To test or not to test? The glycerin debate

On October 11 last year Panama authorities were informed that the epidemic of unexplained deaths ripping through the country was a result of the poison diethylene glycol (DEG). The toxin normally found in antifreeze, had ended up in batches of cough syrup, killing at least 100 people in the Latin American country, who had unsuspectingly taken the medicine. The case hit the headlines with force. While the country reeled in shock, answers were being sought and what the investigations found was alarming - the poisonings were a result of a shockingly glaring failure in the pharmaceutical supply chain. More than 40 barrels of, what was "thought" to be, the sweetener glycerin, journeyed from a warehouse in China, to a Chinese state-owned business, to a trading company in Barcelona, and finally on to Panama, before the Panama government bought them to make cough syrup manufactured by the government agency running the government health program, the New York Times Sunday edition reported last month. But what the newspaper's investigation also found was that the certificate of analysis, which said the shipment was 99.5 per cent pure, was anything but correct. Instead of the excipient glycerin, the barrels contained the deadly diethylene glycol. But worse, a repeated tampering of the certificate of analysis meant the path of the supply chain was bogged down in unknowns. According to the New York Times, The Taixing Glycerin Factory, where the pharmaceutical supply chain started, was not even certified to sell medical ingredients. With the trading middlemen not legally required to test, there was no means by which to discover the inaccuracy of the certificate of analysis during the trading process. Only the supplier and the end manufacturer have the responsibility to test the products, and in the Panama case, for some reason, this seemed to have broken down. The grim reality is that good manufacturing and distribution practices were not adhered to, and if they had, the incident could have been avoided. And, unfortunately, this is not the first time DEG has made its way into medicine. Eighty children died in Haiti in late 1995 and early 1996 from DEG-contaminated glycerin in acetaminophen syrup. Between 1990 and 1998 similar poisoning incidents were reported in Argentina, Bangladesh, India and Nigeria resulting in hundreds of deaths. And in 1937, more than 100 people died in the United States after taking DEG-contaminated Elixir Sulfanilamide, a drug used to treat infections. It was this incident that led to the enactment of the Federal Food, Drug and Cosmetic Act, which included a provision requiring that drugs be demonstrated to be safe before marketing. Aware of the reports, the FDA released guidelines last month for the pharmaceutical industry to keep manufacturers, suppliers and repackers in check. Yet, despite the incidents, DEG poisoning remains a rarity. This suggests current controls and constraints are working fairly effectively, especially considering the lack of incidents in the top three pharma markets of the US, EU and Japan. And while the system is more than mostly working, it does no harm for the FDA to highlight the issue. The agency's guidance is a simple but complete document, putting the onus on every step of the supply chain and repeatedly emphasizing test, test, test. In a nutshell the agency recommends: "Drug product manufacturers perform a specific identity test that includes a limit test for DEG on all containers of all lots of glycerin before the glycerin is used in the manufacture or preparation of drug products . . . Drug product manufacturers know their supply chain for glycerin . . . All manufacturers take every opportunity to ensure proper testing of glycerin . . . Repackers, and others who distribute and prepare glycerin for use in drug products, test glycerin . . . Pharmacies that use glycerin either test the glycerin for DEG content or ensure that such testing was properly done by a reliable supplier."​ The document's accompanying press release states: "[The] FDA is emphasizing the importance of testing glycerin for DEG due to the serious nature of this potentially fatal problem in combination with the global nature of the pharmaceutical supply chain and problems that continue to occur with this kind of contamination in some parts of the global supply of glycerin." ​ It continues: "DEG poisoning is an important public safety issue and FDA is exploring how supplies of glycerin become contaminated. In addition, FDA is working with a variety of manufacturing and pharmacist organizations to raise awareness of this risk and to put into place controls to ensure that this problem does not happen in the US or elsewhere."​ When contacted by US-PharmaTechnologist.com, an FDA spokeswoman said: "The FDA has long required that pharmaceutical manufacturers test and examine components before use in pharmaceutical product manufacturing. "Although such a testing standard exists in the US, we felt a guidance document highlighting the issue was nonetheless indicated."​​ When asked if the FDA thought following the recommendations was feasible, the spokeswoman replied: "Each of the recommendations is achievable with current methods, technology and techniques."​ But is this really easier said than done? Dr Frank Milek worries it could be. The head of quality and good manufacturing practice (GMP) at Hedinger and chairman of the good trade and distribution practice committee on the FECC (the European association of chemical distributors), is concerned that because of globalization there are so many distributors and traders in the pharmaceutical business that it becomes very difficult, and many areas are just not covered by regulations. The problem is, testing for glycerin is part and parcel of current good manufacturing practice - it is already a requirement and it is "irresponsible"​ that people are not taking their roles seriously, he says. Despite a raft of recommendations and professional ethic principals in place - cGMP, good distribution practice (GDP) principles, the World Health Organization's (WHO) Good Trading and Distribution Practices for starting materials, and testing standards under the United States Pharmacopeia monograph - Dr Milek says there are still violations of good practice at every corner. The reason, he says, is based on commercial motives. There is a time and cost factor involved in testing, it is as simple as that. In the past however, suppliers and counterfeiters were also driven by the much lower costs of DEG compared to glycerin and were able to make a nice little profit by purposely making a switch. Nowadays though, glycerin and DEG prices are on a par and theoretically there should be no monetary value in supplying DEG instead of glycerin. While agreeing the FDA is doing the right thing in addressing the issue, the former chairman of the International Pharmaceutical Excipients Council's Europe's GDP committee says the recommendations are nothing new. "What the FDA is writing is a compilation of safety and good practices that are already in regulation and in guidelines. This isn't new. Industry should already be applying this. [But] this terrible case in Panama shows many don't. Everyone should take their responsibility seriously. ​​​"I think this is not safe, and this case shows there should be a more comprehensive regulation."​ Milek believes that if active pharmaceutical ingredients (APIs) are regulated with legislation throughout the supply chain, so too, should excipients. But according to the FDA, the recommendations and the cGMP already in place are just fine. "The current regulations have thus far adequately prevented DEG contamination in US product, and we believe this guidance will reinforce good practices to further reduce the risk to DEG contamination." ​ This might be so for the US, but there remains the slight problem of the developing world, where most of these cases appear to be occurring. Interestingly, the European Commission is looking to adopt a Directive on GMP for certain excipients to look at making some excipients subject to regulation. Manufacturers and suppliers have been asked to contribute their thoughts on the topic by the end of July this year. Glycerin and propylene glycol are currently on a draft list of excipients which should be regulated. This, says Dr Milek, goes some way in alleviating the problem. "I don't want this to happen again." ​