Nitrosamine Impurities: FDA Rejects the Extension of Deadline for Submission of Risk Assessments

FDA's Guidance for Industry "Control of Nitrosamine Impurities in Human Drugs" from September 2020 governs the management of nitrosamine impurities in medicinal products for human use and was published in its updated version in February 2021.
The original submission deadline for risk assessments of authorised medicines already on the market, i.e. 6 months after publication of the Guidance (1 March 2021) was initially extended by 4 weeks (31 March 2021) following pressure from the industry. In a hearing held on 4 May 2021 (memorandum issued on 19 July 2021) involving FDA and industry association representatives (Association for Accessible Medicines, MAA; Consumer Healthcare Products Association, CHPA; and Pharmaceutical Research and Manufacturers of America,PhRMA), a further extension of this deadline was the focus of the discussion. The industry representatives cited the increased time required to complete risk assessments by the deadline, pointing out that this would, among other things, bind necessary resources for drug development on Covid 19 therapies. The request was for an extension of the submission deadline to 1 September 2021.Specifically, this request was supported by the following arguments:

Different regulatory requirements

  • The requirements for testing medicinal products on nitrosamines and submitting risk analyses are not harmonized at the global level. For example, this requirement exists for OTC products in oral dosage form for the USA, but not for Europe or Canada.
  • The production of low-cost generics for the U.S. market, which account for 90% of prescription drugs, is slowed by the lack of time and human resources to do so and, in the worst case, can result in supply bottlenecks or shortages.
  • Delays in procuring information from API, raw material, excipient manufacturers and suppliers of production auxiliaries (solvents, catalysts, etc.) make it virtually impossible to meet this deadline. The same applies to the time-consuming and sometimes complex testing of a large number of substances.

Scientific divergences

  • The analytical methods published by the FDA and the USP for the determination of nitrosamine impurities are not always applicable, since in many cases interactions of the analyte with the matrix may falsify the result. Therefore, new suitable methods have to be developed and validated, which requires additional effort.
  • Studies to determine and apply purge factors as part of a control strategy are in line with the state of the art and would save time. However, no opinion or regulation exists on this issue from the FDA.
  • The 96 ng/day limit is established for all drugs; this is abnormally strict for drugs for short-term or intermediate duration of use. The less-than-lifetime approach of the ICH M7(R1) guideline would be appropriate for this purpose. Industry representatives find it concerning that the FDA deviates from generally accepted, scientifically supported principles of quality risk management in various individual policy documents.
  • In its guidance, the FDA provides no scientific rationale for the AI values set forth in that document. It also lacks a statement or expectation of studies to determine individual, scientifically supported AI values for various nitrosamine species.
  • There is no inclusion of product-specific features related to AI values as described in the ICH S9 Guideline " Non-clinical Evaluation for Anticancer Pharmaceuticals." The FDA guidance contains no reference to this, nor does a corresponding policy document exist on this topic.

The arguments of the industry representatives could not convince the FDA. The extension of the deadline was rejected on the following grounds:

  • In the past, concessions were made to manufacturers who had detected nitrosamines in their products above the AI limits. This flexibility on the part of the FDA allowed for continued marketing of batches to reduce the risk of supply shortages. A case-by-case evaluation for each drug product for the purpose of a risk-benefit trade-off by the agency will continue to be conducted in close collaboration with manufacturers.

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