The European Fine Chemical Group (EFCG), an industry association of chemical manufacturers-including more than 150 devoted to pharmaceutical manufacturing-is calling for mandatory inspections of all global active pharmaceutical ingredient (API) manufacturing sites through the use of mutual recognition agreements.
In a 12 November statement, EFCG said it was, "Proposing a global harmonization of the rules and regulations governing the manufacture of APIs to level the worldwide playing field to ensure the quality of APIs and medicines containing them meet the high standard recognized by the developed economies." Those economies typically regulate API manufacturers through the adoption of the International Conference on Harmonization's (ICH) Q7 guideline, which sets good manufacturing practices (GMPs) for the manufacture of APIs.
The trade group said it was growing increasingly concerned about the global proliferation of API manufacturers, which they claim are under-regulated to the detriment of public safety.
"Today, about 70% of all API's consumed in Europe are imported from China and India, where their factories are rarely inspected for compliance with EU standards by EU authorities," the group writes in an accompanying position paper entitled, "To harmonise the rules in order to guarantee the safety of pharmaceutical products and the citizen's health: Why are mandatory inspections needed?"
API manufacturers in countries with lax regulatory regimes are able to price their products at an advantage relative to ones in highly regulated markets, giving them an edge against competitors when competing on price. "This is of concern to both the EU scientific and medical community for public health reasons and those EU API manufacturers facing unfair competition," observed EFCG.
Further, such API manufacturers can often be difficult to detect because manufacturers can switch-sometimes without giving notice-to another API supplier, or a supplier can switch ingredients. "Such products can be harmful to health, as they may contain unknown impurities that can provoke side effects or adverse reactions," noted EFCG, citing the example of tainted Chinese heparin which was later implicated in at least 100 deaths in the US.
Complicating the problems associated with the globalization of API manufacturing is the response of regulators, claimed EFCG.
The main problem, explained EFCG in a statement, is that inspections are often duplicative in more developed nations and nonexistent in less-developed ones, representing a poor use of scarce inspection resources. The EU's attempts to address this inspection disparity-most notably its Falsified Medicines Directive of 2011-is insufficient to combat the proliferation of substandard medicines, wrote EFCG.
"The recent EU Directive designed to minimize counterfeit medicines entering the EU market, does not adequately address the API quality issue. For example, it allows for preparations and medicines containing APIs to be imported into the EU without checking if the API manufacturer is compliant with EU law, as is required for the API per se."
"[N]either mandatory inspections nor traceability of the API to its original manufacturing site are required," EFCG added. "Instead, the responsibility to verify compliance remains with the EU Manufacturing Authorization Holder auditing the supplier themselves or via a 3rd party."
This, too, is problematic to the group. "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. In addition, Qualified Person's (QPs) are often in conflict between their company's ethics and its financial objectives."
The solution stipulated by the group involves mandatory inspections supported by mutual recognition agreements, saying they would "level the playing field and significantly reduce the competitiveness gap between all API manufacturers."
Such agreements have already been instituted on a pilot basis between regulatory authorities, and have the potential to save money, reduce the burden on each regulatory authority, and reduce needless duplication on manufacturing sites. Particularly among groups that all use the same standard-i.e. ICH's Q7-cooperation would be a "relatively small price to pay to guarantee the quality of API meets the EU standard."