Neviriv 200mg tab 040343 Blister strips 8 × 15 12/05 Kenya � � � � 97.1 � mean: 932.6mg -1.2% to +1.1% 3.50 Neviriv 200mg tab 040344 Blister strips 2 × 60 12/05 Kenya � � � � 96.1 � mean: 935.8mg -1.3% to +1.4% 3.51 Neviriv 200mg tab 031678 Blister strips 2 × 60 11/05 Kenya � � � � 96.7 � mean: 930.2mg -1.0% to +0.8% 3.52 Nevipan 200mg tab 1397709 Blister strips 2 × 60 04/06 Kenya � � � � 97.2 � mean: 803.9mg -1.3% to +2.2% 3.53 Nevir 200mg tab LNL0406 Plastic bottle 2 × 60 05/06 Kenya � � � � 96.1 � mean: 367.8mg -1.5% to +1.8% 3.54 Nevir 200mg tab LNL0405 Plastic bottle 2 × 60 05/06 Kenya � � � � 95.8 � mean: 369.3mg -1.7% to +1.2% 3.67 Okamune 200mg tab S50063 Plastic bottle 2 × 60 03/06 Zambia � � � � 96.1 � mean: 845.3mg -1.9% to +1.1% 3.68 Nevipan 200mg tab 1497485 Blister strips 2 × 60 02/07 Zambia � � � � 99.5 � mean: 811.4mg -1.7% to +1.8% 3.70 Nevir 200mg LNL0407 Plastic bottle 2 × 60 05/06 Zambia � � � � 96.1 � mean: 370.4mg -1.2% to +3.0% 4. Nevirapine Test Plan B: Tablets, prequalified (29 samples) – Swissmedic methods SPECIFICATIONS: Content of nevirapine: 95.0-105.0% of stated amount Related substances: Any individual impurity: ≤ 0.1%; Total impurities:≤ 0.2% Dissolution: Not less than 75% (Q) of the stated amount of nevirapine dissolved in 60 minutes � = Complies; *=WHO-prequalified 32 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dissolution (% of stated amount) Uniformity of mass 3.01* Nevirapine 200mg tab ZEG 4003 Plastic bottle 2 × 60 11/06 Nigeria � � � 98.9 � 85.2-88.2 ξ= 86.9 mean: 453.4mg -0.8% to +1.0% 3.05* Nevivir 200mg tab NV 50213 Plastic bottle 2 × 60 01/07 Nigeria � � � 96.3 � 94.5-98.1 ξ= 96.4 mean: 360.5mg -1.7% to +2.4% 3.06* Viramune 200mg tab 407734 As 3.61 Blister strips 2 × 6 × 10 10/07 Nigeria � � � 97.3 � 88.4-92.9 ξ= 90.0 mean: 807.4mg -2.1% to +1.2% 3.12* Viramune 200mg tab 405312A Blister strips 2 × 6 × 10 06/07 Nigeria � � � 97.6 � 94.9-97.4 ξ= 96.0 mean: 808.5mg -0.8% to +0.8% 3.15* Nevivir 200mg tab NV40101 Plastic bottle 2 × 60 12/05 Uganda � � � 96.0 � 81.0-84.0 ξ= 82.8 mean: 358.9mg -2.3% to +1.1% 3.16* Viramune 200mg tab 409335B Plastic bottle 2 × 60 01/08 Uganda � � � 97.8 � 90.7-95.4 ξ= 93.9 mean: 805.0mg -1.4% to +1.3% 3.19* Nevivir 200mg tab NV40101 Plastic bottle 2 × 60 12/05 Uganda � � � 95.9 � 83.2-85.1 ξ= 84.0 mean: 360.7mg -2.2% to +1.1% 3.21* Nevivir 200mg tab NV40101 Plastic bottle 2 × 60 12/05 Uganda � � � 96.0 � 83.3-86.4 ξ= 84.6 mean: 362.9mg -1.9% to +2.5% 3.23* Nevimune 200mg tab C50046 Plastic bottle 2 × 60 12/06 Tanzania � � � 97.2 � 86.0-93.3 ξ= 89.3 mean: 855.6mg -1.6% to +1.5% 3.24* Viramune 200mg tab 3086588 Blister strips 2 × 60 11/06 Tanzania � � � 96.8 � 81.7-85.3 ξ= 84.2 mean: 807.5mg -1.3% to +0.9% 3.27* Nevimune 200mg tab C40464 Plastic bottle 2 × 60 07/06 Tanzania � � � 98.5 � 82.8-92.3 ξ= 86.9 mean: 849.7mg -1.2% to +2.0% 3.29* Nevimune 200mg tab C40467 As 3.36 Plastic bottle 1 × 60 07/06 Tanzania � � � 99.4 � 84.0-90.4 ξ= 87.3 mean: 852.2mg -2.3% to +2.0% 3.30* Nevimune 200mg tab G54198 Plastic bottle 1 × 60 01/07 Tanzania � � � 97.4 � 92.7-97.9 ξ= 95.1 mean: 845.6mg -1.1% to +1.3% 3.32* Nevimune 200mg tab C40463 Plastic bottle 2 × 60 07/06 Tanzania � � � 96.0 � 80.0-86.4 ξ= 83.2 mean: 846.2mg -2.2% to +1.2% 3.34* Nevimune 200mg tab C40339 Plastic bottle 2 × 60 05/06 Tanzania � � � 98.0 � 91.3-93.3 ξ= 92.4 mean: 847.7mg -2.5% to +2.9% 3.36* Nevimune 200mg tab C40467 As 3.29 Plastic bottle 2 × 60 07/06 Tanzania � � � 98.4 � 94.4-97.7 ξ= 96.2 mean: 846.0mg 19 tablets: -1.8% to +1.1% 1 tablet: + 7.5% 3.37* Nevivir 200mg tab NV41009 Glass bottle 2 × 60 09/06 DRC � � � 97.3 � 89.9-94.7 ξ= 93.4 mean: 358.3mg -1.3% to +1.0% 3.40* Nevimune 200mg tab G54351 Plastic bottle 2 × 60 02/07 DRC � � � 96.5 � 87.3-90.9 ξ= 89.1 mean: 851.0mg -1.9% to +1.5% 3.42* Nevimune 200mg tab G44044 Plastic bottle 2 × 60 12/05 DRC � � � 98.6 � 81.5-86.0 ξ= 84.4 mean: 849.5mg -1.9% to +1.3% 3.44* Viramune 200mg tab 502809 Blister strips 2 × 60 02/07 DRC � � � 97.6 � 91.0-94.2 ξ= 93.1 mean: 808.3mg -2.1% to +1.2% 3.45* Nevivir 200mg tab NV31109 Plastic bottle 2 × 60 10/05 Kenya � � � 100.2 � 92.6-96.4 ξ= 94.5 mean: 360.5mg -0.9% to +3.1% 3.46* Nevimune 200mg tab G44559 Plastic bottle 2 × 60 05/06 Kenya � � � 98.1 � 82.7-85.2 ξ= 84.1 mean: 847.6mg -4.2% to +3.10% 3.47* Nevimune 200mg tab C50261 Plastic bottle 8 × 15 04/07 Kenya � � � 98.8 � 85.2-89.9 ξ= 88.6 mean: 854.4mg -0.8% to +1.4% 3.48* Nevimune 200mg tab C50085 Plastic bottle 8 × 15 01/07 Kenya � � � 100.3 � 81.7-98.6 ξ= 92.1 mean: 859.1mg -1.3% to +2.0% 3.57* Viramune 200mg tab 502154A Blister strips 2 × 60 01/08 Kenya � � � 98.4 � 102.6- 108.8 ξ= 106.0 mean: 804.6mg -1.1% to +1.4% 3.58* Viramune 200mg tab 409351 Blister strips 2 × 60 01/08 Kenya � � � 99.8 � 90.5-93.5 ξ= 92.1 mean: 819.4mg -2.0% to +1.7% 3.59* Viramune 200mg tab 408826 Blister strips 2 × 60 11/07 Kenya � � � 99.2 � 91.6-94.7 ξ= 93.2 mean: 807.4mg -1.8% to +2.5% 3.60* Viramune 200mg tab 408827 Blister strips 2 × 60 11/07 Kenya � � � 99.8 � 93.6-97.2 ξ= 95.8 mean: 812.7mg -1.6% to +1.4% 3.61* Viramune 200mg tab 407734 As 3.06 Blister strips 2 × 60 10/07 Kenya � � � 98.5 � 87.2-90.9 ξ= 89.3 mean: 809.5mg -1.0% to +1.2% 4. Nevirapine Test Plan C: Oral suspensions (28 samples) – Swissmedic methods SPECIFICATIONS: Content of nevirapine: 95.0-105.0% of stated amount Related substances: Any individual impurity (unknown): ≤ 0.1% Total impurities (degradation): ≤ 0.2% pH: 5.4 to 6.0 � = Complies; *=WHO-prequalified 33 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample & pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances pH 3.03 Nevran 50mg/5ml oral suspension 00105 Glass bottle 1 × 200 02/07 Nigeria � � � 99.3 � 6.0 3.04 Nevran 50mg/5ml oral suspension 00104 Glass bottle 2 × 100 01/06 Nigeria � � � 98.3 � 5.9 3.11 Evadine 50mg/5ml oral suspension G30454 Plastic bottle 2 × 100 06/05 Nigeria � � � 104.7 � 5.7 3.13* Viramune 50mg/5ml oral suspension L457744A As 3.64 Plastic bottle 2 × 240- 04/07 Nigeria � � � 95.8 � 5.7 3.14 Virex-N 50mg/5ml oral suspension LA8500N Glass bottle 2 × 100 02/07 Nigeria � � � 93.4 � 3.4 3.17 Nevirapine 50mg/5ml oral suspension G40667 Plastic bottle 2 × 100 07/06 Uganda � � � 98.5 � 5.9 3.18 Nevirapine 50mg/5ml oral suspension G40661 Plastic bottle 3 × 100 07/06 Uganda � � � 106.5 � 5.9 3.20 Okamune 50mg/5ml oral suspension C40556 Glass bottle 5 × 100 08/06 Uganda � � � 107.8 � 5.8 3.22* Viramune 50mg/5ml oral suspension L457823A Plastic bottle 2 × 240 06/07 Tanzania � � � 97.2 � 5.7 3.26* Viramune 50mg/5ml oral suspension L457826A Plastic bottle 2 × 240 06/07 Tanzania � � � 96.9 � 5.7 3.28* Viramune 50mg/5ml oral suspension L457647A As 3.31 Plastic bottle 2 × 240 05/07 Tanzania � � � 97.5 � 5.7 3.31* Viramune 50mg/5ml oral suspension L457647A As 3.28 Plastic bottle 2 × 240 05/07 Tanzania � � � 98.0 � 5.7 3.33* Viramune 50mg/5ml oral suspension L457646A As 3.35 Plastic bottle 2 × 240 05/07 Tanzania � � � 99.6 � 5.7 3.35* Viramune 50mg/5ml oral suspension L457646A As 3.33 Plastic bottle 2 × 240 05/07 Tanzania � � � 99.1 � 5.7 3.38 Nevimune 50mg/5ml oral suspension G40748 Plastic bottle 2 × 100 08/06 DRC � � � 104.8 � 5.8 3.39 Nevimune 50mg/5ml oral suspension G30533 Plastic bottle 2 × 100 08/05 DRC � � � 105.6 � 5.8 3.41 Nevimune 50mg/5ml oral suspension G40186 Glass bottle 2 × 25 02/06 DRC � � � 101.3 � 6.0 3.43* Viramune 50mg/5ml oral suspension L357428C Plastic bottle 1 × 240 08/05 DRC � � � 95.9 � 5.7 3.55* Viramune 50mg/5ml oral suspension K456586J Plastic bottle 10 × 20 04/06 Kenya � � � 97.3 � 5.7 3.56* Viramune 10mg/ml oral suspension K456586H Plastic bottle 10 × 20 04/06 Kenya � � � 98.3 � 5.7 3.62* Viramune 50mg/5ml oral suspension L457822A Plastic bottle 2 × 240 06/07 Kenya � � � 96.5 � 5.7 3.63* Viramune 10mg/ml oral suspension L456090B Plastic bottle 2 × 240 08/06 Kenya � � � 98.3 � 5.7 3.64* Viramune 50mg/5ml oral suspension L457744A As 3.13 Plastic bottle 2 × 240 04/07 Kenya � � � 96.7 � 5.7 3.65* Viramune 50mg/5ml oral suspension L457643A Plastic bottle 2 × 240 04/07 Kenya � � � 96.9 � 5.7 3.66 Nevimune 50mg/5ml oral suspension G41065 Plastic bottle 2 × 100 11/06 Zambia � � � 107.5 � 5.6 3.69 Nevir 50mg/5ml oral suspension RNS0401 Plastic bottle 2 × 100 12/05 Zambia � � � 104.3 � 5.5 3.71 Viramune 50mg/5ml oral suspension 456588° Plastic bottle 2 × 240 05/07 Zambia � � � 97.1 � 5.7 3.72* Viramune 50mg/5ml oral suspension 456585A Plastic bottle 2 × 240 04/07 Zambia � � � 96.8 � 5.7 5. Stavudine Test Plan A: Capsules, not prequalified (32 samples) – USP methods SPECIFICATIONS: Content of stavudine: 90.0-105.0% of stated amount Related substances: Thymine: ≤ 1.0%; Any individual impurity: ≤ 0.2%; Total impurities: ≤ 2.0% (a) Acceptable considering the uncertainty of the test method � = Complies 34 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample & pack size Expiry date Country Label Ap- pear- ance Iden- tity Dis- integra- tion Content (% of stated amount) Related sub- stances Uniformity of mass 1.02 Stag 40mg cap SV 50227 Plastic bottle 2 × 60 01/07 Nigeria � � � � 96.8 � mean: 354.9mg -5.2% to +3.7% 1.03 Avostav 40mg cap 1393469 Blister strips 2 × 60 03/06 Nigeria � � � � 101.2 � mean: 451.6mg -1.2% to +1.1% 1.04 Stavir 40mg cap G33558 Plastic bottle 2 × 60 06/05 Nigeria � � � � 104.8 � mean: 274.6mg -3.4% to +5.1% 1.06 Avostav 40mg cap 1383989 Blister strips 2 × 60 02/06 Nigeria � � � � 101.5 � mean: 450.0mg -1.4% to +1.7% 1.07 Avostav 40mg cap 1384320 Blister strips 2 × 60 02/06 Nigeria � � � � 101.9 � mean: 452.8mg -1.1% to +1.4% 1.08 Avostav 40mg cap 1385790 Blister strips 2 × 60 02/06 Nigeria � � � � 102.5 � mean: 453.4mg -2.0% to +1.3% 1.09 Melxicap 40mg cap G46175 Plastic bottle 2 × 60 01/06 Nigeria � � � � 107.9 (a) � mean: 275.2mg -1.3% to +1.8% 1.10 Melxicap 30mg cap G46174 Plastic bottle 2 × 60 01/06 Nigeria � � � � 102.9 � mean: 274.2mg -1.6% to +2.3% 1.14 Stavin 40mg cap C40326 Plastic bottle 2 × 60 05/06 Uganda � � � � 104.7 � mean: 269.1mg -4.9% to +4.5% 1.15 Stavir 30mg cap G56074 Plastic bottle 2 × 60 12/06 Uganda � � � � 104.3 � mean: 276.2mg -2.8% to +3.7% 1.16 Stavir 30mg cap SG31202 Plastic bottle 2 × 60 11/05 Uganda � � � � 101.7 � mean: 361.7mg -4.5% to +3.0% 1.17 Stag 40mg cap SV40201 Plastic bottle 2 × 60 01/06 Uganda � � � � 101.6 � mean: 362.3mg -3.4% to +4.6% 1.18 Stavin 30mg cap C40341 As 1.32 Plastic bottle 2 × 60 05/06 Uganda � � � � 103.3 � mean: 272.6mg -2.4% to +2.4% 1.19 Stadine 40mg cap LGA 05002 Plastic bottle 2 × 60 02/07 Tanzania � � � � 102.8 � mean: 300.7mg -5.1% to +7.8% 1.20 Stadine 40mg cap LGA 05005 Plastic bottle 2 × 60 02/07 Tanzania � � � � 103.9 � mean: 307.6mg -1.6% to +1.5% 1.21 Stavex 30mg cap SX 3005001 Plastic bottle 2 × 60 04/07 Tanzania � � � � 101.5 � mean: 456.4mg -3.4% to +2.6% 1.22 Stavex 30mg cap SX 3005002 Plastic bottle 2 × 30 04/07 Tanzania � � � � 99.7 � mean: 452.4mg -2.8% to +3.3% 1.31 Stavudine 30mg cap AS05- L9001 Plastic bottle 2 × 14 05/07 DRC � � � � 103.5 � mean: 271.7mg -5.1% to +4.1% 1.32 Stavir 30mg cap C40341 As 1.18 Plastic bottle 2 × 60 05/06 DRC � � � � 104.0 � mean: 271.0mg -3.8% to +3.1% 1.33 Stag 30mg cap S.G40917 Plastic bottle 2 × 60 08/06 DRC � � � � 104.3 � mean: 370.2mg -4.5% to +4.2% 1.34 Stag 40mg cap S.V40915 Plastic bottle 2 × 60 08/06 DRC � � � � 101.8 � mean: 362.1mg -6.4% to +6.8% 1.48 Stag 40mg cap SV41016 Plastic bottle 2 × 60 09/06 Kenya � � � � 100.0 � mean: 362.4mg -2.5% to +5.1% 1.49 Stag 30mg cap SG40916 Plastic bottle 2 × 60 08/06 Kenya � � � � 102.9 � mean: 365.3mg -6.9% to +5.6% 1.50 Stariv 30mg cap 040340 Blister strips 2 × 60 12/05 Kenya � � � � 102.0 � mean: 288.2mg -3.6% to +7.2% 1.51 Stariv 30mg cap 031680 Blister strips 2 × 60 11/05 Kenya � � � � 99.4 � mean: 287.3mg -4.6% to +6.7% 1.52 Stariv 40mg cap 041692 Blister strips 2 × 60 09/06 Kenya � � � � 102.0 � mean: 289.2mg -3.6% to +6.2% 1.53 Stariv 40mg cap 031682 Blister strips 2 × 60 11/05 Kenya � � � � 101.3 � mean: 291.1mg -4.3% to +6.7% 1.54 Avostav 30mg cap 1465726 Plastic bottle 2 × 60 11/06 Zambia � � � � 103.3 � mean: 350.2mg -1.8% to +1.8% 1.55 Stadine 40mg cap OST0301 Plastic bottle 2 × 60 11/05 Zambia � � � � 103.1 � mean: 311.4mg -2.7% to +5.4% 1.56 Stavudine 30mg cap 7200497 Plastic bottle 2 × 60 04/07 Zambia � � � � 102.6 � mean: 318.3mg -3.3% to +2.1% 1.57 Stag 40mg cap SV41217 Plastic bottle 2 × 60 11/06 Zambia � � � � 101.7 � mean: 369.0mg -4.3% to +7.0% 1.58 Stag 40mg cap SV40607 Plastic bottle 2 × 60 05/06 Zambia � � � � 99.0 � mean: 358.8mg -5.9% to +5.0% 5. Stavudine Test Plan B: Oral solutions, not prequalified (2 samples) – USP methods SPECIFICATIONS: Content of stavudine: 90.0-110.0% of stated amount Related substances: Thymine: ≤ 1.0% Unknown impurities each: ≤ 0.2% Total impurities: ≤ 1.5% � = Complies 35 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Appearance Content (% of stated amount) Related substances 1.13 Zerit 200mg, powder for oral solution 0170 Plastic bottle 2 × 200 11/06 Cameroon (2) � 100.2 � 1.24 Zerit 200mg, powder for oral solution 0175 Plastic bottle 2 × 200 01/07 Tanzania (3) � 101.0 � (2) Information items (6), (7) and (8) missing on immediate container (WHO sampling number CAE/STV/Susp/01) (3) Information items (6), (7) and (8) missing on immediate container (WHO sampling number TAN PUT1 S/01/1) 5. Stavudine Test Plan C: Capsules, prequalified (26 samples) – Swissmedic methods SPECIFICATIONS: Content of stavudine: 90.0-105.0 of stated amount Related substances: Thymine: ≤ 2.0% Dissolution: Not less than 80%(Q) of the stated amount of stavudine dissolved in 30 minutes � = Complies *=WHO-prequalified 36 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- solution (% of stated amount) Uniformity of mass 1.01* Stavudine 40mg cap 7200258 Plastic bottle 2 × 60 02/07 Nigeria � � � 102.0 � 94-104 mean: 314.6mg -3.8% to +3.6% 1.05* Zerit 30mg cap 0019 Blister strips 2 × 56 06/06 Nigeria � � � 100.5 � 97-100 mean: 347.3mg -1.4% to +1.2% 1.11* Zerit 30mg cap 0008 Blister strips 3 × 56 08/05 Cameroon � � � 101.0 � 97-100 mean: 348.9mg -2.9% to +2.0% 1.12* Zerit 40mg cap 0012 Blister strips 3 × 56 08/05 Cameroon � � � 100.0 � 98-99 mean: 455.6mg -1.2% to +1.5% 1.23* Zerit 15mg cap 4K93177 As 1.46 Plastic bottle 2 × 60 10/06 Tanzania � � � 100.1 � 98-104 mean: 237.2mg -2.6% to +2.1% 1.25* Zerit 20mg cap 0017 Plastic bottle 2 × 60 02/07 Tanzania � � � 97.4 � 97-101 mean: 331.3mg -4.2% to +2.6% 1.26* Zerit 40mg cap 0023 As 1.28 Plastic bottle 2 × 60 06/06 Tanzania � � � 101.2 � 99-101 mean: 452.0mg -0.8% to +0.9% 1.27* Zerit 30mg cap 0023 As 1.37 Plastic bottle 2 × 60 12/06 Tanzania � � � 101.0 � 100-103 mean: 344.9mg -1.1% to +1.1% 1.28* Zerit 40mg cap 0023 As 1.26 Plastic bottle 2 × 60 06/06 Tanzania � � � 102.1 � 99-101 mean: 451.5mg -0.9% to +1.2% 1.29* Zerit 30mg cap 0033 As 1.23 Plastic bottle 2 × 60 04/07 Tanzania � � � 101.6 � 99-102 mean: 344.9mg -1.2% to +0.9% 1.30* Zerit 30mg cap 0033 Plastic bottle 2 × 60 04/07 Tanzania � � � 101.5 � 100-101 mean: 344.6mg -1.1% to +0.8% 1.35* Zerit 40mg cap 0017 Blister strips 1 × 56 11/05 DRC � � � 100.8 � 99-100 mean: 452.9mg -1.0% to +1.2% 1.36* Zerit 20mg cap 0009 Plastic bottle 2 × 60 12/06 Kenya � � � 101.5 � 99-100 mean: 334.0mg -1.9% to +0.9% 1.37* Zerit 30mg cap 0023 Plastic bottle 2 × 60 12/06 Kenya � � � 101.8 � 100-101 mean: 344.8mg -1.0% to +1.5% 1.38* Zerit 30mg cap 0034 Plastic bottle 2 × 60 04/07 Kenya � � � 100.6 � 98-102 mean: 342.6mg -3.2% to +1.3% 1.39* Zerit 30mg cap 0033 Plastic bottle 2 × 60 04/07 Kenya � � � 101.5 � 99-101 mean: 344.8mg -0.6% to +0.8% 1.40* Zerit 40mg cap 0029 Plastic bottle 2 × 60 11/06 Kenya � � � 102.9 � 100-101 mean: 452.2mg -2.5% to +2.7% 1.41* Zerit 40mg cap 0031 Plastic bottle 2 × 60 12/06 Kenya � � � 102.0 � 100-101 mean: 447.6mg -0.8% to +0.7% 1.42* Zerit 40mg cap 0037 Plastic bottle 2 × 60 04/07 Kenya � � � 102.0 � 100-102 mean: 450.6mg -1.9% to +2.1% 1.43* Zerit 40mg cap 0039 Plastic bottle 2 × 60 04/07 Kenya � � � 102.1 � 99-101 mean: 454.5mg -1.6% to +1.7% 1.44* Zerit 30mg cap 4A80354 Plastic bottle 2 × 60 10/05 Kenya � � � 103.5 � 102-104 mean: 347.0mg -2.2% to +1.7% 1.45* Zerit 15mg cap 5C07315 B Plastic bottle 2 × 60 02/08 Kenya � � � 101.0 � 102-105 mean: 231.3mg -2.6% to +1.9% 1.46* Zerit 15mg cap 4K93177 Plastic bottle 2 × 60 10/06 Kenya � � � 101.1 � 100-104 mean: 234.2mg -3.1% to +2.3% 1.47* Zerit 15mg cap 4A73491 Plastic bottle 2 × 60 10/05 Kenya � � � 99.0 � 96-102 mean: 232.1mg -3.1% to +2.0% 1.59* Zerit 30mg cap 0039 Blister strips 2 × 56 04/07 Zambia � � � 101.3 � 98-100 mean: 345.2mg -1.1% to +0.8% 1.60* Zerit 40mg cap 0038 Blister strips 2 × 56 04/07 Zambia � � � 103.5 � 99-101 mean: 455.7mg -1.8% to +1.8% 6. Zidovudine Test Plan A: Capsules/tablets, prequalified (17 samples) – Swissmedic methods SPECIFICATIONS: Content of zidovudine: Tablets: 95.0-105.0% of the stated amount Capsules: 90.0-110.0% of the stated amount Related substances: Tablets: Thymine: ≤ 3.0% Unknown impurities each: ≤ 0.5% Sum of unidentified impurities: ≤ 1.0% Sum of total related substances: ≤ 4.0% (w/w) Capsules: Sum of total impurities: ≤ 3.0% (w/w) Dissolution: Tablets: Not less than 80% at 30 minutes (Q value 75%) Capsules: Not less than 80% at 45 minutes (Q value of 75% at 45 minutes) � = Complies; *=WHO-prequalified 37 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances Dis- solution (% of stated amount) Uniformity of mass 5.04* Xilec 300mg tab G33616 As 5.26 Plastic bottle 2 × 60 07/06 Nigeria � � � 98.1 � 80-90 mean: 347.0mg -2.1% to +4.0% 5.10* Zidovir 300mg tab G54603 Plastic bottle 2 × 60 04/08 Cameroon � � � 97.0 � 95-98 mean: 350.2mg -1.7% to + 2.4% 5.11* Zidovir 300mg tab G54134 Plastic bottle 2 × 60 01/08 Cameroon � � � 98.5 � 90-99 mean: 350.8mg -2.1% to +2.4% 5.13* Zidovir 300mg tab H54133 Plastic bottle 2 × 60 01/08 Uganda � � � 98.7 � 92-97 mean: 350.1mg -2.5% to +2.7% 5.14* Zidovir 300mg tab G45205 Plastic bottle 2 × 60 11/07 Uganda � � � 99.7 � 91-99 mean: 356.4mg -1.2% to +0.9% 5.17* Zidovir 100mg cap C50074 Blister strips 2 × 200 01/07 Tanzania � � � 101.3 � 95-106 mean: 236.3mg -6.2% to +7.4% 5.18* Zidovir 100mg cap C40618 Blister strips 2 × 200 10/06 Tanzania � � � 99.1 � 86-94 mean : 236.0mg -9.7% to +7.0% 5.19* Zidovir 300mg tab G47056 Plastic bottle 2 × 60 08/07 Tanzania � � � 100.3 � (5) mean: 354.2mg -2.0% to +4.3% 5.26* Zidovir 300mg tab G33616 As 5.04 Plastic bottle 1 × 60 07/06 DRC � � � 96.7 � 89-98 mean: 344.8mg 19 tablets: -2.5% to +2.2% 1 tablet : - 6.0% 5.27* Zidovir 300mg tab G46743 Plastic bottle 2 × 60 04/07 DRC � � � 99.4 � 98-101 mean: 353.8mg -1.5% to +3.8% 5.28* Zidovir 100mg cap G56295 Plastic bottle 2 × 60 02/07 DRC � � � 95.9 � 90-97 mean : 223.3mg 19 capsules : -9.6% to +8.2% 1 capsule: +10.2% 5.30* Zidovir 300mg tab G46529 Plastic bottle 2 × 60 04/07 DRC � � � 99.2 � 87-102 mean: 351.3mg -3.6% to +3.4% 5.31* Retrovir 100mg cap X3958 Blister strips 2 × 100 02/09 DRC � � � 101.1 � (a) mean: 232.2mg -3.5% to +5.3% 5.32* Retrovir 100mg cap X2421 Plastic bottle 1 × 100 09/09 Kenya � � � 99.8 � (a) mean: 228.7mg -2.1% to +1.3% 5.33* Retrovir 100mg cap X2679 Plastic bottle 1 × 100 09/09 Kenya � � � 102.1 � (a) mean: 234.4mg -1.2% to +1.4% 5.38* Retrovir 100mg cap X6627 Plastic bottle 2 × 60 10/07 Zambia � � � 98.7 � (a) mean : 228.2mg 19 capsules : - 0.9% to +2.6% 1 capsule: -11.3% 5.41* Zidovir 300mg tab C40559 Blister strips 2 × 60 09/06 Zambia � � � 96.8 � 94- 104 mean: 354.1mg -1.6% to +1.6% (5) Does not comply (WHO sampling number TAN PUP Z01/1) Stage 1: min. 1: 69%, min. 2: 70%, min. 3: 74%; max.:87% Stage 2: mean: 76%, min.: 58%, max.: 88% Stage 3: mean: 74%, min. 1: 55%, min. 2: 58%, min. 3: 64%, max: 88% (a) Dissolution not performed (not part of prequalified specifications) – disintegration complies 6. Zidovudine Test Plan A: Oral solutions, prequalified (3 samples) – Swissmedic methods SPECIFICATIONS: Related substances: Thymine ≤ 4.5% pH: 3.0 to 5.0 � = Complies; *=WHO-prequalified 38 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances pH 5.06* Retrovir 10mg, oral solution 4E005 Glass bottle 2 × 200 05/06 Nigeria � � � 99.6 � 3.5 5.34* Retrovir 10mg/ml, oral solution 4N014 Glass bottle 2 × 200 12/06 Kenya � � � 99.6 � 3.5 5.35* Retrovir 10mg/ml, oral solution 4M034 Glass bottle 2 × 200 11/06 Kenya � � � 98.7 � 3.5 6. Zidovudine Test Plan B: Oral solutions (19 samples) – USP methods SPECIFICATIONS: Content of zidovudine: 90.0-110.0% of stated amount Related substances: Thymine ≤ 3.0% (w/w) (USP) pH : 3.0 to 4.0 (USP) � = Complies; *=WHO-prequalified 39 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Content (% of stated amount) Related sub- stances pH 5.01 Azido 50mg/5ml oral sol. 00105 Glass bottle 2 × 200 02/07 Nigeria � � � 98.8 � 3.5 5.02 Azido 50mg/5ml oral sol. 00104 Glass bottle 2 × 100 01/06 Nigeria � � � 94.6 � 3.5 5.03* Xilec 50mg/5ml oral sol. G30476 Plastic bottle 2 × 100 07/05 Nigeria � � � 101.3 � 3.5 5.07 Virex-Z 50mg/5ml oral sol. LA8400N Glass bottle 2 × 100 02/07 Nigeria � � � 90.7 � 3.4 5.08* Zidovir 50mg/5ml oral sol. G50487 As 5.43 Plastic bottle 2 × 100 05/07 Cameroon � � � 99.7 � 3.7 5.09* Zidovir 50mg/5ml oral sol. G50249 Plastic bottle 2 × 100 02/07 Cameroon � � � 100.1 � 3.8 5.12* Zidovir 50mg/5ml oral sol. G50198 Plastic bottle 2 × 200 02/07 Uganda � � � 99.3 � 3.8 5.15* Zivir 50mg/5ml oral sol. CA0506 Plastic bottle 2 × 100 07/06 Uganda � � � 99.5 � 3.7 5.16* Zidovir 50mg/5ml oral sol. C40599 Plastic bottle 2 × 200 09/06 Tanzania � � � 99.5 � 3.8 5.20* Zidovir 50mg/5ml oral sol. C40489 Plastic bottle 2 × 100 07/06 Tanzania � � � 100.3 � 3.7 5.21* Zidovir 50mg/5ml oral sol. G50245 Plastic bottle 2 × 100 02/07 Tanzania � � � 100.7 � 3.9 5.22* Zidovir 50mg/5ml oral sol. C40496 Plastic bottle 2 × 100 07/06 Tanzania � � � 98.2 � 3.5 5.23* Zidovir 50mg/5ml oral sol. C40502 Plastic bottle 2 × 100 07/06 Tanzania � � � 100.1 � 3.7 5.24* Zidovir 50mg/5ml oral sol. G50238 Plastic bottle 2 × 100 02/07 Tanzania � � � 100.5 � 3.9 5.25* Zidovir 50mg/5ml oral sol. G41066 Plastic bottle 2 × 100 11/06 DRC � � � 101.0 � 3.8 5.40 Zidine 50mg/5ml oral sol. 02A05005 Glass bottle 2 × 100 12/06 Zambia � � � 97.7 � 3.5 5.42* Zidovir 50mg/5ml oral sol. G40839 Plastic bottle 2 × 100 09/06 Zambia � � � 100.3 � 4.0 5.43* Zidovir 50mg/5ml oral sol. G50487 As 5.08 Plastic bottle 2 × 100 05/07 Zambia � � � 97.7 � 3.7 5.44* Zidovir 50mg/5ml oral sol. G40838 Plastic bottle 2 × 100 09/06 Zambia � � � 99.8 � 3.9 6. Zidovudine Test Plan C: Tablets (5 samples) – USP methods SPECIFICATIONS: Content of zidovudine: 90.0-110.0% of stated amount Related substances: Thymine: ≤ 1.5% Any individual impurity: ≤ 0.2% Total impurities: ≤ 2.0% � = Complies; *=WHO-prequalified 40 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Iden- tity Dis- integra- tion Content (% of stated amount) Related sub- stances Uniformity of mass 5.05 Retrovir 300mg, tab V14 As 5.36 Blister strips 2 × 60 11/07 Nigeria � � � � 100.8 (a) mean: 374.3mg -2.1% to +1.5% 5.29 Zido-H 300mg, tab ZH40502 Plastic bottle 2 × 60 04/06 DRC � � � � 99.8 � mean: 370.9mg -1.8% to +2.5% 5.36 Retrovir 300mg, tab V14 As 5.05 Blister strips 2 × 60 11/07 Kenya � � � � 101.1 (b) mean: 374.7mg -0.7% to +1.0% 5.37* Zidovudine 300mg, tab ZV 3003005 Plastic bottle 3 × 10 11/06 Zambia � � � � 98.8 � mean: 346.0mg -1.5% to +0.8% 5.39 Zidine 300mg, tab LZI0401 Plastic bottle 2 × 60 06/06 Zambia � � � � 99.3 � mean: 424.9mg -1.3% to +0.9% 7. Lamivudine/zidovudine Test Plan A: Tablets, not prequalified (8 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content: 90.0-110.0% of stated amount for both active ingredients Related substances: Thymine: ≤ 2.0% β-thymidine: ≤ 1.0% Salicylic acid: ≤ 0.2% Any individual impurity: ≤ 0.5% Total impurities: ≤ 3.0% � = Complies 41 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Ap- pear- ance Dis- integra- tion Content (% of stated amount) Related sub- stances Uniformity of mass Identity of each active ingre- dient lami- vudine zido- vudine 7.04 Virex-LZ 150/300mg, tab TA4100N Plastic bottle 2 × 60 02/07 Nigeria � � � (4) 94.7 95.4 � mean: 615.3mg -1.4% to +1.9% 7.20 Lazid 150/300mg, tab 01A05005 Plastic bottle 2 × 60 02/07 Tanzania � � � � 97.6 96.4 � mean: 622.7mg -1.2% to +1.4% 7.26 Zidolam 150/300mg, tab ZL40817 Plastic bottle 2 × 60 07/06 DRC � � � � 98.3 98.9 � mean: 715.2mg -3.3% to +3.4% 7.27 Zidolam 150/300mg, tab Zl40938 Plastic bottle 2 × 60 08/06 DRC � � � � 97.1 98.7 � mean: 714.6mg -2.8% to +2.0% 7.28 Zidolam 150/300mg, tab ZL41043 Plastic bottle 2 × 60 09/06 Kenya � � � � 98.3 101.3 � mean: 710.5mg -3.5% to +2.4% 7.34 Lazid 150/300mg, tab 01A05002 Plastic bottle 2 × 60 02/07 Zambia � � � � 98.5 97.1 � mean: 626.7mg -1.5% to +1.9% 7.35 Avocomb 150/300mg, tab 1419577 Plastic bottle 2 × 60 06/06 Zambia � � � � 98.1 96.5 � mean: 763.4mg -1.1% to +0.9% 7.37 Bivir 150/300mg, tab S50060 Plastic bottle 2 × 60 03/06 Zambia � � � � 96.6 99.0 � mean: 760.7mg -1.1% to +: 0.9% (4) Does not comply (WHO sampling number NG41LZT) 7. Lamivudine/zidovudine Test Plan B: Tablets, prequalified (29 samples) – Swissmedic methods SPECIFICATIONS: Content: 95.0-105% of the stated amount for both active ingredients Related substances : Impurity A - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.3% Impurity B - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.2% Thymine: ≤ 3.0% Impurity B - Ph.Eur. 5.1, 04/2005:1059: ≤ 1.0% Any unspecified impurity: ≤ 0.5% Total lamivudine-related impurities ≤ 0.6% Total zidovudine-related impurities ≤ 4.0% Dissolution: Not less than 80% (Q) of the stated amount of both active ingredients dissolved in 30 minutes � = Complies; *=WHO-prequalified 42 OMCL No. Trade name, strength and dosage form Batch number Primary pack Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related sub- stances Dissolution (% of stated amount) Uniformity of mass Sample and pack size Identity of each active ingre- dient lami- vudine zido- vudine lamivudine zidovudine 7.01* Combivir 150/300mg, tab B136096 Blister strips 2 × 6 × 10 06/06 Nigeria � � � 98.0 98.1 � 101.3-104.8 ξ= 103.5 99.6-102.5 ξ= 101.1 mean: 771.2mg -1.8% to +2.3% 7.02* Arved 150/300mg, tab G32655 Plastic bottle 2 × 60 11/05 Nigeria � � � 99.1 96.5 � 98.9-103.7 ξ= 101.9 99.3-105.7 ξ= 102.7 mean: 764.0mg -0.9% to +1.3% 7.03* Combivir 150/300mg, tab B136389 Blister strips 2 × 6 × 10 06/06 Nigeria � � � 96.9 97.8 � 101.2-103.7 ξ= 102.4 100.4-102.4 ξ= 101.1 mean: 768.6mg -1.9% to +1.3% 7.05* Duovir 150/300mg, tab G44493 Plastic bottle 2 × 60 04/06 Cameroon � � � 95.6 97.1 � 95.3-98.5 ξ= 97.1 101.6-105.3 ξ= 103.5 mean: 757.5mg -2.3% to +2.9% 7.06* Duovir 150/300mg, tab G54307 Plastic bottle 2 × 60 02/07 Cameroon � � � 96.6 101.8 � 101.8-104.5 ξ= 102.9 100.1-103.9 ξ= 101.6 mean: 753.8mg -3.5% to +3.1% 7.07* Duovir 150/300mg, tab G54308 Plastic bottle 2 × 60 02/07 Cameroon � � � 97.3 98.3 � 94.1-100.6 ξ= 98.0 100.5-101.0 ξ= 100.8 mean: 758.2mg 19 tablets : -4.0% to +3.2% 1 tablet : + 8.4% 7.08* Duovir 150/300mg, tab G44538 Plastic bottle 2 × 60 05/06 Cameroon � � � 96.1 97.9 � 95.9-99.9 ξ= 98.5 98.4-99.8 ξ= 99.4 mean: 756.9mg -3.2% to +2.8% 7.09* Duovir 150/300mg, tab C40301 Plastic bottle 2 × 60 04/06 Cameroun � � � 96.8 98.7 � 98.7-101.5 ξ= 99.8 99.9-103.2 ξ= 101.1 mean: 757.6mg -1.4% to +3.1% 7.10* Bivir 150/300mg, tab G54200 As 7.15 Plastic bottle 1 × 60 01/07 Uganda � � � 96.1 99.2 � 98.9-101.0 ξ= 99.9 98.5-104.4 ξ= 102.1 mean: 754.0mg -3.2% to +2.9% 7.11* Bivir 150/300mg, tab C30521 Plastic bottle 1 × 60 11/05 Uganda � � � 98.8 100.2 � 97.0-100.6 ξ= 98.6 88.6-100.4 ξ= 96.6 mean: 756.1mg -1.5% to +2.0% 7.12* Combivir 150/300mg, tab R170752 As 7.14 Plastic bottle 2 × 60 04/07 Uganda � � � 95.2 97.3 � 97.6-98.5 ξ= 98.2 98.6-100.9 ξ= 100.0 mean: 763.2mg -1.2% to +2.2% 7.13* Duovir 150/300mg, tab G54306 Plastic bottle 2 × 60 02/07 Uganda � � � 96.3 100.0 � 96.4-99.6 ξ= 98.2 100.3-104.6 ξ= 102.1 mean: 761.0mg -3.4% to +3.5% 7. Lamivudine/zidovudine Test Plan B: Tablets, prequalified (29 samples ) – Swissmedic methods (continued) SPECIFICATIONS: Content: 95.0-105% of the stated amount for both active ingredients Related substances : Impurity A - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.3% Impurity B - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.2% Thymine: ≤ 3.0% Impurity B - Ph.Eur. 5.1, 04/2005:1059: ≤ 1.0% Any unspecified impurity: ≤ 0.5% Total lamivudine-related impurities ≤ 0.6% Total zidovudine-related impurities ≤ 4.0% Dissolution: Not less than 80%(Q) of the stated amount of both active ingredients dissolved in 30 minutes � = Complies; *=WHO-prequalified 43 OMCL No. Trade name, strength and dosage form Batch number Primary pack Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related sub- stances Dissolution (% of stated amount) Uniformity of mass Sample and pack size Identity of each active ingre- dient lami- vudine zido- vudine lamivudine zidovudine 7.14* Combivir 150/300mg, tab R170752 As 7.12 Plastic bottle 2 × 60 04/07 Uganda � � � 97.3 99.1 � 98.9-103.4 ξ= 100.9 100.0-100.9 ξ= 100.5 mean: 765.4mg -1.9% to +2.5% 7.15* Duovir 150/300mg, tab G54200 As 7.10 Plastic bottle 2 × 60 01/07 Uganda � � � 96.0 99.5 � 97.4-104.0 ξ= 101.0 102.1-104.5 ξ= 103.3 mean: 762.0mg -1.9% to +2.5% 7.16* Duovir 150/300mg, tab C40031 Plastic bottle 2 × 60 12/05 Tanzania � � � 96.5 98.6 � 100.1-102.9 ξ= 101.6 102.7-104.1 ξ= 103.5 mean: 763.5mg -1.6% to +2.8% 7.17* Duovir 150/300mg, tab C50088 Plastic bottle 2 × 60 01/07 Tanzania � � � 100.2 96.1 � 95.2-101.3 ξ= 98.6 99.8-101.3 ξ= 100.7 mean: 762.8mg -1.7% to +1.5% 7.18* Combivir 150/300mg, tab B142682 As 7.23 Plastic bottle 2 × 60 09/06 Tanzania � � � 96.8 97.4 � 94.9-102.4 ξ= 98.1 100.7-102.0 ξ= 101.3 mean: 761.3mg -1.9% to +0.9% 7.19* Duovir 150/300mg, tab 050194 Plastic bottle 2 × 60 02/07 Tanzania � � � 98.1 98.9 � 97.9-101.5 ξ= 99.4 98.5-101.8 ξ= 100.4 mean: 764.1mg -2.5% to +1.9% 7.21* Duovir 150/300mg, tab C50145 Plastic bottle 2 × 60 02/07 Tanzania � � � 96.8 99.5 � 95.6-100.9 ξ= 98.7 100.7-103.5 ξ= 101.7 mean: 762.2mg -2.8% to +2.9% 7.22* Combivir 150/300mg, tab B140423 Plastic bottle 2 × 60 08/06 Tanzania � � � 98.9 98.7 � 99.1-101.2 ξ= 100.0 99.7-101.8 ξ= 100.5 mean: 766.6mg -2.1% to +2.2% 7.23* Combivir 150/300mg, tab B142682 As 7.18 Plastic bottle 2 × 60 09/06 Tanzania � � � 96.5 98.7 � 99.1-100.7 ξ= 99.8 100.6-102.1 ξ= 101.1 mean: 763.1mg -2.3% to +1.4% 7.24* Duovir 150/300mg, tab G32493 Plastic bottle 1 × 60 09/05 DRC � � � 99.0 95.8 � 51.6-93.8 ξ= 77.5 (6) 50.6-93.2 ξ= 75.0 (6) mean: 762.3mg -3.0% to +1.8% 7.25* Duovir 150/300mg, tab G44055 Plastic bottle 2 × 60 12/05 DRC � � � 98.5 96.8 � 92.5-99.2 ξ= 96.9 100.6-102.8 ξ= 102.0 mean: 752.6mg -1.4% to +1.5% (6) Dissolution of lamivudine and zidovudine were below specifications (WHO sampling number BR 004/RDC) 7. Lamivudine/zidovudine Test Plan B: Tablets, prequalified (29 samples ) – Swissmedic methods (continued) SPECIFICATIONS: Content: 95.0-105% of the stated amount for both active ingredients Related substances : Impurity A - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.3% Impurity B - Ph.Eur. 5.3, 01/2006:2217: ≤ 0.2% Thymine: ≤ 3.0% Impurity B - Ph.Eur. 5.1, 04/2005:1059: ≤ 1.0% Any unspecified impurity: ≤ 0.5% Total lamivudine-related impurities ≤ 0.6% Total zidovudine-related impurities ≤ 4.0% Dissolution: Not less than 80%(Q) of the stated amount of both active ingredients dissolved in 30 minutes � = Complies; *=WHO-prequalified 44 OMCL No. Trade name, strength and dosage form Batch number Primary pack Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related sub- stances Dissolution (% of stated amount) Uniformity of mass Sample and pack size Identity of each active ingre- dient lami- vudine zido- vudine lamivudine zidovudine 7.29* Duovir 150/300mg, tab C50286 Plastic bottle 2 × 60 04/07 Kenya � � � 100.2 97.8 � 99.1-101.7 ξ= 100.4 101.0-103.1 ξ= 101.9 mean: 762.3mg -1.0% to +1.1% 7.30* Duovir 150/300mg, tab C50239 Plastic bottle 2 × 60 03/07 Kenya � � � 99.3 96.2 � 98.9-102.4 ξ= 100.7 99.8-102.2 ξ= 100.8 mean: 760.0mg -1.9% to +2.0% 7.31* Combivir 150/300mg, tab R156514 Plastic bottle 2 × 60 02/07 Kenya � � � 95.5 97.6 � 94.4-102.4 ξ= 99.5 100.0-100.3 ξ= 100.2 mean: 761.1mg -2.9% to +1.4% 7.32* Combivir 150/300mg, tab R154801 Plastic bottle 2 × 60 11/06 Kenya � � � 97.7 98.1 � 101.4-103.1 ξ= 102.2 100.4-101.8 ξ= 101.0 mean: 768.0mg -1.3% to +1.0% 7.33* Combivir 150/300mg, tab R172060 Blister strips 2 × 60 04/07 Kenya � � � 98.1 97.3 � 101.0-102.7 ξ= 102.0 100.1-101.5 ξ= 101.1 mean: 770.9mg -1.5% to +1.9% 7.36* Duovir 150/300mg, tab C50268 Plastic bottle 2 × 60 04/07 Zambia � � � 101.7 95.3 � 91.6-101.5 ξ= 98.6 99.5-101.0 ξ= 100.1 mean: 759.2mg -1.1% to +1.2% 8. Stavudine/lamivudine Tablets, not prequalified (16 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content: 90.0-110.0% of stated amount for both active ingredients Related substances: Thymine: ≤ 3.0% Any other impurity: ≤ 1.0% Total impurities: ≤ 3.5% � = Complies 45 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Ap- pear- ance Identity of each active ingre- dient Disintegra- tion Content (% of stated amount) Related substances Uniformity of mass stavu- dine lami- vudine 8.01 Stavudine 40/150mg, tab 050705 Blister strips 2 × 60 04/07 Kenya � � � � 100.8 98.3 � mean: 455.8mg -1.6% to +1.9% 8.02 Stavudine 40/150mg, tab SA0403003 Plastic bottle 2 × 60 11/05 Kenya � � � � 103.2 99.4 � mean: 458.7mg -2.5% to +3.3% 8.03 Coviro-LS 30/150mg, tab 1386490 Blister strips 2 × 60 02/06 Kenya � � � � 99.9 99.0 � mean: 497.2mg -1.7% to +1.4% 8.04 Coviro-LS 30/150mg, tab 1386499 Blister strips 2 × 60 02/06 Kenya � � � � 98.6 99.9 � mean: 498.1mg -1.7% to +1.4% 8.05 Coviro-LS 30/150mg, tab 1386486 Blister strips 2 × 60 02/06 Kenya � � � � 98.4 100.9 � mean: 498.4mg -1.5% to +1.8% 8.06 Lamivir-S 30/150mg, tab K41005 Plastic bottle 2 × 60 10/06 Kenya � � � � 100.9 98.2 � mean: 445.6mg -1.8% to +1.2% 8.07 Lamivir-S 30/150mg, tab K41090 Plastic bottle 2 × 60 11/07 Kenya � � � � 99.9 101.5 � mean: 448.7mg -1.6% to +2.1% 8.08 Lamivir-S 30/150mg, tab K40631 Plastic bottle 4 × 30 06/06 Kenya � � � � 97.5 100.1 � mean: 450.2mg -1.9% to +1.7% 8.09 Lamivir-S 30/150mg, tab K50287 Plastic bottle 4 × 30 03/07 Kenya � � � � 104.5 98.0 � mean: 455.2mg -1.7% to +2.0% 8.10 Lamivir-S 30/150mg, tab K50374 Plastic bottle 4 × 30 04/07 Kenya � � � � 99.8 100.8 � mean: 450.4mg -2.5% to +3.9% 8.11 Lamivir-S 40/150mg, tab K50138 Plastic bottle 2 × 60 02/07 Kenya � � � � 97.6 99.6 � mean: 451.4mg -2.5% to +2.2% 8.12 Lamivir-S 40/150mg, tab K50425 Plastic bottle 4 × 30 05/07 Kenya � � � � 99.0 98.9 � mean: 452.2mg -2.3% to +4.6% 8.13 Lamivir-S 40/150mg, tab K40632 Plastic bottle 4 × 30 06/06 Kenya � � � � 97.5 100.6 � mean: 452.4mg -2.1% to +1.9% 8.14 Lamivir-S 40/150mg, tab K50288 Plastic bottle 4 × 30 03/07 Kenya � � � � 102.3 98.5 � mean: 454.9mg -2.2% to +3.7% 8.15 Stavudine + Lamivudine 40/150mg, tab 7200585 Plastic bottle 2 × 60 05/07 Zambia � � � � 101.1 101.8 � mean: 351.0mg -1.8% to +4.1% 8.16 Emduo 40/150mg, tab LEMH0401 Plastic bottle 2 × 60 06/06 Zambia � � � � 90.5 92.1 � mean: 420.0mg -1.6% to +2.7% 9. Stavudine/lamivudine/nevirapine Test Plan A: Tablets, not prequalified (21 samples) – methods of the Indian Pharmacopoeia SPECIFICATIONS: Content: 90.0 to 110.0% of stated amount for each active ingredient Related substances: Thymine: ≤ 3.0% Any individual impurity: ≤ 1.0% Total impurities: ≤ 3.5% � = Complies 46 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Ap- pear- ance Disintegra- tion Content (% of stated amount) Related substances Uniformity of mass Identity of each active ingre- dient sta- vudine lami- vudine nevi- rapine 6.01 Stavex 30/150/200mg LN tab SN0304002 Plastic bottle 2 × 60 12/05 Nigeria � � � � 102.0 103.5 102.7 � mean: 723.7mg -2.4% to +2.9% 6.09 Stavudine Lamivudine Nevirapine 40 / 150 / 200mg tab ZEQ3009 Plastic bottle 2 × 60 08/05 Cameroon � � � � 98.1 99.5 98.9 � mean: 725.6mg -1.4% to +1.0% 6.22 Afri-Vir 30/150/200mg tab AV05- L9001 Plastic bottle 2 × 60 04/07 DRC � � � � 103.7 99.1 97.1 � mean: 770.8mg -2.8% to +3.4% 6.27 Triviro- LNS 40/150/200mg tab 1395014 Blister strips 2 × 60 03/06 Kenya � � � � 100.4 100.2 99.3 � mean: 803.1mg -1.6% to +2.1% 6.28 Triviro- LNS 40/150/200mg tab 1386859 Blister strips 2 × 60 02/06 Kenya � � � � 99.9 101.0 100.0 � mean: 797.3mg -1.8% to +1.1% 6.29 Triviro- LNS 30/150/200mg tab 1410508 Blister strips 2 × 60 05/06 Kenya � � � � 100.3 103.8 102.4 � mean: 799.3mg -1.5% to +2.0% 6.30 Nevilast 30/150/200mg tab NLT50403 Plastic bottle 2 × 60 03/07 Kenya � � � � 102.5 102.6 102.5 � mean: 702.5mg -1.8% to +1.7% 6.31 Nevilast 40/150/200mg tab NST50303 Plastic bottle 2 × 60 02/07 Kenya � � � � 99.9 100.0 99.5 � mean: 699.5mg -1.8% to +2.8% 6.36 Emtri 30/150/200mg tab HEMS502 Plastic bottle 2 × 60 12/06 Kenya � � � � 99.0 101.8 103.1 � mean: 576.8mg -1.2% to +1.2% 6.37 Emtri 30/150/200mg tab HEMS404 Plastic bottle 2 × 60 06/06 Kenya � � � � 98.8 100.5 102.6 � mean: 575.7mg -0.8% to +1.3% 6.38 Emtri 30/150/200mg tab HEMS506 Plastic bottle 2 × 60 01/07 Kenya � � � � 97.9 99.7 102.5 � mean: 577.0mg -1.1% to +1.1% 6.39 Emtri 30/150/200mg tab HEMS 505 Plastic bottle 2 × 60 01/07 Kenya � � � � 98.1 99.7 102.0 � mean: 575.0mg -1.2% to +1.4% 6.40 Emtri 30/150/200mg tab HEMS501 Plastic bottle 2 × 60 12/06 Kenya � � � � 99.3 101.7 103.3 � mean: 576.3mg -1.0% to +0.9% 6.41 Emtri 40/150/200mg tab LTM0403 Plastic bottle 2 × 60 02/06 Kenya � � � � 94.7 97.1 100.5 � mean: 573.0mg -0.9% to +1.5% 6.42 Emtri 40/150/200mg tab LTM0402 Plastic bottle 2 × 60 02/06 Kenya � � � � 94.5 97.4 100.5 � mean: 570.7mg -0.9% to +2.3% 6.43 Emtri 40/150/200mg tab LTH0404 Plastic bottle 2 × 60 02/06 Kenya � � � � 94.8 97.1 100.2 � mean: 572.0mg -1.1% to +0.9% 9. Stavudine/lamivudine/nevirapine Test Plan A: Tablets, not prequalified (21 samples) – methods of the Indian Pharmacopoeia (continued) SPECIFICATIONS: Content: 90.0 to 110.0% of stated amount for each active ingredient Related substances: Thymine: ≤ 3.0% Any individual impurity: ≤ 1.0% Total impurities: ≤ 3.5% � = Complies 47 OMCL No. Trade name, strength and dosage form Batch Primary pack Sample and pack size Expiry date Country Label Ap- pear- ance Disintegra- tion Content (% of stated amount) Related substances Uniformity of mass Identity of each active ingre- dient sta- vudine lami- vudine nevi- rapine 6.44 Emtri 40/150/200mg tab LTH0401 Plastic bottle 2 × 60 02/06 Kenya � � � � 95.6 97.5 100.6 � mean: 573.2mg -0.8% to +1.6% 6.45 Emtri 40/150/200mg tab 01A05003 Plastic bottle 2 × 60 02/07 Zambia � � � � 97.6 98.6 100.8 � mean: 573.8mg -1.4% to +1.0% 6.46 Triviro- LNS 30/150/200mg tab 1411652 Blister strips 2 × 60 05/06 Zambia � � � � 102.5 104.2 100.2 � mean: 806.0mg -1.1% to +1.6% 6.47 Maxivir 30/150/200mg tab S50061 Plastic bottle 2 × 60 09/05 Zambia � � � � 96.4 99.6 100.5 � mean: 721.4mg -1.0% to +1.8% 6.48 Maxivir 40/150/200mg tab S50062 Plastic bottle 2 × 60 09/05 Zambia � � � � 97.8 95.3 95.9 � mean: 720.9mg -2.2% to +2.3% 9. Stavudine / lamivudine / nevirapine Test Plan B: Tablets, prequalified (31 samples) SPECIFICATIONS: Content: 90.0 to 110.0% of stated amount for each active ingredient Related substances: For stavudine and lamivudine: Thymine: ≤ 1.50% Any other impurity (anhydrothymidine, β-thymidine, isomer of β-thymidine, carboxylic acid, salicylic acid, any individual unknown impurity): ≤ 0.50% Sum of all impurities: ≤ 3.00% For nevirapine: Any individual impurity: ≤ 0.50% Sum of all impurities: ≤ 1.00% Dissolution: Not less than 80%(Q) of stated amount of each active ingredient dissolved in 45 minutes � = Complies *=WHO-prequalified 48 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related substances Dissolution (% of stated amount) Uniformity of mass Identity of each active ingre- dient sta- vudine lami- vudine nevi- rapine sta- vudine lami- vudine nevi- rapine 6.02* Triomune 30/150/200mg, tab G54286 Plastic bottle 2 × 60 08/07 Cameroon � � � 96.4 96.0 98.4 � 93-103 96-101 94-104 mean: 715.1mg -2.8% to +2.9% 6.03* Triomune 30/150/200mg, tab G45275 Plastic bottle 2 × 60 04/07 Cameroon � � � 96.8 98.3 100.4 � 94-99 97-99 96-99 mean: 723.9mg -1.2% to +1.4% 6.04* Triomune 30/150/200mg, tab G45274 Plastic bottle 2 × 60 05/07 Cameroon � � � 94.9 97.9 99.8 � 93-100 99-103 98-102 mean: 723.2mg -1.9% to +1.9% 6.05* Triomune 30/150/200mg, tab G47409 Plastic bottle 2 × 60 04/07 Cameroon � � � 90.2 98.9 99.8 � 85-96 101-106 99-103 mean: 713.0mg -2.8% to +3.0% 6.06* Triomune 30/150/200mg, tab G56978 Plastic bottle 2 × 60 11/07 Cameroon � � � 91.3 99.6 97.9 � 87-95 99-103 97-103 mean: 724.3mg -4.8% to +2.1% 6.07* Triomune 30/150/200mg, tab G45203 Plastic bottle 2 × 60 05/07 Cameroon � � � 97.5 96.7 97.2 � 90-100 94-99 93-97 mean: 722.9mg -3.6% to +2.2% 6.08* Triomune 30/150/200mg, tab G47132 Plastic bottle 2 × 60 02/07 Cameroon � � � 95.6 98.5 99.2 � 91-99 99-102 96-99 mean: 720.8mg -2.9% to +2.5% 6.10* Triomune 30/150/200mg, tab G47133 As 6.13 Plastic bottle 2 × 60 02/06 Uganda � � � 100.0 97.1 99.7 � 92-103 97-104 97-102 mean: 723.9mg -1.9% to +1.5% 6.11* Triomune 30/150/200mg, tab G46767 Plastic bottle 2 × 60 12/06 Uganda � � � 90.3 (a) 98.4 99.0 � 90-96 99-105 98-104 mean: 719.3mg -4.1% to +3.2% 6.12* Maxivir 30/150/200mg, tab SK4008 Plastic bottle 2 × 60 08/05 Uganda � � � 93.4 101.1 102.1 � 90-94 101-105 99-103 mean: 732.3mg -1.3% to +1.5% 6.13* Triomune 30/150/200mg, tab G47133 As 6.10 Plastic bottle 2 × 60 02/06 Uganda � � � 99.9 96.0 96.5 � 96-104 95-98 94-98 mean: 721.2mg -2.1% to +2.1% (a) 88.8% (n=2); check: 91.8% (n=2); ∅: 90.3% Results: Stavudine / lamivudine / nevirapine Test Plan B: Tablets – prequalified (31 samples) (continued) SPECIFICATIONS: Content: 90.0 to 110.0% of stated amount for each active ingredient Related substances: For stavudine and lamivudine: Thymine: ≤ 1.50% Any other impurity (anhydrothymidine, β-thymidine, isomer of β-thymidine, carboxylic acid, salicylic acid, any individual unknown impurity): ≤ 0.50% Sum of all impurities: ≤ 3.00% For nevirapine: Any individual impurity: ≤ 0.50% Sum of all impurities: ≤ 1.00% Dissolution: Not less than 80%(Q) of stated amount of each active ingredient dissolved in 45 minutes � = Complies *=WHO-prequalified 49 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related substances Dissolution (% of stated amount) Uniformity of mass Identity of each active ingre- dient sta- vudine lami- vudine nevi- rapine sta- vudine lami- vudine nevi- rapine 6.14* Triomune 30/150/200mg, tab K50051 Plastic bottle 2 × 60 06/06 Tanzania � � � 105.8 97.5 98.5 � 97-103 94-99 94-97 mean: 729.7mg -1.2% to +1.7% 6.15* Triomune 30/150/200mg, tab K50160 Plastic bottle 2 × 60 08/06 Tanzania � � � 98.0 100.1 99.6 � 91-98 97-104 97-102 mean: 725.2mg -2.7% to +1.6% 6.16* Triomune 30/150/200mg, tab K41017 Plastic bottle 2 × 60 04/06 Tanzania � � � 117.0 (7) 95.3 99.4 � 95-135 (a) 92-101 98-101 mean: 723.1mg -2.7% to +2.8% 6.17* Triomune 30/150/200mg, tab K50097 Plastic bottle 2 × 60 07/06 Tanzania � � � 98.2 96.5 101.6 � 91-99 95-102 99-102 mean:731.4mg -1.4% to +1.6% 6.18* Triomune 30/150/200mg, tab K50123 Plastic bottle 2 × 60 07/06 Tanzania � � � 98.7 98.8 100.0 � 94-100 99-102 98-101 mean: 724.5mg -1.0% to +1.2% 6.19* Triomune 30/150/200mg, tab K50101 Plastic bottle 2 × 60 07/06 Tanzania � � � 98.1 99.6 97.9 � 93-99 98-102 96-100 mean: 724.7mg -2.0% to +1.1% 6.20* Triomune 30/150/200mg, tab K50050 Plastic bottle 4 × 60 06/06 DRC � � � 97.3 100.2 100.8 � 90-95 97-100 96 -99 mean: 723.7mg -3.0% to +2.1% 6.21* Triomune 40/150/200mg, tab K41012 Plastic bottle 2 × 60 04/06 DRC � � � 100.8 102.5 102.2 � 93-101 96-100 95-99 mean: 731.0mg -2.1% to +2.1% 6.23* Triomune 40/150/200mg, tab K41094 Plastic bottle 2 × 60 05/06 DRC � � � 104.2 101.1 99.2 � 96-103 97-100 93.95 mean: 736.3mg -3.6% to +2.2% 6.24* Triomune 30/150/200mg, tab K50432 Plastic bottle 2 × 60 11/07 DRC � � � 97.7 101.5 101.5 � 94-98 100-102 98-100 mean: 730.4mg -1.7% to +1.9% (7) Confirmed by dissolution testing and test for uniformity of content (WHO sampling number: TAN PUT1 LSN 01/1) (a) 95%-135%, checked: 93%-130% Results: Stavudine / lamivudine / nevirapine Test Plan B: Tablets – prequalified (31 samples) (continued) SPECIFICATIONS: Content: 90.0 to 110.0% of stated amount for each active ingredient Related substances: For stavudine and lamivudine: Thymine: ≤ 1.50% Any other impurity (anhydrothymidine, β-thymidine, isomer of β-thymidine, carboxylic acid, salicylic acid, any individual unknown impurity): ≤ 0.50% Sum of all impurities: ≤ 3.00% For nevirapine: Any individual impurity: ≤ 0.50% Sum of all impurities: ≤ 1.00% Dissolution: Not less than 80%(Q) of stated amount of each active ingredient dissolved in 45 minutes � = Complies *=WHO-prequalified 50 OMCL No. Trade name, strength and dosage form Batch Pri- mary pack Sample and pack size Expiry date Country Label Ap- pear- ance Content (% of stated amount) Related substances Dissolution (% of stated amount) Uniformity of mass Identity of each active ingre- dient sta- vudine lami- vudine nevi- rapine sta- vudine lami- vudine nevi- rapine 6.25* Triomune 40/150/200mg, tab K50401 Plastic bottle 2 × 60 10/07 DRC � � � 99.3 98.5 99.8 � 90-93 93-97 92-95 mean: 723.7mg -1.4% to +1.7% 6.26* Triomune 40/150/200mg, tab K50334 Plastic bottle 2 × 60 04/07 DRC � � � 100.8 102.3 102.1 � 92-99 92-99 94-97 mean: 724.8mg -1.4% to +1.3% 6.32* Triomune 30/150/200mg, tab K40887 Plastic bottle 2 × 60 03/07 Kenya � � � 100.7 99.6 100.4 � 94-102 97-102 96-100 mean: 724.8mg -2.3% to +2.0% 6.33* Triomune 30/150/200mg, tab G46590 Plastic bottle 2 × 60 10/05 Kenya � � � 102.5 100.1 99.2 � 89-110 94-99 93-99 mean: 727.8mg -2.8% to +1.5% 6.34* Triomune 30/150/200mg, tab K40448 Plastic bottle 2 × 60 09/05 Kenya � � � 95.1 100.6 99.7 � 87-92 97-99 93-95 mean: 723.5mg -1.3% to +1.2% 6.35* Triomune 40/150/200mg, tab K50006 Plastic bottle 2 × 60 06/07 Kenya � � � 100.3 99.4 101.5 � 94-101 93-97 93-96 mean: 723.0mg -2.6% to +2.4% 6.49* Triomune 40/150/200mg, tab K50278 Plastic bottle 2 × 60 09/07 Zambia � � � 99.0 101.2 101.4 � 89-99 94-99 93-97 mean: 722.8mg -2.6% to +1.5% 6.50* Triomune 40/150/200mg, tab AS5398 Plastic bottle 2 × 60 07/07 Zambia � � � 102.6 98.1 100.7 � 98-104 94-99 93-98 mean: 721.9mg -2.0% to +2.2% 6.51* Triomune 30/150/200mg, tab K50280 Plastic bottle 2 × 60 09/07 Zambia � � � 99.2 101.1 100.8 � 91-97 96-102 94-97 mean: 728.2mg -1.6% to +1.1% 6.52* Triomune 40/150/200mg, tab K50279 Plastic bottle 2 × 60 09/07 Zambia � � � 102.6 98.1 100.7 � 95-102 94-97 93-98 mean: 728.0mg -2.5% to +2.5% 51 Appendix 2: Batches with multiple samples tested Active ingredient(s) Test Plan Batch number OMCL numbers and countries of samples tested efavirenz A HV77220 4.21 Tanzania 4.24 Tanzania NB35330 4.15 Uganda 4.17 Uganda B NB17260 4.07 Cameroon 4.32 Kenya lamivudine A 1375882 2.05 Nigeria 2.06 Nigeria 01A05002 2.40 Tanzania 2.63 Zambia 031674 2.51 Kenya 2.62 Kenya B 169400 2.22 Uganda 2.26 Uganda 2.57 Kenya B144178 2.07 Nigeria 2.13 Nigeria G54329 2.37 Tanzania 2.39 Tanzania Y41272 2.29 Tanzania 2.35 Tanzania nevirapine B 407734 3.06 Nigeria 3.61 Kenya C40467 3.29 Tanzania 3.36 Tanzania NV40101 3.15 Uganda 3.19 Uganda 3.21 Uganda C L457646A 3.33 Tanzania 3.35 Tanzania L457647A 3.28 Tanzania 3.31 Tanzania L457744A 3.13 Nigeria 3.64 Kenya stavudine A C40341 1.18 Uganda 1.32 DRC C 0017 1.25 Tanzania 1.35 DRC 0023 (40mg cap) 1.26 Tanzania 1.28 Tanzania 0023 (30mg cap) 1.27 Tanzania 1.37 Kenya 0033 1.29 Tanzania 1.30 Tanzania 1.39 Kenya 4K93177 1.23 Tanzania 1.46 Kenya zidovudine A G33616 5.04 Nigeria 5.26 DRC B G50487 5.08 Cameroon 5.43 Zambia C V14 5.05 Nigeria 5.36 Kenya B B142682 7.18 Tanzania 7.23 Tanzania lamivudine/ zidovudine G54200 7.10 Uganda 7.15 Uganda R170752 7.12 Uganda 7.14 Uganda stavudine/ lamivudine/ nevirapine B G47133 6.10 Uganda 6.13 Uganda The samples with the OMCL Numbers 1.43 (stavudine 40mg capsules) and 1.59 (stavudine 30mg capsules) shared batch number 0039. They were manufactured at different sites.

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