Monitoring the manufacturing and quality of medicines: a fundamental task of pharmacovigilance.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed. PLAIN LANGUAGE SUMMARY: