Development of FDCs; pharmaceutical considerations Susan Walters presented her keynote paper that addressed the many issues related to the sustained quality of products once they have been produced, stored and distributedⁱ (p. 169). She emphasized the importance of validation after any changes are made in the manufacture of a product.

ⁱ http://www.who.int/medicines/organization/par/FDC/WHOGenevaSMW1203.ppt

Vinod Arora (Ranbaxy, India) presented information on his experience with the production of ARV FDCs.ⁱⁱ He made a detailed presentation of the methods used to establish bioequivalence and to assure the quality of FDCs as compared to originator products.

ⁱⁱ http://www.who.int/medicines/organization/par/FDC/VKAroraWHOGenevaDec.ppt

Witold Wieniawski (Polish Pharmaceutical Society) emphasized the need to identify what products are needed before the formulators are asked to produce the required products. Regulators will be assisted by having external validation.

In addition to the prequalification scheme, he suggested that there is also a need for specifications and quality standards to be produced. These standards are expensive and need to be managed in cooperation with organizations such as the USP and European Pharmacopoiea.

János Podgorny (Hungary) reported in detail on the WHO prequalification scheme.ⁱ He presented detailed case studies on the prequalification of the 4FDC TB product and FDC ARVs. He concluded that there were no regulatory obstacles to the production of quality assured FDCs.

ⁱ http://www.who.int/medicines/organization/par/FDC/Janos_FDCFPPs_Experience_LaingRv1.ppt

Lembit Rago (WHO/QSM) reviewed the WHO prequalification project.ⁱⁱ He emphasized that sampling for QC testing was at the post-marketing level.

ⁱⁱ http://www.who.int/medicines/organization/par/FDC/Lembit-FDC2003adec18.ppt

Leonard Sachs (FDA, USA) highlighted the many issues around the approval of FDCs.ⁱⁱⁱ He pointed out that assuring the quality of the product affected clinical factors.

ⁱⁱⁱ http://www.who.int/medicines/organization/par/FDC/WHOSacksFDCs.ppt

Roger Williams (USP, USA) discussed the issue of comparator products.^iv He pointed out that individuals may respond to drugs in different ways. He emphasized that packaging was an important component of product quality.

^iv http://www.who.int/medicines/organization/par/FDC/19-comparatorproduct-williamsdec18.ppt

Jérôme Barré (France) confirmed that for well established drug combinations, all the regulatory authorities agree that there is no need to perform extensive studies. Proper pharmaceutical development and a study demonstrating that the components in the FDC are bioequivalent to the components administered in the free combination are sufficient. In the situation where one active component should be administered with food and the others without food, the food effect on the FDC has to be investigated. He pointed out that the regulatory requirements for new drug combinations with which we lack experience were not addressed in this session. In this situation things are much more complex, especially with regard to toxicology and safety pharmacology requirements. Unfortunately these points are often overlooked although safety problems are at stake.

He commented that Roger Williams had presented a very comprehensive review on comparator products stressing the importance of a good choice for comparator. Formulations of brand products which are used as reference drugs can vary slightly from one country to another. In Susan Walters presentation, she mentioned some of the reasons for these variations including new source of excipients, new manufacturing equipment, new site of manufacture etc. These variations may produce different in vitro dissolution profiles. In some cases, these changes in dissolution profiles do not translate into different bioavailability while in other cases they do and with confidence intervals beyond the usually accepted ranges, as regulatory authorities have sometimes noted. For some pharmaceutical products there are publications reporting substantial differences in bioavailability of the same brand product sold in various countries and showing slight variations in the formulation. This is why there is a need to be very stringent when choosing the reference drugs to be administered in loose combination to demonstrate the bioequivalence with the test FDC. The reference drugs should originate from the country in which the clinical trials were performed to evaluate the efficacy of the free drug combination. This will avoid having FDCs with sub-optimal efficacy.