The bio/pharma industry is urging FDA to postpone its October 2023 deadline for testing for novel nitrosamine impurities in drugs. The industry provided the feedback in response to FDA’s call for input on how it should regulate these impurities.

Nitrosamine impurity testing under scrutiny
The issue of nitrosamine impurities first arose in the industry in 2018, when the US Food and Drug Administration (FDA) and the European Medicines Agency initiated investigations of nitrosamine impurities in certain “sartan”-containing active pharmaceutical ingredients (APIs), used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach, and later metformin extended-release products, used to treat Type II diabetes. As part of their investigations, the regulatory agencies issued guidelines for testing of products to detect nitrosamine impurities, acceptable daily intake levels, and risk evaluation and risk assessment.

FDA’s 2020 final guidance on nitrosamine testing recommended that manufacturers conduct testing on all their drug products and APIs to ensure they do not have unacceptable high levels of nitrosamines by October 1, 2023. The recent request issued by the FDA in May (May 2023) asked for public input by July 3, 2023, on whether this deadline should be extended and for further input on the identification, assessment, and control of N-nitrosamine drug substance-related impurities (NDSRIs) that may be considered by the agency in its regulation of these types of impurities in drug products. FDA’s May 2023 notice identifies scientific and regulatory considerations regarding the identification, assessment, and control of NDSRIs, including areas that may benefit from collaborative efforts.

The FDA’s 2020 Nitrosamine Guidance recommended that manufacturers of APIs and drug products should take steps to detect and prevent unacceptable levels of nitrosamine impurities in drug products, or avoid their presence when feasible. Specifically, FDA recommended a three-step process that manufacturers should take to mitigate nitrosamine impurities in their products: (1) conduct risk assessments for nitrosamines in their products; (2) conduct confirmatory testing if risks are identified; and (3) report changes implemented to prevent or reduce the presence of nitrosamine impurities in drug products in approved and pending new drug applications (NDAs) and abbreviated new drug applications (ANDAs). The Nitrosamine Guidance describes some conditions that may introduce or create nitrosamine impurities (a nitrosating reaction between secondary, tertiary, or quaternary amines and nitrous acid (nitrite salts under acidic conditions)) and provides FDA-recommended acceptable intake limits for six nitrosamine impurities that could be present in drug products.

More recently, and often in response to the risk assessment recommended in the Nitrosamine Guidance, FDA said it has received an increasing number of reports of certain types of nitrosamine impurities that have formed in drug products across multiple drug classes. These NDSRIs are a class of nitrosamines sharing structural similarity to the API, and thus, differ in certain respects from small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API, and are therefore, not considered NDSRIs) identified in FDA’s Nitrosamine Guidance.

NDSRIs can be generated during manufacturing, or during the shelf-life storage period of the drug product. They can also be generated during the synthesis of the drug substance. In some cases, the root cause of NDSRI formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts. Nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs in certain drug products. In general, there is a risk of generating nitrosamine impurities when nitrites are in the presence of secondary, tertiary, or quaternary amines. Secondary or tertiary amines are known to be part of the chemical structure of several hundred APIs. Accordingly, says FDA, depending on the formulation and manufacturing process for the drug product, as well as ongoing oversight of the quality of materials produced by suppliers, there may be a risk of nitrosamine formation in a substantial number of drug products.

In November 2021, FDA alerted the public regarding the presence of NDSRIs and indicated that manufacturers could ascertain the presence of NDSRIs using the same three-step process as outlined above in FDA’s Nitrosamine Guidance. FDA also conveyed possible mitigation strategies and encouraged applicants to develop control strategies or design approaches to reduce NDSRIs to acceptable levels or eliminate them (where feasible). NDSRIs present unique scientific and regulatory challenges for FDA because each NDSRI is unique to the API, and there is limited compound-specific data that are available to inform safety assessments. Additionally, design of validated test methods for identification of NDSRIs and modification of existing test methods for assessment of their mutagenic potential may raise novel scientific considerations.

Industry feedback
In all, FDA received 33 comments on its recent (May 2023) notice, including feedback from industry trade groups, the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents innovator drug companies, the Association for Accessible Medicines (AAM), which represents generics and biosimilar companies and manufacturers, and the Consumer Healthcare Products Association (CHPA), which represent over-the-counter companies and manufacturers. They and other stakeholders requested an extension for meeting the requirements and also provided feedback on the testing methods and processes recommended by FDA in its May 2023 notice.

In considering the extension date, PhRMA said in its comments that it is important to understand that it will take until the end of 2023 for the Health and Environmental Sciences Institute (HESI, a non-profit institute that engages scientists from academia, government, industry, non-government organizations (NGOs), and other strategic partners on global health and environmental issues, to complete specific work related to the Ames test, used for mutagenic testing that is intended to inform the optimal protocol for N-nitrosamine hazard identification. PhRMA also pointed out that industry currently has in vivo transgenic mutation assays scheduled throughout 2024, and thus, acceptable intake limits for NDSRIs of interest would not be available until late 2024, at the earliest. Accordingly, PhRMA said it “strongly recommends” that FDA extend this deadline accordingly to allow time for corrective and preventive actions (CAPA) implementation. It said FDA should adopt a less-than-lifetime approach recognizing the limited duration of exposure for many products at issue and that FDA should use existing testing capacities with a focus on confirmatory testing, prioritization of high-risk small nitrosamine compounds, and investigational activities to develop mitigation actions.

PhRMA also commented that priority for evaluating NDSRIs should be set using patient-centric considerations, such as criticality of medicines to patients and the possibility of drug shortages and that prioritization can be enabled by establishing a practical framework for differentiating NDSRIs. “This framework would provide a way to evaluate NDSRIs more quickly, allowing for supply to continue while freeing Agency resources to focus on NDSRIs identified in a cohort of concern,” said PhRMA in its comments of July 3, 2023. Other priority factors PhRMA said that FDA should consider include the following: maximum daily dose, duration of use, indication (critical medical need in terms of impact and chronicity), availability of alternate treatments for the indication, toxicological profile of the API (benefit/risk balance), availability of pharmacovigilance data (less safety data would mean higher priority), and patient impact (e.g., number of patients affected).

In commenting on behalf of the generic-drug and biosimilars industry, AAM underscored the need to provide additional time in not only meeting the testing requirements but gaining additional input on the testing criteria and acceptable intake limits for nitrosamine impurities. It pointed out that some large generics companies may have as many as 250 ANDAs that could be affected, each requiring significant time and resources to complete testing and remediation when necessary. “Companies need sufficient time and resources to procure impurities in adequate amounts and of adequate quality to perform the studies, develop sufficiently sensitive analytical methods, validate those methods, and perform the necessary testing,” said AAM in its comments. “In addition, once the potential for formation of nitrosamines is confirmed, companies need to identify the root cause of the impurity and develop a remediation plan, which may include reformulation of the product and new stability and bioequivalence studies.”

AAM also pointed out that FDA, other health authorities, and the industry are grappling with the scientific challenges associated with assessing the hazards and establishing appropriate acceptable intake limits, in particular for NDSRIs. “There are currently too many unknowns related to setting appropriate AI [acceptable intake] limits for NDSRIs, determining the root causes of NDSRI formation, and performing remediation when necessary,” said AAM in its comments. “Whether and if so how to remediate depends greatly on the limits set for NDSRIs and may involve revision of limits for impurities in U.S. Pharmacopeia monographs, or inclusion of nitrites in excipient specifications, which would require support from excipient and drug-substance manufacturers and would likely take a substantial amount of time to complete.”

In its comments, AAM also said that FDA should adopt a strategy that allows the industry to prioritize assessments based on the risks to patients if nitrosamines are likely to form in particular classes of drugs and individual drug products. It outlined several factors that should be taken into account. These include: (1) whether the drug is on the World Health Organization’s essential medicines list; (2) whether a class of drugs is known to be particularly susceptible to nitrosamine formation (e.g., ACE inhibitors, beta blockers, or antidepressants); (3) treatment duration and maximum daily dose, saying that lifelong treatments for chronic disease states should be a higher priority than acute treatments for short-term or episodic illness; (4) whether consideration of a compound-specific assessment can be used for an entire class of structurally similar NDSRIs, saying if it can, it should be given a higher priority; (5) number of patients treated with the drug, saying that drugs with high patient exposure should be a higher priority; and (6) low molecular weight N-nitrosamines should be a higher priority than higher molecular weight compounds. In addition, AAM says that FDA should publish criteria that industry could use to prioritize the assessments of their particular products and ask manufacturers to develop a plan to complete the assessment phase of the work for their drug products by a target date based on the criteria.