Quality Assurance
Organization of National Quality Assurance programs for malaria RDTs A system for checking the continued accuracy of diagnostic services is essential in any large program determining treatment for a severe disease. Quality assurance (QA) should be an integral part of RDT budgets and implementation plans in the same way that it forms an important part of a microscopy-based program. This should extend from testing at the time of purchase to testing and supervision at a peripheral level, and include monitoring of transport and storage. Responsibility for overseeing QA processes should be clearly defined and coordinated from a central level.
National quality assurance coordinator (coordinate all levels)
Manufacture Good procurement
National level Lot-testing
Clinic-Level RDT quality monitoring
End-user Training and supervision
Storage and transport
Sensitivity of RDTs should be checked at a central laboratory on receipt from the manufacturer, and periodically the recommended shelf life at a temperature during storage at a temperature close to the maximum recommended by the manufacturer. Monitoring of sensitivity at a peripheral level and adequate training and supervision of end-users should be integrated as far as possible into existing health worker training and quality assurance schemes. Instructions for RDT preparation and interpretation should be clear and concise in local languages. Health workers using the tests should be trained and assessed, and systematically monitored on test preparation and interpretation. As RDTs must be read soon after preparation, this should be done on real cases rather than by review of previously prepared tests.
Establishing Quality Assurance Systems for Malaria RDTs
• The Need for Quality Assurance • Procuring Good Quality Malaria RDTs • Lot-testing: Using quality control parasite dilutions to test the sensitivity
of malaria RDTs
• Quality Assurance of Malaria RDTs after deployment in field • Preserving the quality of malaria RDTs during transport and storage
Relevant links • Read more on Establishing Quality Assurance systems for malaria RDTs
The Need for Quality Assurance
Variation in RDT accuracy in published trials and operational experience underline the need for an accurate, transparent system for monitoring the accuracy of RDTs after release by the manufacturer. The development of a comprehensive quality assurance scheme is essential to ensure that test quality is maintained, reducing the likelihood of misdiagnosis and maintaining confidence of health service providers and consumers. In time, such a scheme will provide standardized evidence of test performance to guide purchasing and development. Malaria RDTs are affected by various conditions of manufacture, storage and use that can impair their accuracy and reliability. The global initiative to scale-up the introduction of RDTs to aid in the management of malaria, especially in locations where laboratorybased diagnosis is unavailable, therefore requires a system in place to assure that service quality is guaranteed. Quality assurance (QA) is defined as a total process, both in and outside the laboratory, including performance standards, good laboratory practice (GLP) and management skills to achieve and maintain a quality service and provide for continuing improvement. The purpose of QA is to provide reliable, relevant, timely test results that are interpreted correctly thereby increasing efficiency, effectiveness, enhancing patient satisfaction and decreasing costs brought about by misdiagnosis. This is increasingly important with the advent of combination therapies and their higher associated costs. A QA process for malaria RDTs should aim to ensure high accuracy of tests in the hands of end-users. This will include both monitoring of the technical standard of the RDTs, processes to minimize environmental insult and training and monitoring of preparation and interpretation by end-users. A summary of WHO recommendations on quality assurance of RDTs in national programmes is found here.
Quality control (QC) describes all the activities taken by a laboratory to monitor each stage of a test procedure to ensure that tests are performed correctly and are accurate and precise. Quality control must be practical, achievable and affordable. A system for laboratory-based assessment of performance of RDTs throughout their shelf-life and the appropriate Standard Operating Procedures has been established by WHO. For more information please read the section on 'Lot Testing' under relevant links. Relevant Documents and Links • Information on Lot testing • More information on Quality Assurence of Malaria RDT
Procuring Good Quality Malaria RDTs
Procurement of good quality RDTs, with characteristics appropriate for the conditions in which they will be used, is essential to ensure good quality diagnosis. A detailed guide to malaria RDT procurement is found under the section of Selecting and Purchasing RDTs of this website (link given below) and in the WHO guide ' Quality Assurance of Malaria Rapid Diagnostics' (link given below).
Relevant Links and documents • Selecting and Purchasing RDTs • WHO Guide on 'Quality Assurance of Malaria Rapid Diagnostics'
Lot-testing: Using quality control parasite dilutions to test the sensitivity of malaria RDTs
Lot-testing of malaria RDTs involves testing of samples of RDTs for a manufacturing lot to ensure performance reaches an acceptable standard. This can be done before or after arrival in the country. Why lot-test? • Lot-lot variation noted in most products • Ensure no damage during transport to country • Manufacturers likely to submit atypically good product for product-testing • Need to convince clinicians / users / regulatory authorities that tests are working WHO, in collaboration with FIND and partner institutions in endemic countries, has established a network of laboratories that collect and prepare standardized samples of malaria parasites for use in the WHO product testing programme based at US
Centers for Disease Control and Prevention, and for retention at these institutions for product testing. Three of these laboratories are supported by WHO and FIND to test large number of malaria RDT lots for other country programmes, the others for testing within the country in which they operate. Further details, and Contacts and Request Forms for lot-testing are found under the Lot testing section of WHO RDT Evaluation Programme and in the WHO document on Quality Assurance of Malaria Rapid Diagnostic Tests – Buying well and Maintaining Accuracy'. Producing and storing quality control dilutions of parasites obtained from field samples Testing malaria RDTs in a laboratory setting against stored samples allows greater consistency and control of testing methods, and greater control over the parasite densities used as standards, but has the disadvantage that stored blood and parasites may react differently than fresh parasitized blood on an RDT. To guide this process, a Methods Manual has been produced. This manual is designed to facilitate consistency of testing in laboratories where concepts of quality assurance may not be well established. The manual is intended for internal WHO use and use by institutions collaborating with WHO in the development and implementation of quality control testing for malaria rapid diagnostic tests. Careful reference should be made to the notes under ‘Objectives and Scope of the Methods Manual’ when using this manual. The SOPs within this manual related directly to the production and use of QC samples for malaria RDTs are derived from field and laboratory development coordinated by the World Health Organization in collaboration with a number of institutions, published research, and discussions with a range of developers and manufacturers of malaria RDTs, and reviewed by the WHO Specimen Bank Steering Committee. Further SOPs relating to ancillary laboratory procedures (e.g. microscopy, and equipment calibration) necessary for preparation of the quality control samples are included. These latter SOPs are written specifically for malaria RDT QA and are not necessarily applicable to other laboratory procedures. Relevant Links and Documents • More information on WHO RDT Evaluation Programme • WHO document on Quality Assurance of Malaria Rapid Diagnostic Tests • More information on WHO Partners and Specimen Bank Steeering Committee • RDT Laboratory Quality Control Testing Methods Manual
Quality Assurance of Malaria RDTs after deployment in field
The degree to which individual countries/malaria control programmes implement RDT QA schemes will depend on practical and organizational issues. While it should be mandatory that large purchases of RDTs are checked before use and monitored during their shelf-life, practical decisions must be made on the extent of product monitoring at the end-user level.
Distribution of small numbers of RDTs to various health centres and health workers in remote areas from a district or municipality level makes it neither feasible nor practical for each testing centre to remove one to two tests per month for QC. Similarly, the transportation and storage of QC panels (e.g. frozen parasite samples) beyond the central level to district or peripheral locations, and maintenance of standards of use, would be highly problematic and is therefore not recommended. Current possibilities At present, it is recommended to compare RDT results with microscopy at a small number of 'sentinel' sites, using slides stained on-site and checked centrally and RDTs which have undergone typical storage and distribution. A designated person in charge of QA should be in charge of monitoring results. At present, the following procedure is recommended: • Compare RDT results with expert light microscopy. RDTs and blood films (BF) should be taken from the same patients in selected health facilities where RDTs which have undergone typical storage and distribution. • E.g. Every month, 40 RDTs (20 positive and 20 negative) should be crosschecked against the corresponding 40 BF obtained from the same patients and examined by expert microscopist. Where >10% discordant results occur, a more detailed field evaluation should be rapidly performed or the remaining RDTs should be returned for laboratory testing (see 'lot-testing' above). • Expert microscopy may be available at the 'sentinel' sites used for monitoring therapeutic efficacy of antimalarial medicines, or at the central/regional reference laboratory. It is important that the microscopists selected for the evaluation of RDT performance have high competency. In addition it is important to supervise the health workers performing RDTs on a regular basis (e.g. every 3 months) in order to: • evaluate health worker capacity of interpreting a set of prepared RDTs, • assess health worker technique in RDT preparation, • review diagnosis and treatment records. • ensure good blood safety practices are maintained • ensure sufficient supplies are in place for management of malarial and non-malarial fever. Training and Instructions for users Appropriate training of health workers is needed prior to introduction of RDTs, and instructions should be clear, in locally-appropriate language, and tested. WHO and partners have developed generic job-aids and a training manual for health workers, based on trials in Asia and Africa with several partners. These materials are available in English and French, and can be adapted to other languages. Examples are available here.
Treatment Practices and Blood Safety QA monitoring should include monitoring of health worker practices. Monitoring of action on results is complicated by the effect of observers on health worker practices, but good record keeping should be developed and records reviewed. Methods for assessing RDT quality in remote areas, including temperature monitors and positive control wells, are under development. All health workers should be provided with sharps containers that cannot be accessed by children, for disposal of lancets. Used RDTs should be similarly disposed of or burned. Clean disposable gloves should be warn by health workers while finger-pricking and handling blood.
Future Directions Positive Control Wells WHO is collaborating in development of stable, well-calibrated positive control wells LINK TO PCW BUTTON UNDER WHO RDT EVALUATION PROGRAMME TAB, containing recombinant antigens and designed to allow testing of malaria RDTs at clinic or village levels. These positive control wells will enable rapid direct evaluation of RDTs performance in remote locations without the need for crosschecking against expert microscopy. A panel of wells containing different antigens is also under development for standardized testing to be carried out at national level, which could have application for national regulatory testing and pre- or postpurchase lot-testing. Positive control wells are expected to be available within the next two years.
Water added Dried antigen, agent to raise viscosity Contents placed on RDT
Relevant Links and Documents • More information on RDT Training materials • More information on RDT Evaluation Programme
Preserving the quality of malaria RDTs during transport and storage Malaria RDTs are biological tests, containing antibodies and other organic substances and therefore susceptible to degradation by heat and moisture. Most products are well protected from moisture during storage as they are packaged in moisture-proof envelopes. As they are intended primarily for diagnosis of fever in malaria-endemic areas of the tropics and sub-tropics, they will commonly be subjected to prolonged storage at ambient temperatures well over 30°C. In many malaria-endemic countries, room temperatures rise to over 40°C at certain times of the year. While malaria RDTs do not require refrigeration, they do require protection of extremes of temperature, and from prolonged storage outside the range recommended by the manufacturer. This requires special measures to be put in place, similar to those required for good management of medicines. Degradation of RDTs by high temperatures can be reduced by the following strategies: • Procure tests demonstrated to withstand the expected conditions of transport and storage • Stagger delivery from manufacturer (reduces the storage time required before use) • Use 'cool chain' where possible: a. Avoid high temperature exposure during transport (e.g. do not park vehicles in direct sun) b. Store in central controlled environment as long as possible c. Store in coolest part of clinic (thatch roofs, evaporative cooling cabinets or in-ground storage) d. Test at periphery in typical conditions of use. Detailed recommendations on transport and storage (Please click here)
Relevant Links and Documents • More information on Storage and Transport of RDTs • More information on Quality Assurance of RDTs after deployment