Provisional observations

1. Quality must be built into the product - it cannot be tested, inspected or assessed into the product. Scientifically-based formulation and production will minimize problems with product quality. Quality assurance needs to extend beyond product quality to include programme quality.

2. Serious product quality problems have been documented for several malaria, TB and ARV single ingredient products as well as fixed-dose combinations.

3. FDCs are more technically demanding than single-ingredient preparations to develop and to produce.

4. The WHO-managed UN Prequalification Project assesses the quality of selected medicines for HIV/AIDS, TB and malaria to produce a positive list of prequalified products and manufacturers assessed according to established criteria of safety, efficacy and quality (including bioequivalence). WHO prequalification work and standard-setting are clearly endorsed by established regulators.

5. Targeted sampling and testing to monitor the market should be actively expanded. Test results conducted by procurement agencies should be shared with national regulatory authorities.

6. A single comparator based on the original single dose innovator product should be used to determine the bioequivalence of FDCs. In general, this should be the product (s) that was used for the original clinical trials.

7. The Prequalification Project includes ongoing monitoring of prequalified products and manufacturers; strengthens local regulatory and production capacity; and provides innovator companies with a fast-track process when their product has been already evaluated by a stringent agencies.

8. As yet, too few products meet WHO prequalification standards, especially in the case of TB and newer antimalarials.

9. In addition to the WHO Prequalification Project, quality specifications need to be made available to national drug regulatory authorities (NDRAs). WHO has developed an abbreviated protocol for TB bioequivalence testing. Such protocols may be necessary for ARV and malarial FDCs.

10. Countries are encouraged to use the results of WHO prequalification to provide fast track registration.

Some ways forward

1. Improved medicines quality requires substantial political commitment and commitment of resources, both nationally and internationally.

2. Development of CBCs is a practical step towards development of FDCs; it may avoid some of the more time-consuming and costly steps in product development and regulatory approval.

3. Specifications for APIs and finished products as well as methods of analysis and reference standards need to be made available to national drug regulatory authorities.

4. Under some unusual circumstances, a new product study may be needed when a new FDC is produced. This may require both preclinical and clinical trials to be undertaken.

5. Packaging is also an important part of quality. Defining the storage conditions for new products, especially FDCs and CBCs, should be a priority.