Can Pharma Learn From the Unfolding Gluten Contamination Story?

Last month's contaminated pet food story has been followed by news of contaminated feed reaching pigs and chickens.  Theories are still being explored.  Melamine has been identified as the key culprit, but API manufacturing expert Girish Malhotra, who doesn't buy the "contaminated process water" theory, asks "did we miss other contaminants?" The melamine added would have been considered "off spec" in the U.S., he believes. Impurities in the melamine manufacturing process itself would cause the reactions, he says.  Melamine can be produced in two ways: via a urea/ammonia process, or using dicyandiamide as a precursor.  (Dicyandiamide is also used to make metformin hydrochloride, the active ingredient in the Type 2 Diabetes drug, Glucophage, and most of the dicyandiamide used today in the U.S. comes from China, Mr. Malhotra says). For either melamine process route, he notes, it would be important to study possible process impurities and their potential impact on animals and humans. For example, he notes, Shandong Mingshui Great Chemical Group, which produces melamine, also makes urea, so it likely makes melamine via the urea/ammonia route.  "Has anyone tested the impact of urea [and its possible process impurities] on humans or animals?" Mr. Malhotra asks.  The same would hold for dicyandiamide. Whatever lessons learned from this case must be applied to drug manufacturing.  The key lesson seems to be that using process analytical technology (PAT) methods to characterize raw materials and verify their quality will be essential from now on.  PAT experts note that the quality of ingredients such as excipients can vary tremendously from batch to batch---understanding the source of such variation, and its impact on final product, is critical. (A brief aside - Could PAT also be the key to eliminating complaints that we often hear about generic drugs? How often have I heard people complain that the generic version of a drug "just isn't the same" as the name brand version. Of course, the active ingredient is the same, but could the very tiny, nonreportable "adverse reactions" that some consumers complain of stem from untraced variability of ingredients, even if they were legally "safe" enough to be used to make the drug?) More urgently, this story underscores the need for better traceability of imported pharmaceutical raw materials. Currently the industry is importing a growing volume of bulk chemicals, excipients and APIs from China, whose food and drug safety regulations are still in their infancy.  By 2020, 80% of APIs are expected to come from China and India. However, some API manufacturers in China and India are producing ingredients that meets chemical, rather than USP requirements, and selling them via the Internet, and they often end up in counterfeit drugs. FDA is currently backlogged in its GMP inspections of manufacturing facilities outside the U.S. To offer some reassurance to both buyers and sellers, USP recently launched an ingredient certification program, in which manufacturers receive verification of the safety of pharmaceutical raw materials. India's Dr. Reddy's has been the first drug manufacturer to sign up for the program.  Will there be others? In the meantime, if any of you, chemists or nonchemists, in the drug industry or outside it, have any theories on the gluten/melamine story, or any responses to Mr. Malhotra's comments, please write in.