14/15 June 2021
The Heparin Scandal has changed the regulation and the enforcement actions against API manufacturers like no other case in the last 20 years. Now, it seems that falsification of Heparin was detected again at a manufacturer in China.
In 2008 adulterated Heparin from China caused the death of 81 people and 785 reports of serious injuries. The reason for the adverse reaction which caused the deaths and injuries was identified later. The contaminant was an "over-sulphated derivative of chondroitin sulfate, a closely related substance obtained from mammal or fish cartilage and often used as a treatment for arthritis. Since over-sulphated chondroitin is not a naturally occurring molecule, costs a fraction of true heparin starting material, and mimics the in-vitro properties of heparin, the counterfeit was almost certainly intentional as opposed to an accidental lapse in manufacturing. The raw heparin batches were found to have been cut from 2-60% with the counterfeit substance, and motivation for the adulteration was attributed to a combination of cost effectiveness and a shortage of suitable pigs in China." (Source Wikipedia)
A comprehensive investigation of the US congress identified weaknesses in the GMP Inspection by FDA. The US congress discovered that the frequency of inspections was not as required by FDA's internal standards. FDA took multiple actions as a consequence of the scandal. Among others the FDA opened overseas Inspectorates in India and China and initiated a number of new regulatory initiatives. Also in the EU the Heparin scandal has impacted the regulation and inspections. The so-called Counterfeit Directive, the GDP Guidelines and changes in the EU GMP Guide (especially with regard to supplier qualification) have been havily impacted by the Heparin case. Today manufacturers of a medicinal products are obliged to control the GMP compliance of each API manufacturer.
It was therefore a surprise when French Inspectors just recently found worrying details at Dongying Tiandong Pharmaceutical Co., Ltd., No. 1236, Nan-er Road, Dongying City, Shandong Provice, China. According to the non-compliance report published in the EudraGMDP Database: "Overall, 10 deficiencies were observed during the inspection, 2 Critical and 3 Major deficiencies:
[Critical 1] PCR results of Crude Heparin showing the presence of ruminant DNA received from approved suppliers were manipulated. There was no evidence that the samples retested came from the same batch tested initially;
[Critical 2] The quality system implemented by the company for ensuring the full traceability of crude Heparin was identified as very weak : e.g., the traceability from slaughterhouses/abattoirs was not available and not assessed during the audits of the suppliers (lack of supporting documents for the received lots)"
The inspectors also found out that 7 batches of crude Heparin received in 2014 and 2015 were obtained OOS for potency and used for the manufacturing of finished APIs without any OOS investigation. New suppliers of crude Heparin were not qualified in a systematic manner to guarantee the quality of the product. As a consequence of the findings EMA published the GMP Non-Compliance Report on 25 February 2016. Also, the CEP 2005-258 was suspended. Manufactures of Medicinal Products using the Heparin from Dongying Tiandong Pharmaceuticals should consider a recall of their batches based on a risk assessment.