The Falsified Medicines Directive (FMD) was designed to improve supply-chain security by reducing the flow of falsified and sub-standard APIs and excipients into Europe from non-EU sources. Through the written confirmation requirement, the number of such non-EU manufacturing sites (mainly in China and India) exporting APIs in particular into the EU was severely limited. Nonetheless, doubts remain about patient safety and the quality of future EU API imports from such countries on which the EU national health services are already heavily reliant. Whilst the EU authorities are encouraging and assisting Chinese and Indian authorities to improve their manufacturing standards to the EU level, most exporting suppliers will take a considerably long time to achieve them. Until then, the risk-control rules (a written confirmation and/or an audit) to protect EU patients are much less reliable than an official inspection by an EU (or equivalent) authority.
Over the past decade, the market for generic APIs has increased dramatically, driven by the need for cheaper medicines. Today, approximately 70% of all APIs consumed in Europe are imported from China and India, where their factories are rarely inspected for compliance with EU standards by EU authorities. This situation has led to certain unregulated API manufacturers in developing countries, especially in China and India, to compete aggressively in the market with approximately 30% lower prices (due to cheaper costs of labour and non-compliance with local environmental and safety regulations) for an API quality often less than the required EU standard. Such products can be harmful to health, as they may contain unknown impurities that can provoke side effects or adverse reactions (e.g., the case of the Chinese heparin in the US that caused more than 100 deaths were due to a deliberately included and undeclared impurity—oversulphated chondroitin sulphate [OSCS]).
The present EU Directive (2001/83/EC) cannot ensure that APIs used in EU medicines are GMP-compliant because neither mandatory inspections nor traceability of the API to its original manufacturing site are required. The most recent Directive (2011/62/EU), also known as the FMD covering human medicines, published on 1 July 2011, has been implemented by EU member states by 2 July 2013. Like Directive 2001/83/EC, it does not require either mandatory inspection of all global API manufacturers for GMP compliance, or the traceability of the manufacturing sites that produce APIs sold in the EU. Instead, the responsibility to verify compliance remains with the EU manufacturing authorisation holder auditing the supplier themselves, or by using a third-party auditor. There is a big difference in the quality of an audit and an inspection performed by a national authority. The date of an audit and its limited scope has to be pre-agreed with the supplier, but an inspection date is imposed on a supplier and they can demand to see everything. Also, many small European medicine manufacturers do not have adequate qualification, experience or resources to conduct API audits abroad.
The FMD (2011/62/EU), although designed to minimise counterfeit medicines entering the EU market, does not adequately address API quality issues, and in reality, does little to improve on the present Directive (2001/83/EC). Indeed, the FMD accepts that the continued risk to EU citizens is the normal situation, adopting the safe solution only as an exception to be used when there is a lack of key medicines requiring APIs from non-EU sources. However, it needs to be recognised that non-EU authorities, such as the Chinese in particular, have increased their efforts in inspecting domestic manufacturers of APIs as part of their implementation of the FMD.
Since 2004, the European Fine Chemicals Group (EFCG) and the Active Pharmaceutical Ingredients Committee (APIC), representing the majority of the European API manufacturers, have formulated a number of position papers and presented them to the responsible EU bodies—DG Enterprise and DG Sanco. We believe that much of our input has been embraced by the FMD except for our consistent call for mandatory inspections of all global API sites to ensure that their quality systems meet EU standards for the benefit of patients. Such global harmonisation would help improve supply-chain security by levelling the regulatory playing field and significantly reduce the flow of falsified and sub-standard medicines into Europe. In the absence of such inspections, the risks to EU patient safety and the competitiveness of EU API manufacturers can only be improved over a longer period by a stepwise improvement in global regulatory oversight and enforcement based on the principle of sharing inspection resources and inspection outcomes via mutual recognition agreements to yield a more level playing field for all.
About the Author
Hubert Stückler, PhD, is CEO of Cardiolynx AG and sector group manager of EFCG of CEFIC.