Two Recent FDA Warning Letters to Chinese API Manufacturers Reveal Enormous Risks in the Procurement of Starting Materials

Last year impure heparin from Chinese manufacturers of active pharmaceutical ingredients led to grave side effects in patients in Europe and several deaths in the USA. As a consequence, the FDA intensified its inspection activities and, in doing so, did not only find GMP deficiencies in the inspected firms, but also the firms' massive attempts of concealment and deception by deliberately passing on false information. Inspections of two heparin manufacturers in China at the end of July and in August last year resulted in two warning letters, which were now published on 14 April 2009. These documents describe the facts of the case, which read like a mystery thriller.

What happened beforehand?

  • A manufacturing facility in Shanghai, which delivers heparin to the USA, had assured to the FDA in a written message in 2004 that the heparin was exclusively manufactured at their site and that no other subcontractors were involved.
  • A few days prior to the start of the inspection, the FDA received a note saying that there was actually an alternative manufacturing facility for heparin.

In the course of the inspection, the FDA investigators found out the following:

  • The manufacturing site in Shanghai had never produced heparin itself.
  • The heparin was delivered to the site in 5-kg bags inside fibre drums. The original labels on the bags were removed and replaced by the labels of the Shanghai production site. Finally, the bags were repackaged into other drums.
  • The heparin did not originate from the subcontractor whose name had been given to the FDA shortly before the inspection. Instead, the heparin deliveries effected between 2001 and 2006 came from a third, undisclosed manufacturer, which had never been inspected by the FDA and which could not be inspected by the Agency any longer, since it had closed down its heparin production in 2006.
  • During an inspection of the manufacturer who had been delivering the heparin to Shanghai since 2006, apart from some GMP deficiencies, the inspectors found among other things that there had never been a GMP-compliant transfer of the production process from the former manufacturer to this one.

The fact that some batches of heparin were contaminated with over-sulfated chondroitin sulfate, which causes the known grave side effects, supports the suspicion that the FDA had been deceived on purpose with false information.

This case shows how important it is for manufacturers of medicinal products to know in detail the sources and the distribution chain of raw materials and active ingredients including the proceedings at all wholesalers and repackagers, especially if they come from the Far East.

Here you can find the warning letters to the manufacturing facility in Shanghai and to the subcontractor.

Recommended event: The situation of the API manufacturers in China seen from the point of view of a GMP auditor and China expert is among the topics of the 4th EFCG Conference in Brussels on 13-14 May 2009. The details can be found here.

Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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