Substandard APIs: we must tackle the problem together

In 2005, a small delegation (myself included) of the European Fine Chemicals Group (EFCG) met with the deputy head of the cabinet of Commissioner Kyprianou (the then Commissioner responsible for health and consumer protection). Our mission was simple — we were there to raise a red flag.

We were concerned that substandard APIs were a growing problem and, in our opinion, the root-cause lay in break-neck globalization and rogue players taking advantage of the virtual absence of effective oversight on European laws governing minimum quality standards. We were given 20 minutes, by which time it was made abundantly clear to us that we must be from another planet. We were told that all was well, and that "in the EU the architecture of quality of medicines is firmly based around the Qualified Person and that there is no such issue of substandard APIs in the EU". In several other meetings with the Commission and with the EMEA, we were looked at with disbelief and almost horror every time we raised the spectre of noncompliance as a deliberate business strategy. In between the lines we could read "how can the EU's API industry sink so low as to try to make up for its lost competitiveness by scare-mongering".

Living in the past

During the last few years, the EFCG has worked hard to provide the correct data to EU regulators, but it has been a struggle; in part because EU officials and EU medicines agencies hate to leave their comfort zone and explore new territory where values and society are vastly different from those of Socrates, Beethoven, Pasteur, Galileo or Churchill. Even today in 2009, only at the very top of the European Commission or of the EMEA do we find leadership that is cognizant that EU medicines agencies are obsolete in so far as their oversight role is concerned regarding API compliance; the 27 agencies still inspect on proximity and not on risk. In June 2008, when a newspaper quoted me on this and the head of one of the EU medicines agencies was confronted in a public conference on the matter, my comments were dismissed as unfounded and coming from someone that had little understanding of the operations of EU medicines agencies.

Most regulators still live in the 20th century. During the last 25 years, Europe — with the explosion of off-patent medicines — has moved from being the cradle of the pharmaceutical industry, and the dominant player in the fermentation and synthesis of APIs, to a hasbeen; fermentation has virtually disappeared from Europe and the EU API industry is only thriving because of innovators and because of the US market where tough hurdles set up by the FDA separate the wheat from the chaff.

Asian revolution caught regulators by surprise

Today, approximately 80% of all EU medicines are made with APIs that have come from India or China, which in itself is not a problem were it not for the fact that these APIs come from plants that are unlikely to ever have been inspected by an EU official. Furthermore, the absence of effective enforcement encourages criminals to flourish and profit, and allows them to get away without any consequences.

Shifting a major part of API production to Asia took place at lightening speed; within 25 years the shape of the industry was transformed. The medicines agencies, however, were created when businesses were national in geographical spread, and it is understandable that regulators were caught by surprise. What we cannot accept is that those charged to ensure medicines are safe and effective remain in denial. It is difficult to understand why inspectors from the medicines agencies do not attend the annual CPhI meeting — the largest global exhibition of pharmaceutical ingredients producers held in Europe each Autumn — if anything as part of their training to really grasp the size and nature of the market they are responsible for supervising.

In 2005, the EFCG issued a questionnaire to the 27 European medicines agencies to assess their ability to enforce compliance with GMPs for APIs that had only become law in October 2005. Six agencies responded and we could conclude that a law existed, but had no enforcement. It appeared that most respondents were happier to remain in their comfort zone.

Globalization has provided us with many lowcost items, which has enabled the West to enjoy an unprecedented standard of living. Competition is desirable, but as far as medicines are concerned, in the absence of an arbiter of quality, the most unscrupulous player is sure to win every time.

The EFCG's argument is that API producers must be the object of more than just self-regulation; there is too much at stake and regulators must assure four elements:

• A clear, well-understood set of laws, guidelines and rules setting out the minimum quality standard that must be met and demonstrated.
• A registration system that gives regulators an inventory of all foreign producers that intend their APIs to be made into EU medicines.
• A sufficient amount of oversight mechanisms and inspections, which are likely to result in the identification of noncompliant firms.
• Sanctions of a wellcalibrated severity that, combined with precedent (the probability of being caught), deter firms from adopting noncompliance as a strategy and ensure that they do not ever knowingly release noncompliant products.

The European Directorate for the Quality of Medicines & Healthcare (EDQM) is probably the only agency in Europe that, for many years now, has done its best to inspect facilities in Asia. In 10 years, they have conducted approximately 160 API inspections and as a result more than 50 certificates of suitability (CEPs) were either withdrawn or suspended. All these suspended/withdrawn CEPs covered APIs manufactured in India or China whereas to date, not one CEP relating to an API manufactured in Europe has been suspended/withdrawn. These results show that many unsafe APIs — and certainly many more than these ca. 50 as the EDQM only inspects a fraction of all CEP holders — had been included in medicines for European patients for years. The health implications of this are, as yet, unknown.

Too little too late?

By December 2007, the tide had started to change. The majority of the MEPs had signed the written declaration on the need for much stricter authority oversight over APIs; at the same time the US Congress was lambasting the FDA for not protecting the American people against unsafe APIs. Indeed, well before the 2008 Heparin incident, the EU Commission, EMEA and FDA had already sent clear signals: new measures were necessary to address globalization and the growing incidence of substandard and rogue APIs, as well as counterfeits.

In 2008, there were approximately 150 deaths in the US because of contaminated heparin. No one has come forward with a more plausible explanation than pointing at greedy criminals keen on making a profit. Yet the issue has further ramifications, and many are still surprisingly in denial:

• Every time we face a serious global threat — gentamicin (1994, 1999), Ltryptophan (1989) or heparin (2008) — the casualties are all in the US. Are Europeans more resistant against toxic contaminants or is our data collection faulty?
• EU medicine agencies still lack information on the names of the API manufacturers that import into Europe, unlike the US or Japan that have lists.
• There is no mechanism for EU medicines agencies to enable EU customs services to block entry of APIs coming from plants known to be severely noncompliant or fraudulent.
• The European Generics Association has stated that there was still no evidence to date of any counterfeited generics being on the market in Europe.
• In Europe, if pharmaceutical companies are aware of noncompliance issues they must notify health authorities and initiate a recall from the market. However, if they become aware of counterfeit versions of their medicines, there is no legislation to oblige them to notify health authorities or to trigger a recall from the market.

Starting to move in the right direction

Finally, the pharmaceutical industry, in a bid to address these issues, is beginning to work together. Rx360 is an international industry consortium that brings together the complete global supply chain: innovators and generics; East and West; primary and secondary manufacturers and middlemen; and medicines agencies have also been invited to participate. The consortium will hold its first meeting in Washington (USA) on 5 June, and the EFCG and the Active Pharmaceutical Ingredients Committee will be present and are supporting this initiative.

There is still so much to do, but finally we seem to be moving in the right direction. In June 2008, Thomas Lönngren, Head of the EMEA, said: "This is a new scenario for us as regulators on both sides of the Atlantic. Suddenly we discover that we have important manufacturing far away that we don't have any control of."

Guy Villax is Chief Executive Officer of Hovione FarmaCiencia SA and a member of the Board of the EFCG.