Heparin in the FDA's Focus once more: Warning Letter for Chinese Contract Lab

Recommendation

23-25 April 2024
Barcelona, Spain

Global Registration and Life Cycle Management for APIs

The heparin scandal was one of the worst drug incidents of the last 20 years. In 2008, 81 people died due to administration of heparin which had contained over-sulfated chondroitin sulfate, a substance that is hard to differentiate from heparin analytically. Raw heparin had been cut with this chondroitin derivative in order to maximize profits. The scandal had a lasting effect on the regulatory environment back then: the FDA established inspections in India and China and issued the revision or complete rewrite of several guidelines. In the EU, the Directive for Prevention of Falsified Medicinal Products was published and implemented in July 2011 (FDA Inspections in China - Consequences from the Heparin Case). Still, more and more "black sheep" were discovered amongst the API manufacturers who produced heparin. One of the most recent cases is that of a Chinese manufacturer who received a GMP non-compliance report on February 25th, 2016 after having been visited by European GMP inspectors (Chinese Heparin Manufacturer again involved in Falsification and GMP Non-Compliance).

Recently, the FDA issued another Warning Letter concerning heparin. Recipient this time was the Chinese contract laboratory Shandong Analysis and Test Center. The inspectors found the following severe GMP violations:

• The used testing procedures were not scientifically sound and unsuitable for proving the GMP compliance of their API. In this laboratory, heparin samples were analysed using Nuclear Magnetic Resonance (NMR) spectroscopy in the presence of over-sulfated chondroitin sulfate (OSCS) (NMR spectroscopy enables to analytically differentiate between heparin and OSCS). There was no established routine for system suitability testing (SST), though. An SST which had been performed at an earlier date had failed; the reason hadn't been investigated. Without a valid SST, neither the procedure nor the results are valid.
• Access to electronically-stored analysis data hasn't been controlled. The FDA inspectors fruitlessly demanded access to the raw data of heparin sample analyses. When asked, an analyst explained that he deleted the data in order to make free space for newer data.
• Information has been withheld. The list of customers who commissioned a heparin analysis at Shangdon Analysis and delivered heparin products to the USA which was given to the inspectors had been incomplete. The disclosure of the missing customer information had been refused with the reason that they had to seek the relevant customers' permission first. This was deemed unacceptable by the inspectors and rated as an obstruction to the inspection according to guidance document "Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection".

Until all corrective measures have been implemented and following the GMP compliance of Shandong Analysis has been confirmed, the FDA won't process any authorisation applications listing this contract laboratory.