Relation between solid-state properties and pharmaceutical quality of generic drug raw materials available in South Africa

Abstract

Although improving the quality of drugs is a responsibility to be shared, the generic sector of the pharmaceutical industry, as the source of the majority of essential drugs, must play a critical role in improving drug quality. One sector often overlooked is raw material manufacturers and suppliers. The quality of these materials is essential for the safety, efficacy and quality of drug products. The aim of this study was to investigate the pharmaceutical quality of generic raw materials available to manufacturers in South Africa, as well as the influence that variations in the solid-state properties of these raw materials have on the in vitro availability (dissolution) of these drugs. In order to save time and cost it is very important to choose the most suitable form of the crystalline drug substance in the initial stages of drug development. Differences in physical properties of various solid forms have an important effect on the processing of drug substances into drug products. Substantial inconsistent and questionable pharmaceutical quality were found among 135 drugs available on the South African market. In particular differences in crystal form, solubility and dissolution were seen. Worldwide regulatory agencies and national and international pharmacopoeias are relying on the dissolution test, not only for assessment of drug products, but for relevance to in vivo performance. There is still much to be done to establish dissolution testing as a harmonized regulatory quality control procedure, although the ICH initiative has moved significantly towards resolution of regulatory harmonization. Dissolution problems experienced in this study with specific generic raw materials and drug products, namely piroxicarn, oxytetracycline and mebendazole, showed that harmonization is urgently needed. Harmonization of dissolution should however not be done in isolation from other regulatory requirements, because it was found that accelerated stability testing at 40°C + 75% relative humidity for three months leads to physicochemical changes in oxytetracycline capsules and that the BP dissolution method was not able to measure the effect of these changes on the dissolution properties of the capsules. This study shows that professional judgement must he exercised in the purchase of generic drug raw materials by manufacturers. Existing techniques such as X-ray analysis, melting point measurements and especially dissolution testing can be used by manufacturers to monitor and detect variations in product quality due to changes in the solid-state properties of drugs.