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COVER STORY
Europe Adopts GMP Regulations
Europe has long been the center of global active pharmaceutical ingredient (API) production, but producers in India and China are rapidly eroding the region's leading position. When it comes to making generic APIs, the volume from India and China together already outstrips that from Europe. Along with this stiff competition, European producers face overcapacity problems at home and a crowded, undifferentiated marketplace.
More than 70% of APIs used in Europe are imported from India and China, many via brokers and traders. Many of these products or the plants where they are produced have never been inspected. For at least a decade, European producers have sought to level the competitive playing field by curtailing the use of low-priced APIs not produced under Good Manufacturing Practices. Conformance to GMP addresses consistent product quality by ensuring an API's composition and purity.
Implementing and maintaining GMP can amount to a significant percentage of a company's operating costs, European API producers say, and many do so because they supply the U.S. market, where adherence to GMP is mandatory. But in selling to Europe, other suppliers have kept their costs down by not following such standards. This situation has changed with a European Union directive now being implemented by the member countries: As of Oct. 30, 2005, all APIs going into drugs sold in Europe must be from GMP-compliant sources.
"Having GMP for APIs recognized as a directive is welcomed by industry," says Matt Moran, director of PharmaChemical Ireland, a trade group representing about 50 pharmaceutical and chemical companies. He is also on the board of the European Fine Chemicals Group (EFCG), created in 2004 to represent the industry as part of the European Chemical Industry Council (CEFIC), and he heads CEFIC's API Committee (APIC).
"It's welcome, but it probably hasn't gone far enough," Moran adds. "What we were looking for was mandatory GMP licensing for all API manufacturers that would be policed through the competent authorities." This would be comparable to the situation in the U.S., where the API producer has the responsibility for GMP compliance and the Food & Drug Administration does the checking via inspections.
FDA inspects all API manufacturing facilities, including those outside the country supplying products to the U.S. In Europe, both drug and API manufacturers have had to complete filings with the regulatory authorities, but these filings have not automatically involved inspections. Although inspections on finished dosage forms are required, the new law does not include any obligation for API inspections.
Instead, the drug manufacturer or firm holding a drug marketing authorization is responsible for ensuring that any APIs it uses are GMP compliant. More specifically, it will be up to a so-called qualified person to sign a certificate of conformance. National or EU authorities, such as the European Medicines Evaluation Agency (EMEA), may choose to inspect API producers, but there isn't yet any system in place, and different countries' interpretation and implementation of the directive vary considerably.
Meanwhile, the European Directorate for the Quality of Medicines (EDQM) issues certificates, called CEPs, under European Pharmacopoeia standards. CEPs are popular with API producers supplying established ingredients to multiple customers because a product can be shown to meet certain specifications by going through a single, centralized certification process.
CEP holders may be subject to inspections, although they are not regular or compulsory. Between 1999 and late 2005, EDQM reports, it inspected 74 sites and suspended nine certificates from seven different holders: five covering API manufacture in India and four, held by European traders or brokers, that cover manufacture in China. In early 2006, EDQM restored one Indian producer's CEP.
Overall, FDA inspects about 1,000 API producers for U.S. pharmaceuticals. The scale of the task is much larger in Europe, where as many as 10,000 firms are estimated to be supplying APIs to EU drug producers. "The authorities realize they have a real problem on their hands," says Guy Villax, chief executive of fine chemicals producer Hovione and chairman of EFCG's pharmaceutical business committee. "They can't hire hundreds of inspectors overnight." Many companies, however, are willing to support inspections through a system of user fees.
"Obviously, it would be a significant challenge in terms of time, money, and the practicality of it for the competent authorities to try to inspect all non-European API manufacturers," Moran agrees. Instead, it's incumbent on the drug company to determine one way or another if GMP standards are being met and then vouch for the APIs, he points out. And EMEA has indicated that certificates from health authorities are not sufficient evidence of adherence to GMP.
"It's unclear at the moment, but the assumption is that a drug manufacturing company will audit its supplier," Moran explains. "I imagine that we'll see significant audit activity begin, and it will be a question of trying to manage that. The concern is that there will be an audit burden placed on the API industry, which, in a worst-case scenario, has companies spending more time auditing than manufacturing." These audit reports will not be confidential and are to be shared with regulators.
To help API producers and users comply, EFCG is providing a simple guide to GMP compliance. It is also helping set up a third-party auditing scheme based on an existing APIC certification program and outside providers. Meanwhile, EFCG is conducting a benchmarking survey to assess the state of readiness, plans, and allocation of resources by EU member state health authorities to enforce the new directive. The group plans to report the survey results at its first business conference, which will involve regulators, in Barcelona in late April.
EMEA indicated in a Question & Answer response posted on its website in late 2005 that it may accept audits from credible third parties if they are conducted on-site by qualified and trained staff following approved procedures. EMEA also suggests that under certain circumstances different drug manufacturers using the same active-substance supplier could share audit reports. Paper-based audits, however, and those conducted by other authorities are not enough to fulfill a company's obligations, but they can be used as guidance for planning auditing activities.
Moving ahead, EFCG hopes to work with regulators to harmonize and improve the format of inspections and certifications, as well as to better understand and clarify inspection triggers and sanctions. The industry would like to see a centralized EU inspectorate, and EFCG says "constructive discussions" with EMEA are ongoing on this and other issues. "Our continuing lobbying efforts are now trying to influence the fine print for how inspections are conducted," Villax says.
European fine chemicals companies are still concerned, however, that the new directive lacks teeth and represents little movement toward consistent and uniform enforcement. Deterrents and meaningful sanctions are required to make the directive credible and to ensure compliance, Villax believes. For instance, he suggests that inspections should be conducted not only when there is suspicion or a report of a problem-possible triggers that EMEA proposes-but also on a random basis so that all API producers know they could be inspected.
Industry participants accept that offenders should face stiff penalties, despite a lack of any precedent in Europe. "It's very simple. In America, if you don't play by the rules, you go to jail. So people are very careful," Villax says. "But in Europe, no one has ever gone to jail, and it's very frustrating because people who don't play by the rules tend to win a lot."
Nevertheless, APIs can no longer be purchased from brokers or traders who hide the identity of their sources, Villax says, through repackaging, relabeling, or even blending products. Information on APIs is included in drug master files (DMFs) that then become part of a marketing authorization dossier. Inspections and certifications need to be traceable and specific to particular APIs made according to the description in the DMF, he suggests. EFCG has even said it would like to see no new marketing authorizations approved without GMP certification and that existing ones should be withdrawn unless GMP compliance for the APIs can be demonstrated.
"The industry wants the regulations and is saying 'please make sure you regulate us properly,' because we are fed up at not having a level playing field," Villax remarks. Fine chemicals are a key piece of the European chemical industry, but rather than advocating protectionism, he says, "the message is that we cannot survive if there isn't fair competition." Villax admits it will take time to bring about the needed changes but says he is much more optimistic than he was a year ago that the new directive will make a difference.
One such difference is in potential public health consequences. A frequently mentioned example is gentamicin, which caused as many as 17 deaths in the U.S. that were not explained by the drug's pharmacology or toxicology but presumably by faulty manufacture and impurities. Subsequently, researchers at the University of Wurzburg, in Germany, analyzed 39 samples supplied from 14 U.S. and German producers and found the composition to be highly variable (Pharmaeuropa 2003, 15, 273).
The possible link to GMP compliance got stronger when the researchers looked at up to 50 sample lots, including ones involved in the deaths or severe side effects (Am. Pharm. Outsourcing 2004, 5, 24). Their results have suggested that plants and producers other than those listed in regulatory filings may have been the source of the APIs. These findings have raised serious concerns about how widespread the variability in APIs might be.
Similarly, researchers at Catholic University of Leuven, in Belgium, have analyzed 19 products containing the antithrombolytic agent clopidogrel (J. Pharm. Biomed. Anal. 2004, 34, 341). The drug, sold by Sanofi-Aventis and Bristol-Myers Squibb under the brand name Plavix, had estimated 2005 sales of more than $6 billion. Other producers have introduced copies of the chiral drug in Asia and South America; the Leuven researchers compared 18 of these with three Plavix batches.
The active compound is the S-enantiomer, and health authorities generally require control over levels of other nonactive enantiomers. They found that the brand-name tablets all fell within "generally accepted 95-105% limits" of the label claim of 75 mg per dose, whereas half of the copies failed to fall within this range. The researchers note, however, that there is no European Pharmacopoeia monograph setting impurity and content limits for clopidogrel.
More than 60% of the copies also contained high levels of impurities, more than four times the amount of hydrolysis degradation product or R-enantiomer, compared with the brand-name drug. This indicates that "the excipients, production technology, and packaging of the samples are also important and may have a major influence on the global quality of the products," the researchers wrote, and that "these parameters were best controlled by the originator."
Major pharmaceutical and API producers that have been meeting FDA standards are expected to see little impact under the new EU directive. "When you are an innovator company, you watch this with a microscope," Villax explains. "Your market is so huge that the potential risk of using bad APIs is unacceptable." But smaller firms, supplying smaller markets or generics, may not have been able to shoulder the costs or were uninterested in the absence of regulations.
Now drug manufacturers must know their suppliers and address the quality of the APIs. "It's their responsibility," Villax remarks, "and there is going to be a bit of mind-set change to deal with."
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