Study design
This was a prospective cross sectional study.
Study settings
This study was conducted in 20 out of 26 regions of Tanzania mainland namely; Morogoro, Tanga, Dar es Salaam, Dodoma, Coast, Simiyu, Njombe, Arusha, Shinyanga, Kagera, Singida, Rukwa, Iringa, Geita, Kilimanjaro, Mara, Mbeya, Mtwara, Mwanza and Ruvuma. The regions were selected based on the pre-defined criteria including, highly populated regions, regions bordering other countries, regions with high prevalence of HIV infection and those reported to have medicine quality problems.
Study duration
Antiretroviral drugs (ARVs) samples were collected from medicines distribution outlets in 20 regions of Tanzania Mainland, between 2012 and 2015 and port of entry between 2012 and 2018.
ARVs sample size and collection
Convenience sampling method was used in the collection of selected ARVs. Samples were collected from the port of entry (POEs) and medicines distribution outlets such as Medical Stores Department (MSD), public and private hospitals, dispensaries, health centres, retail and wholesale pharmacies and Accredited Drug Distribution Outlets (ADDO) in two distribution levels. Level I covered POEs and MSD and level II covered public and retail healthcare facilities, wholesale and retail pharmacies and ADDOs. Samples were collected by trained drug inspectors according to the prepared sampling plan and Tanzania Medicines and Medical Devices Authority (TMDA) standard operation procedures. Drug inspectors were able to collect two (2) brands per surveyed medicines at each collection site. All samples were collected in their original containers and information details were filled in the sample collection tool. Each collected sample was coded according to the prescribed coding format. Coded samples with their respective sample collection tool were kept in the labelled sampling envelope and sealed. Storage and handling of samples during collection, transportation and before analysis complied with the manufacturer’s instructions and TMDA sample chain of custody procedures.
Samples collected from POEs and medicine distribution outlets were subjected to screening test at TMDA zone laboratories and respective quality assurance (QA) centres. Those from medicine distribution outlets were further subjected to product information review (PIR).
Of the sampled ARVs from medicines distribution outlet, 100% of them that did not comply with screening testing requirements or yielded doubtful results and 10% of those that complied with screening test requirements were transported to TMDA-WHO prequalified laboratory at the headquarter office for further analysis.
ARVs selection criteria
ARVs selected in this surveillance were those frequently prescribed for the management of HIV-infection with main focus on first line regimen as per National Guidelines for Management of HIV/AIDS [25] or those reported to have quality problem. These included the following active pharmaceutical ingredient (API): Efavirenz, nevirapine, lamivudine, zidovudine, abacavir sulphate, tenofovir disoproxil fumarate and fixed dose combination (FDC) containing tenofovir disoproxil fumarate /emtricitabine, lamivudine/zidovudine/nevirapine, lamivudine/stavudine/nevirapine, tenofovir/lamivudine/efavirenz, tenofovir/ emtricitabine/efavirenz and lopinavir/ritonavir.
Site sampling techniques
A purposive sampling technique was used for the selection of medicine collection sites, from regions and district levels down to the distribution channels.
Quality evaluation
Product information review
Prior to further laboratory analysis, samples collected from medicine distribution outlets were subjected to PIR. Each sample was evaluated visually on physical appearance of primary and secondary packaging. Availability and information on package information leaflets (PIL) based on the TMDA labelling requirements and approved product information was also assessed.
Parameters checked during PIR included but not limited to appearance or description of the dosage forms, product’s brand and generic name, dosage form and strength, name and address of the manufacturer, batch or lot number, date of manufacturing and expiration, TMDA registration number, packaging and pack size, PIL, language and storage instruction. The information was recorded on a designed form.
Tier I laboratory screening testing
All samples were subjected to screening test using Global Pharma Health Fund® (GPHF) Mini-Lab kits manual. The performed tests were simple visual inspection, disintegration for solid dosage forms and identification test using Thin Layer Chromatography (TLC) method. Oral solutions were also tested for pH appropriateness and microbial limit as described in the United States Pharmacopoeia (USP, NF 32).3
Visual inspection
All sampled solid dosage forms were checked for uniformity of shape, physical damage, altered surface, odor, color uniformity and dirty marks. Liquid dosage forms were examined for clarity, odor and colour uniformity.
Simple disintegration test
A simple disintegration test was performed to assess the possibility of instant-release of oral solid dosage forms. This was done by using a 100mL wide neck glass bottle filled with water heated to 37oC. Tablets were shaken or stirred occasionally. Disintegration was required to occur within 30 minutes. The sample was considered failed if did not disintegrate within 30 minutes in three (3) consecutive independent tests.
Product identification by thin layer chromatograph
TLC method was used for product identification and qualitative determination of active ingredients, related substances and impurities present in the dosage forms. This method employed the principle of comparing spots test sample and reference solutions according to GPHF Minilab. The principal spot obtained with the test sample was required to correspond with the chromatographic runs of the standard solution in terms of colour, shape, size, intensity and retardation factor (Rf) value. The test sample was considered failed if the Rf value of the test sample was different by more than 10% from that of the standard sample. Also, the sample was considered failed if the intensity of the spot was less than that of a reference containing 80% of the stated amount of the API and if failure was observed in all three independent experiments.
Tier II laboratory confirmatory testing
All samples collected from medicines distribution outlets that had failed screening test, 10% of those which had passed screening test, and those with doubtful results were subjected to confirmatory testing. Confirmatory testing was carried out at the TMDA-WHO prequalified laboratory as per USP pharmacopoeia monograph requirements [26] and/or in house specifications where no official pharmacopoeia monograph existed. Typical parameters tested were physical appearance, identification, disintegration, dissolution, assay, related substances, weight uniformity and microbial limit.
Data management and analysis
The collected data were checked for any inconsistencies. The data was double-entered into a Microsoft Access database, verified and exported to SPSS (version 20) software for analysis. Descriptive statistics was used and results for PIR, screening and conformity were expressed in percentage form.