Quality Assurance Organization of National Quality Assurance programs for by marcjackson


									                                     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

                             National quality
                          assurance coordinator
                           (coordinate all levels)

 Manufacture                                 Clinic-Level      End-user
                    National level
    Good                                     RDT quality      Training and
 procurement                                  monitoring      supervision

                               Storage and

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

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 laboratory-
based 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

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
   • 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

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 cross-
        checked 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'
      • 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

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
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 cross-
checking 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 post-
purchase lot-testing. Positive control wells are expected to be available within the
next two years.

                      Water added
  Dried antigen,                                         placed on
  agent to raise                                            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
    • 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

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