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Unsafe material may remain in the US supply chain, according to a March 29th letter to FDA Commissioner Califf
Who could forget the tainted heparin recall of 2007 and 2008? Batches of the workhorse blood thinner supplied by Baxter were found to be contaminated with a synthetic chemical, overly sulfated chondroitin sulfate (OSCS), from a Chinese API supplier. More than 140 patients injected with the contaminated material died. FDA and other regulators launched an investigation, and the US Pharmacopeia and FDA approved analytical methods for assuring legitimacy of material.
More than anything, the case revealed a new pattern for crime: economically-motivated adulteration of APIs and drugs. Instead of greedy thugs or ignorant traders using the wrong material, the perpetrators had a sophisticated knowledge of chemistry and analytics.
The case also revealed the need for faster regulatory action, improved communication between different branches of FDA, more collaboration with regulatory authorities outside of the US, and greater vigilance within the industry.
Today, even drug manufacturers with more advanced supply chain management programs in place admit to being able to see only a few levels down into their supply chains. Complex supply chains involving spot buys of raw materials are extremely hard to control.
At the same time, the US is sourcing most of its APIs and ingredients from a country that is known as source of illegal counterfeit drugs. The potential for cases like this to recur seems almost limitless.
Eight years after the heparin recall, there is no room for complacency about the safety of the US (or global) heparin supply. A letter sent to FDA Commissioner Robert Califf on March 29, 2016, by US Representatives Fred Upton and Frank Pallone, points out reasons and asks some difficult questions.
Most significantly, the letter says, the identities of the perpetrators in the first heparin recall remain unknown, although ample evidence was available to help nail them. “Loopholes and exemptions that permit part of the Chinese drug supply chain to operate without outside government scrutiny still remain,” the representatives wrote.
Illustrating this sense of entitlement most dramatically was a situation in 2014, mentioned in the representatives’ letter, which involved the heparin API supplier, Beijing Shunxin Meihua Biotech Co. Ltd. Ultimately, the company received a warning letter from FDA, but initially, staff at the factory did not allow FDA inspectors onto the production area or permit them to access inventory records.
Eventually, inspectors found that the address for one of Shunxin’s heparin suppliers was identical to that of a heparin supplier that had been put on FDA’s Import Alert list. They also found that crude heparin processed at the facility contained ungulate (i.e., goat or sheep) DNA.
Another problem pointed out in the letter was the failure of different divisions within FDA to work together and collaborate fully on the case. (Coincidentally, FDA’s Commissioner’s blog post this week underscores the need for teamwork at the Agency).
FDA offices failed to work together
As the letter explains, FDA’s Center for Drug Evaluation and Research (CDER) and its Office of Criminal Investigations (OCI) failed to communicate or to hand off investigative work as they should have.
For instance, the company that sent the problematic API to Baxter, Changzhou Scientific Protein Labs, maintained traceability records for each individual lot of crude heparin. Maintained on spreadsheets, this information would have allowed crude lots to be traced back to individual suppliers back in 2008, the letter explains. However, the OCI did not use the information in its official report, or make it available to CDER at the time, the representatives say.
After requesting the information separately, CDER received it in 2012 and acted on it, but the companies involved had continued to supply the US market during the four intervening years, the letter says.
In addition, the representatives say, FDA did not follow up with another “respected government agency” from another country, which had found that the two crude heparin suppliers in China had a less-than-transparent relationship, which, for example, allowed one to export heparin under the other’s label, the letter says, even though the company on the label had not manufactured it.
This government agency had also found that the owner of one of the companies admitted to falsifying test results, the letter says, and the agency had also found inconsistencies in batch numbering, as well as information and signatures on certificates of analysis.
The company's owner reportedly admitted to using an unregistered company in Shandong to make crude heparin, some of which was sold to Italy. He was also said to display an “unusually profound and extensive knowledge of modern testing methods (for a trader),” the letter says. Ultimately the agency described the company and owner as untrustworthy, but FDA did not investigate these claims in sufficient depth, the representatives say.
Increased use of non-porcine materials
The letter also faults FDA for failing to respond to evidence that more Chinese suppliers have been using non-porcine materials, derived from cows, goats, and sheep, to manufacture crude heparin. Use of non-porcine derivatives can have an impact on final product efficacy, but beef products in particular present a potential risk of contamination that could cause mad cow disease.
As the representatives point out in their letter, there is little known in China about the risk of mad cow disease, and, until 2015, the Chinese Pharmacopeia permitted the use of bovine materials to manufacture heparin. A common practice in China, the letter says, has been to mix porcine derivatives with those from other animals.
Weak quality management systems and traceability
And, as the letter points out, in December 2015, French regulators found that heparin supplied by Dongying Tiandog Pharma company in China, contained sheep DNA. Weak quality management systems could not provide traceability to the original source of materials.
Beyond concerns about source, there are concerns that suppliers in China have been stockpiling heparin contaminated with OSCS, treating it and releasing it into the supply chain, the letter says, faulting FDA for failing to investigate this possibility.
On a fundamental level, the letter blames FDA for failing to take into account basic supply and demand within China. According to the representatives’ research, the amount of heparin that China exported could not have been made with the number of pigs available. Back in 2008, there was a shortfall of 100 million pigs, the letter says, and similar gaps were likely for each of the subsequent years, raising concerns that illegal methods are being used to make up for the deficit.
The letter heightens concerns about the quality and safety of offshore materials and gaps in the industry’s and regulators’ ability to keep up with a massive challenge, and a moving target. FDA officials have said that they will respond formally and follow up directly with the Representatives. Please let us know what you think.