The regulator detailed its concerns this week, reporting that inspectors who visited Dongying’s site in Shandong province in October 2015 found evidence the firm was not adequately monitoring raw material suppliers or investigating out-of-spec test results.
The Food and Drug Administration (FDA) wrote: “Our investigator reviewed your Q-PCR method to determine whether crude heparin batches you receive were contaminated with ruminant DNA.
“Our investigator identified deficiencies in your validation of your test method for detecting ruminant DNA, including failure to directly compare your Q-PCR method to FDA’s posted method.”
The agency also criticised Dongying for failing to investigate deviations in high pressure liquid chromatography (HPLC) tests, explaining that failed samples were reanalysed rather than being invalidated.
It said: “The failure of your HPLC system suitability testing calls the validity of OSCS testing performed on the same equipment into question.”
Dongying declined to comment when contacted by this publication.
The US FDA warning letter comes 10 months after French regulator ANSM raised concerns about heparin produced by Dongying.
In 2008, more than 100 people died after suffering allergic reactions to heparin that had been made using active pharmaceutical ingredient (API) contaminated by OSCS (oversulfated chondroitin sulphate).
Back then heparin API cost $12,000 a kilo and OSCS, which has similar chemical properties and was not detectable using analytical tests employed at the time, cost $20 a kilo.
These economics were at the heart of the tragedy according to then US Food and Drug Administration (FDA) Commissioner, Andrew von Eschenbach.
He told a Senate Committee at the time that starting materials used by API supplier Scientific Protein Laboratories-Changzhou (SPL-CZ) had been bulked up with OSCS at an earlier point in the supply chain for economic reasons.
The tragedy prompted the FDA to ask manufacturers of heparin drugs and APIs to “audit and qualify their crude heparin suppliers to ensure conformance to appropriate quality standards.”
Similarly, the European Medicines Agency (EMA) issued a reflection paper in 2012 which made clear that marketing authorization dossiers “should cover the whole manufacturing process starting from the sourcing of the mucosa.”