Quality questions

EU-manufactured drugs are more likely than not to contain APIs sourced from uninspected facilities in India or China

Consumers take it for granted that the medicines they buy are manufactured to the highest standards, and expect the regulatory authorities to make sure that this remains the case. Manufacturing plants have to meet strict standards to ensure the products they make are up to scratch and not contaminated. But in reality, there is a high possibility that the medicines on the shelves of European pharmacies will contain active pharmaceutical ingredients (APIs) that were made in Asian factories that have never been inspected. And new regulations due to come into force later in the year will not solve the problem.

consistency not assured

'Enforcement is currently focused on those who need it least - those in Europe,' claimed Hovione's ceo Guy Villax at the formal launch of the European Fine Chemicals Group in Brussels in December. 'But 70% of APIs in EU pharmaceutical products today are imported from India or China, and the vast majority of those in generics.' The APIs are usually imported by brokers who relabel them, which makes traceability extremely difficult.

Compliance with GMP regulations means that batches of an API remain of consistently good quality. Any changes to the process can be implemented only after the impact on quality has been assessed, and records must be kept so that all actions can be traced if necessary. But without GMP, consistency is not assured, the process may be changed, regardless of its effect on product quality, and deficient record keeping makes investigation almost impossible.

This means that a number of problems are more likely to occur without being noticed, such as changes in impurity profile, contamination with other APIs because of ineffective cleaning, or altered crystal forms or particle sizes, which can impact on bioavailability.

It is not just a theoretical danger - there are real examples. The best documented was found by researchers at Wuerzburg University in Germany, in a study commissioned by the German licensing authority. The team looked at 21 samples of the antibiotic genta-mycin on sale in Germany, and found that in 17 cases, the API had not been made in the plant listed in the drug master file. And, by extrapolation, it claimed that as many as a third of the APIs on sale in Europe may not have been made by the registered manufacturer.

The number of plant inspections by European authorities is limited, and they are currently carried out by the European Directorate for the Quality of Medicines (EDQM), the body which is also responsible for the European Pharmacopoeia. Since 1999, EDQM has carried out 58 inspections targeting the most sensitive APIs, resulting in no suspensions of certificates of suitability (CEPs) in Europe, but seven in Asia - four of them in India and three in China. Five of the 28 Asian sites inspected failed. 'Although they will naturally select for inspection those they are most worried about, it does show where the problem is,' Villax said. 'And it's not likely to be in Europe.'

From the end of October this year, EU Directive 2004/27 is due to be implemented; this will put a legal requirement on companies to ensure that any APIs used to make medicines for the EU comply with GMP. However, GMP certificates will not be mandatory, and there is to be no requirements for API manufacturers to be subject to inspections. The system will remain essentially one of self-regulation, unless more stringent national rules are in force.

not mandatory

While they welcome the directive in principle, European manufacturers of APIs are not happy that GMP certificates will not be mandatory, believing that the search for profits may override GMP compliance. It costs money and takes time to ensure a plant is compliant, with more costs incurred every time a change is made to a process, however minor.

The US FDA inspects all facilities that supply the country with APIs, regardless of location. This means that only around 300 or 400 facilities sell APIs to the US, compared with the thousands of uninspected plants whose products reach the European market.

It also leads to the insane situation of European API manufacturers selling their ingredients for use in the US, while they are left unable to sell them in Europe because they are undercut by lower cost - uninspected - Asian manufacturers.

way forward

So what should the way forward be? 'We would like the European Commission to set up an EU foreign inspection service,' said Villax. 'We think the US system works - so let's copy it.' He added that it should be done centrally, otherwise the situation will arise when inspectors in one country audit in a different way from those in another. He said that EMEA or EDQM should be exclusively responsible for ensuring that companies comply, regardless of their location, and should also be in charge of training the inspectors. The system should be self-financing through the imposition of user fees, which Villax claims companies would be happy to pay if proper enforcement resulted.

'To make sure there are teeth, we feel that marketing authorisations, if they are to be approved, should have a certificate of GMP compliance with them,' he added. 'They should provide evidence that the manufacturer of the API can prove their quality. And all existing marketing authorisations should have a transition period for companies to provide a certificate. Otherwise, the authorisation should be withdrawn.

'We want an EU inspection service, based on verifiable inspections, not paper. Every manufacturer wants to pass an FDA inspection; it is the "gold standard". Why can't we aim to be the gold standard? And we should be able to recognise inspections from other reputable bodies. The European Commission can't just wait for an adverse effect to happen.'