The European Fine Chemicals Group (EFCG), a CEFIC sector group representing 37 European-based fine chemicals companies and nine national associations, demanded standards for excipients used in pharmaceutical manufacturing in a position paper issued recently.
Dr Arnulf Heubner of Merck KGaA, who has recently replaced Guy Villax, CEO of Hovione, as chairman of the EFCG's Pharmaceutical Business Committee, noted that excipients, the pharmaceutically inactive substances including fillers, binders, disintegrants, solubilisers and coatings that are used alongside APIs in drugs, constitute the vast majority of the final dosage form by weight and volume.
However, Heubner continued, their manufacture "is neither as regulated nor controlled as it should be, lacks legal enforceability and therefore poses potential risks to the quality of pharmaceutical products". For this reason, the paper calls for the proper enforcement of standards and regulation.
"It is nonsense that regulation should be so intense on the API that makes up about 10% of the tablet and not on the remaining 90%. The issue is the final dosage form, not just the API or the excipient," observed Villax, who now heads the EFCG's newly formed task force on China.
Under EU Directive 2002/83/EC, as amended by 2004/27/EC, a still to be defined list of 'Certain Excipients' must be produced to GMP standards, like APIs. The EFCG paper believes that 'Specific Excipients' (including these 'Certain Excipients') and the smaller 'Novel Excipients' group should also be covered by these regulations, because of their relatively high risk profile by comparison with 'Common Excipients'.
'Specific Excipients' comprise biologically derived and sterile excipients, plus others with a known track record of toxic contamination, plus fully synthetic polumers, based on monomers such as acrylates or vinyl pyrrolidone. 'Novel Excipients' refers to all new chemical entity excipients named in a recent EMEA draft and all 'novel biological excipients' in a draft position paper by IPEC Europe, though not simple physical mixtures of compendial excipients.
'Common Excipients' are by far the most widely used in pharmaceuticals. The EFCG believes that they should conform to an amended version of General Chapter 1078 of the US Pharmacopeia, including the ISO-certified requirements it contains. Finally, these and all other requirements should be certified and enforced effectively.
The ISO requirements include the formal release of every batch based on validated analytical methods or compendial methods, close monitoring of suppliers and manufacturing processes, assurance of traceability and comprehensive change control agreements along the whole supply chain, assurance of hygienic manufacture and the minimisation of the known quality risk of the substances.
Currently, Heubner said, standards for 'Common Excipients' are based on the 'Joint IPEC-PQG GMP Guide for Pharmaceutical Excipients'. However, these are not certifiable and therefore have no legal basis; they merely form a 'Manual for Orientation to Excipients Manufacturers'.
Villax added that the EFCG has been in close contact with the European Parliament since it first raised the issue of better control of APIs and last year's joint paper on the subject with SOCMA. Since then, there have been regular meetings and actions, which took on a new dimension with the recent scandals over fake drugs, DEG in cough syrup and toothpaste, lead paint in toys, melamine in pet food and others.
Although there is aggressive Asian competition in excipients as well as APIS, both Heubner and Villax stressed that the EFCG's position is not anti-Asian. "What we are against is the sub-standards companies who offer sub-standard products and we are frustrated at the lack of enforcement," Villax said.
"The recent scandals have led many to think that low cost manufacturing comes with a hidden price tag," said Heubner. "However, there are plenty of very good Indian and Chinese firms in this field and we believe that they would like a level playing field as much as we would."
"We believe that the emotional views expressed by some politicians about 'paying the new China price' are wrong," added Villax. In his view, the issue is not one of good European standards and bad Chinese ones; much of it is down to unscrupulous European traders and heads of purchasing who push so hard on price that it has led to cutting corners.
In some cases, traders have been accused of telling traders to make API and leave the label blank so that they can add a brand label. "China has fixed the issue of false labeling; Europe hasn't," Villax observed.
A major issue is that traders often end up doing the documentation for those producers who they are trying to get up to speed to sell in registered markets. Some may be claiming better compliance than is really the case. Certainly, he noted, all of the 17 CEP suspensions to have taken place in Europe involved a Chinese or Indian company, about half of whom had the trader named as the CEP holder.
Moreover, no doubt in part due to the press coverage, China has worked hard to tighten its laws. "China has moved forward by leaps and bounds and is trying hard to raise its standards," Villax continued.
Indeed, in September the Chinese SFDA issued regulations that go beyond European requirements; now, manufacturers have to assure that the APIs they export comply with the law in the country to which they are exported, on pain of a fine of up to three times the cost of the goods and confiscation of all illegal products and profits.
In early September, the US FDA posted a warning letter involving an import ban and a possible product recall on Kunshan Chemical & Pharmaceutical Factory with regard to doxycycline. "This is serious evidence of a manufacturer with a problem, so flags should have gone up in Europe but they haven't yet," said Villax.
The problem thus lies mainly in the gaps in enforcement in Europe. Until recently, there was no legal requirement for Chinese suppliers to comply with European laws. Now they must, but the lack of enforcement and common customs procedures still allow the unscrupulous to flout the law.
"Our concern is not with those who occasionally fall short of compliance but those for whom non-compliance is a strategy, those who make their living off fake medicines," concluded Villax. The EFCG's advice to the authorities is to focus on the supply chain, where the root cause of the problem usually lies.