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Regulatory News | 30 March 2016 | By Zachary Brennan
Several members of the House Committee on Energy & Commerce are raising new concerns over the US Food and Drug Administration’s (FDA) investigation into intentionally adulterated Chinese heparin that led to the deaths of 149 Americans in 2007 and 2008.
One of the lingering concerns in the letter sent to FDA Commissioner Robert Califf on Wednesday is that a lack of communication between FDA’s Office of Criminal Investigations (OCI) and its Center for Drug Evaluation and Research (CDER) resulted in a four-year delay in imposing import alerts on the more than 20 Chinese firms at the source of the contaminated crude heparin that was supplied to Baxter and eventually resulted in the deaths and other adverse events.
What's worse is that the committee found that some of the contaminated Chinese heparin suppliers that FDA placed on import alert in 2012 had been used as suppliers by Chinese heparin manufacturers shipping directly to the US between 2008 and 2012, according to the letter signed by five Republican congressmen.
Since 2012, FDA has finalized guidance recommending practices for monitoring the quality of crude heparin and the US Pharmacopoeia (USP) has released heparin quality standards meant to boost the safety and quality of the drug.
In 2014, however, Beijing Shunxin Meihua Bio-technical Co., Ltd., a manufacturer of heparin active pharmaceutical ingredients (APIs), received a warning letter after it barred FDA inspectors from accessing parts of its manufacturing site. A list of suppliers provided by the firm contained a company with an address identical to another firm subject to one of the FDA import alerts, likely implying that it was providing raw ingredients to Shunxin under an alias.
In this latest letter, the congressmen noted that FDA received leads on heparin contamination from an unidentified foreign drug regulator that conducted inspections in 2008 on two Chinese heparin firms, though that information was not used by FDA and “none of the leads developed by the foreign agency were pursued.”
FDA also never followed up on concerns that heparin contaminated with overly sulfated chondroitin sulfate (OSCS) was being stockpiled despite “credible allegations made to FDA investigators in 2008” that were corroborated by internal industry emails obtained by the committee.
The congressmen raise other questions about faulty statistics on the pig supply in China used to make heparin, noting the “supply in legal slaughterhouses in China would not be sufficient to support the number of pigs needed to manufacture the amount of Chinese heparin for export alone, not even taking into account the amount needed for the domestic Chinese market.”
In addition, the Chinese pharmacopeia monograph for heparin sodium until 2015 permitted the use of ruminant material in heparin, though FDA “failed to respond to credible evidence of non-porcine contamination of the Chinese heparin supply prior to the 2008 heparin crisis.”
The perpetrators who added the OSCS contaminant have still not been found seven years after the patient deaths, though the committee notes that they seemed to be economically motivated. The committee previously questioned if FDA can properly oversee the pharmaceutical supply chain in China and India.
The congressmen are calling on FDA to investigate whether previously contaminated crude heparin from China was not recycled and imported into the US, and how FDA accounts for raw material shortages in China that may increase the risks of adulteration and affect the integrity of drug manufacturing there.
FDA is also asked if they would be willing to reach out to its contacts in the Chinese government to find out why the government changed its position on OSCS in heparin and whether the government would be willing to work with FDA in preventing such contamination moving forward.
The letter comes as questions over Chinese heparin manufacturers are ongoing.
French regulators recently found that inspections from December of Dongying Tiandong Pharmaceutical Co.’s Dongying City-based manufacturing site for heparin uncovered PCR (polymerase chain reaction) results of crude heparin showing "the presence of ruminant DNA received from approved suppliers were manipulated.”
In addition, 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.”
Tags: heparin, tainted heparin, FDA and heparin, Chinese heparin manufacturing