A Matter Of Record Keeping

The Swiss generic drugmaker Acino announced late last month that it suffered a loss of $3.3 million in the first half of the year because European authorities had forced it to recall batches of the drug clopidogrel that it had formulated with an active ingredient from its Indian supplier. European regulators ordered the recall after an inspection of the Indian firm revealed that it had compromised production records for clopidogrel.

Clopidogrel is the generic name of Plavix, a blood-clot inhibitor sold by Sanofi-Aventis and Bristol-Myers Squibb. Generic forms of Plavix have been sold in Europe since 2009, and the branded drug will lose patent protection in the U.S. next year.

The falsification of production records for a lifesaving drug such as clopidogrel is a violation of standard manufacturing procedures. But opinions in the drug industry are divided on the severity of the offense committed by Glochem, Acino’s Indian supplier. Glochem is also approved by the U.S. Food & Drug Administration to supply certain active pharmaceutical ingredients, or APIs, to U.S. drugmakers.

Acino views the European recall as wholly “unnecessary” because there is no evidence that the products it sold in finished dosage form had any quality problems. “New and comprehensive analyses and quality controls by independent laboratories confirm the impeccable quality of clopidogrel-containing medicines from Acino,” the company said in April, a few weeks after the recall was ordered. It contends that the brouhaha is simply over improper record keeping by its supplier.

“This can only be viewed as fraud,” counters François Vandeweyer, director of global compliance at Johnson & Johnson and a member of the API committee of the European Chemical Industry Council (CEFIC). “In a case like this, patient safety is compromised, and you can no longer trust the producer and its management.”

The manufacture of APIs for prescription drugs such as clopidogrel follows strict government-sanctioned procedures called Good Manufacturing Practices (GMP). During the production process, plant operators must write down and sign every action they perform on a particular batch, a log that in the end becomes the “batch record” of the production run.

When representatives of the European Medicines Agency inspected the Glochem facility in India, they found in the plant’s dump site more than 70 discarded batch records. Inside the plant, the records had been replaced by new ones.

“Practices such as rewriting batch records is [sic] contrary to basic GMP rules, and the impact on the quality of the product by the tampering with source data is unknown,” wrote the European Medicines Agency in a report attached to its recall order. “The amount and the variety of records discovered showed that this was not an isolated practice.”

Rewriting of batch records is common in India, says Peter Saxon, a New Jersey-based consultant who has trained dozens of drug producers in China and India in regulatory compliance. “I’ve never seen it personally, but I’ve heard about this time and time again from many different people in India,” he says. Glochem is not a client of Saxon’s firm, Saxon International.

Although he has no idea why Glochem changed batch records or what the impact might have been on product quality, Saxon believes that one of the reasons Indian producers alter batch records is to make them look neater to the eyes of foreign regulatory inspectors. “In India, the batch records tend to look too perfect,” he says. “They rewrite the batch records to make them look perfect—and whether the batch was run properly, who knows?”

Saxon notes that he is constantly urging his Indian customers to instruct plant operators to write batch records in their native language rather than in English, which they almost never speak. Indian plant managers prefer to teach their operators to write a few sentences in English because they think it will please foreign inspectors, he says, whereas writing in a native Indian language would actually appear more credible. In China, Saxon notes, plant operators fill in their batch records in Chinese.

As more and more drugs come off-patent and patients look for cheaper generic alternatives, increasing quantities of APIs are originating from India, China, and other countries where manufacturing costs are lower than in the West.

Fine chemicals manufacturers based in Europe argue that European authorities are incapable of ensuring that APIs manufactured under questionable conditions abroad don’t reach patients. Guy Villax, chief executive officer of the Portuguese drug ingredients producer Hovione and a board member of CEFIC’s European Fine Chemicals Group, says, “This case provides some food for thought on how fraudulent APIs find their way into the legal supply chain.”