Guest Column | September 10, 2020

Unpacking FDA's New Guidance On Controlling Nitrosamine Impurities In Drugs

By Barbara Unger, Unger Consulting Inc.

Ever since the identification of nitrosamines in human medicines in 2018, global health authorities have issued guidance, analytical methods for the detection of these compounds, acceptable limits, and requirements for proactive assessments of potential sources of nitrosamines in human medicines. In addition, they have taken enforcement actions with recalls, and the FDA has issued warning letters to API manufacturers, dosage form manufacturers, and CMOs that perform solvent recovery under contract to API manufacturers. The health authorities that have issued guidance in this area include, but are not limited to: Health Canada, WHO, European Directorate for the Quality of Medicines (EDQM), TGA, and USP, which has proposed a General Chapter on the topic. The EMA recently published a detailed “lessons learned” report that we analyzed in a previous article.

The FDA took enforcement actions soon after these potential carcinogenic compounds were identified in human medicines, and these are identified in an article published early this year. It encouraged dozens of voluntary recalls from many manufacturers. This initially started with the “sartan” blood pressure medicines but soon expanded to include ranitidine and metformin.

On Sept. 2, 2020, the Federal Register announced the availability of a final FDA guidance, Control of Nitrosamine Impurities in Human Drugs. This guidance is immediately effective and was not subject to the usual comment period “…because of the importance of providing timely information to manufacturers regarding risk assessments, testing, and other appropriate actions they should take to reduce and mitigate nitrosamine impurities in active pharmaceutical ingredients (APIs) and drug products.” This guidance and the recommendations apply to all chemically synthesized APIs and drug products that contain chemically synthesized APIs. This is in stark contrast to the most recent guidance from EMA, where biological products also require assessment, though the likelihood of nitrosamine contamination of these products is minimal. Both guidances take a similar approach with their requests of industry. This includes analysis of the potential for nitrosamine formation, confirmatory testing if nitrosamine formation is possible, and modification of raw materials or manufacturing processes to minimize or prevent their formation.

The FDA has identified seven potential nitrosamine contaminants that may be found in human medicines and reports that five of the compounds have been identified in drug substances or drug products. Nitrosamine compounds are reported to demonstrate genotoxic activity in several animal species and are classified as “probably or possible human carcinogens.” The FDA established interim limits on the concentration of these compounds for human drugs and will likely revise these in the future as additional information becomes available.

The guidance identifies general conditions that may result in the formation of nitrosamines in APIs and drug products. In addition to the unintended formation of nitrosamines during chemical synthesis of APIs, the FDA identifies raw materials that may be a source of nitrosamine contaminants. These include:

  • Contamination during shipment of solvent, particularly transfer between storage vessels that may not have been subject to adequate cleaning.
  • Contaminants in starting materials that may react with amines under acidic conditions in chemical synthesis.
  • Impurities in raw materials, including solvents.
  • Cross contamination of starting materials or intermediates if they are produced at a site where nitrosamine impurities may be present in other processes.

The guidance addresses the potential for recovered materials, including solvents and catalysts, as a source of contamination. The FDA has identified this as a source of contamination in a variety of warning letters to API manufacturers. Outsourcing the recovery process to a CMO provides yet another source of potential contamination, particularly when cleaning between operations and client materials is not adequate. This becomes further compounded when firms that outsource solvent recovery to a CMO fail to perform adequate testing upon the receipt of the solvent, which might have prevented the use of contaminated material. In addition to solvents serving as a source of nitrosamine contaminants, quenching step(s) during chemical synthesis may lead to nitrosamine formation, and lack of adequate purification will carry these contaminants through the process stream. Another source may simply be a lack of process optimization and controls. The FDA states it has “seen instances in which reaction conditions vary widely between batches and even between different processing equipment in the same facility for the same API.” This also reflects one of the lessons learned from the EMA studies, where lack of process understanding can be a prime contributor to nitrosamine contamination. And finally, nitrosamines may be found in excipients so supplier qualification and oversight programs should consider this possibility.

The FDA provides a series of recommendations for manufacturers that should be guided by the ICH Quality Risk Management guidance, ICHQ9. In addition to determining potential sources of nitrosamines or nitrosamine formation in the API and drug product, firms are to conduct confirmatory testing with appropriately sensitive analytical methods when risk is present and take mitigation steps to minimize or eliminate contamination. Firms should prioritize evaluation of APIs and drug products based on factors including daily dose, length of treatment, the therapeutic indication of the medication, and the number of patients who receive the medication.

The FDA provides a tabulation of various nitrosamine contaminants and their daily acceptable intake (AI) limits, which may be revised as additional information becomes available. These limits range from 26.5 ng/day for the four most potent nitrosamine compounds to 96 ng/day for two of them. These limits are applicable when a single nitrosamine compound is present. For situations where multiple nitrosamine contaminants are present, and the value exceeds 26.5 ng/day, established for the most potent nitrosamines, manufacturers should contact the FDA.

Where nitrosamines are identified or where their formation is highly likely, the FDA askes that manufacturers make changes to minimize or mitigate their presence. A separate set of detailed recommendations is provided for API manufacturers and for drug product manufacturers. Recommendations are also provided for firms that may have applications currently under review at the FDA or where products are undergoing clinical investigation.

The FDA specified timelines for completing the risk assessments for drugs in commercial distribution, for those in review and those  undergoing investigational studies. Risk assessments for commercially available drugs and their APIs should be completed by March 2, 2021. Firms are not required to submit the risk assessments to the FDA; we can only assume this will be evaluated upon inspection. Process changes or other remediation should be completed by Sept. 2, 2023 and supported by the necessary regulatory filing.

Overall, it appears that the process the FDA is putting in place is similar to that which the EMA has implemented. Of particular importance in both cases is an evaluation of the potential sources of nitrosamines, confirmatory testing, and mitigation actions. This should also prompt a review of supplier qualification and ongoing controls, possibly including testing of all purchased chemically synthesized APIs.

About The Author:

BarbaraBarbara Unger formed Unger Consulting, Inc. to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data management and data integrity. Her corporate auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. In addition, she was previously co-lead of the Rx-360 Data Integrity Working Group. You can contact her at