Despite EU and U.S. concerns about Dongying Tiandong Pharmaceutical Co. Ltd.’s sourcing and testing of crude heparin, the FDA waited more than a year after inspecting the company’s API plant in Shandong, China, to send it a warning letter spelling out the possibility that tainted heparin once again could have been used to manufacture API for the U.S. market.

During an October 2015 inspection, an FDA investigator noted that the company repeatedly resampled and retested its crude heparin for ruminant DNA until it got passing results. For instance, the results for one batch varied from an out-of-specification (OOS) 343 ppm to an acceptable 2.3 ppm for ruminant DNA.

An anticoagulant frequently used to treat deep-vein thrombosis or pulmonary embolisms, as well as in treatment after heart attacks, heparin should be manufactured only from pig intestines, because raw material sourced from ruminant animals, such as cows, could be contaminated.

Because of Dongying’s practice of “testing into compliance,” the FDA said the company used crude heparin that was potentially OOS for ruminant DNA to manufacture heparin sodium API that may have been shipped to the U.S.

The Nov. 10 warning letter, posted to the FDA’s website Tuesday, also questioned the adequacy of an alternative testing method Dongying used to check for ruminant DNA. Other methods are allowed, but they must be validated and robustly compared with the posted FDA test to demonstrate that they’re at least as sensitive as the agency’s method. Dongying didn’t report a comparability study with the FDA’s approved method.

The company’s supplier qualification program raised additional concerns. When considering a potential supplier, Dongying sampled and tested the supplier’s crude heparin for ruminant DNA. If the material failed, Dongying appropriately rejected that supplier. However, when it received material that failed ruminant DNA testing from an already qualified supplier, the company didn’t reject the material and failed to reevaluate the supplier’s qualification status, according to the warning letter.

Dongying sought to resolve the investigator’s observations shortly after the inspection last year, but its response was inadequate, the FDA said, because it didn’t address how the company would investigate OOS lab results prior to resampling.

The agency also asked the company to submit its retroactive review of all the results from its quantitative polymerase chain reaction testing for ruminant DNA in crude heparin used to manufacture API for the U.S. Along with those results, Dongying is to include the procedure it used for preparing the crude heparin samples for analysis.

Besides trailing the inspection by more than a year, the FDA warning letter came eight months after France’s National Agency for Medicines and Health Products Safety (ANSM) cited similar problems and called on the EMA to revoke Dongying’s good manufacturing practice certificate. The ANSM recalled the company’s products in March and urged other EU members to do the same. (See BioWorld Today, March 9, 2016.)

The quality of crude heparin has been a global concern since adulterated heparin from China caused 149 deaths and sickened more than 700 people around the world in 2007 and 2008. Raw heparin batches associated with that scandal were later found to have been cut from 2 percent to 60 percent with a counterfeit substance designed to dilute the active ingredient and lower cost. The FDA came under heavy congressional criticism for not taking action against at least two Chinese companies thought to be responsible for that tainted product. (See BioWorld Today, Oct. 31, 2011, and March 9, 2016.)

The agency did place 22 Chinese heparin producers on import alert in 2012. The only other company to be added to that list was Beijing-based Shunxin Meihua Bio-technical Co. Ltd. It was put on the import alert in 2014 after refusing to allow FDA investigators into its facility.

PADE TUTORIAL

Another warning letter the FDA posted Tuesday reads like a tutorial on documenting, evaluating and reporting postmarket adverse drug experiences (PADEs).

The Nov. 21 letter to STI Pharma LLC, of Langhorne, Pa., follows a July inspection in which FDA investigators found that neither STI nor its contractor had the required written procedures showing how they comply with the agency’s PADE regulations.

In response to the inspection, STI drafted standard operating procedures (SOPs) to deal with PADEs, but the FDA pointed out that they were just draft SOPs and they included no implementation date nor corrective action plan to address incidents already received.

Given the company’s reliance on contractors to carry out its PADE activities, the FDA said it was concerned about STI’s “fundamental understanding and implementation of PADE regulations.”