The US FDA has released a new guidance to help pharmaceutical manufacturers assess and control impurities that could cause DNA mutations in patients. Because of chemical synthesis or subsequent degradation, all drug products contain some impurities – guidance for the majority of impurities already exists but there hasn’t been a great deal to go on when it comes to DNA-reactive impurities. The new guidance aims to provide a “practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities” (1). It establishes appropriate levels of impurities to minimize carcinogenic risk, and outlines recommendations for their assessment and control.
“The focus of this guidance is on DNA-reactive substances that have a potential to directly cause DNA damage when present at low levels, leading to mutations and therefore, potentially causing cancer,” the guidance states. “This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities.” So who should take notice? The guidance does not apply to existing marketed products, but it does affect new drugs during clinical development and applications for marketing, as well as post-approval submissions of marketed products and, in certain cases, new marketing applications for products containing a previously approved drug substance. It does not apply to biologic drugs or to products intended for advanced cancer indications. The guidance also states, “Additionally, there may be some cases where a drug substance intended for other indications is itself genotoxic at therapeutic concentrations and may be expected to be associated with an increased cancer risk. Exposure to a mutagenic impurity in these cases would not significantly add to the cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable levels for non-mutagenic impurities.” It also isn’t intended for leachables associated with packaging, but can be used in this application if warranted. Similarly, the FDA says the guidance is not intended for excipients in currently marketed products but it could be used if necessary for impurities in chemically synthesized excipients that are being used for the first time in a drug product. The FDA is encouraging manufacturers to implement the guidance as soon as possible, but expects that it could take around 18 months, given the complexity of the document.
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References
- FDA, Guidance for Industry, “M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk,” (May 2015). http://www.fda.gov
