U. S. government officials both inside and outside of FDA have acknowledged that the Agency currently lacks the resources, both financial and human, to adequately monitor the materials going into products being used in the United States. The answer? In the case of the somewhat notorious contaminant melamine, the answer is to make regulated industry responsible. The Guidance for Industry, Pharmaceutical Components at Risk for Melamine Contamination, announced in the August 7 Federal Register, states that the Agency is “alerting” drug manufacturers to the risk of melamine contamination in “at risk components”. So what’s an at-risk component? The guidance first states that it means “…those ingredients or raw materials that rely on a test for nitrogen content for their identity or purity or strength, and that contain nitrogen in amounts greater than 2.5 percent. Such a component can be derived from source material that might be contaminated with melamine or the component itself can be directly contaminated by melamine in an attempt to reduce its quality or strength or to substitute for it.” The Agency also provides a “non-exhaustive” list of 27 components as examples of materials which would meet the definition of “at risk components”. The list includes several common pharmaceutical excipients, including crospovidone, gelatin, lactose, and povidone.
Citing 21 CFR 211.84(b) and (d), the Agency specifically recommends that at risk components be tested for melamine before release for use, providing a link to methods used in food analysis.
FDA also recommends that manufacturers “know and monitor” their supply chain, especially the actual manufacturers, repackers and distributors of components, and also require certification from the components manufacturers that components are tested for the absence of melamine. Distributors are placed under essentially the same recommendation. Also stated is “Manufacturers should also audit their component suppliers to ensure CGMP compliance.”
What are the implications for Camargo customers? Often, FDA will supplement guidances such as this with “recommendations” in deficiency letters during the application process. In the interest of obtaining a prompt approval, companies will often implement recommendations even in marginal circumstances. So, if you have a pending application which is formulated with an “at risk” component, you may want to anticipate the Agency asking for melamine testing, or a justification for its absence. If you are in the drug development stage, you’ll need to evaluate the components you select, especially considering the source, and plan accordingly