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30 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m first request for these assessments from marketing application holders (MAHs) was made in September 2019, setting a dead- line of March 31, 2020. However, that deadline was extended to March 31, 2021, given the fact that tens of thousands of risk assessments would need to be conducted worldwide (3–7). Many global regulators are requiring these assessments and, although there are similarities among the various guidance doc- uments, there are also multiple differences in guidance, making compliance challenging within the given timelines. Table I de- scribes the different regulatory guidance documents covering NAs for a fraction of countries that require risk assessments. In addition, regulators have set NA impurity limits that are more conservative than those suggested by ICH M7(R1) guidance, such as the class-specific limit, which does not allow higher limits for less-than-lifetime (LTL) exposures, and groups all exposures of NAs to a single combined limit. Collaborative research effort The IQ drug substance leadership group, which first consid- ered the formation and the reaction or purge of NAs, formed a small team at the end of 2019 to draw from expertise of other leadership groups within pharmaceutical sciences or chemistry, manufacturing, and control (CMC) disciplines, as well as toxicology experts, to discuss and arrive at sci- entific conclusions. The goal was to create a science-based approach to evaluate the risk of contamination of NAs in drug substance, drug product, and drug-product packaging in synthesized small molecules; it was later realized that these principles can be applied to biologic compounds. Subteams with experts in synthetic chemistry, analytical chemistry, formulation, and drug-product packaging were created, allowing the work to be conducted in parallel and creating touch points (deep dives) where the groups would gather to summarize and share what they found in the lit- erature, and determine what experiments should be done. A baseline of knowledge was thus established in all areas, and the teams shared references while scouring the literature and considering the application of the findings to the NA problem, all while companies were starting to evaluate their products and assess risks. Once global regulatory agencies extended the initial deadlines for assessments, companies with hundreds or thousands of products scrambled to confirm the safety of their portfolios to the patients. After the literature review, team members designed experiments and used the work on surrogate compounds to augment what was found in the literature. Currently, experiments to fill knowledge gaps in each particular area are on-going, and experimental plan- ning will continue as new information is obtained. Since the end of 2019, IQ members have remained in contact with other groups (e.g., European Federation of Pharmaceutical Industries and Associations, Lhasa Lim- ited, and the Pharmaceutical Research and Manufacturers of America) to ensure minimal duplication of work and to share information in real time. Risk models and analysis By mining the information in the literature, sufficient data were present to allow a kinetic model describing the rate of formation of NAs in water to be developed and published (8). This con- servative model allows the risk of formation of NAs in aqueous systems to be assessed. Others have published a review on the formation of NAs, which includes a discussion of organic solu- tions (9); and a general review on the topic has recently appeared (10). The formation of NAs is generally described in Figure 1, wherein a vulnerable amine is reacted with a nitrosating agent. A working group has drafted a review of the literature on the reactions and purging of NAs, which will be submitted soon. The model for aqueous chemistry is foundational in con- sidering the formation of NAs in other areas of processing and can be used to calculate worst-case scenarios of what could occur within a drug product. Several companies started studies using surrogate compounds under model formulation conditions (e.g., wet- and dry-granulation processes) for drug products. Part of the goal is measuring the stability of the model formulation, not only at T 0 but at various timepoints under various storage conditions. As part of the collaborative efforts, drug-product packaging experts discussed unusual findings that had been reported for packaging risks. This group examined the packaging process itself; specifically, the components involved (including ink, lidding, and sealing components) that could result in higher levels of NAs and contaminate the packaged product. Common components used for many blister-sealed processes may use nitrocellulose in the lidding or lacquers, and some inks may contain nitrocellulose and/or vulnerable amines. During heat-sealing, NAs may form, volatilize, and deposit on exposed tablets (11). At this point, experts do not believe that NAs generated during the packaging process contaminate the sealed drug product. The overall amounts of NA generated in these processes and subsequently found in the drug prod- uct have been well below the acceptable intake (AI), allowing companies to consider many potential solutions. However, com- panies may establish exhaust lines around the heat-sealing ma- chine to mitigate any potential risk or choose to use alternative components in their packaging processes. Putting overall risks into context Scientists from IQ, in collaboration with Lhasa Limited and Leadscope Inc., recruited experts in genetic toxicology, pathol- ogy, computational toxicology, and risk-assessment toxicology to better evaluate the safety aspects of NAs. To put overall risk into context, exposure to NAs is also prevalent in foods, water, beverages, tobacco, cigarettes, and personal care products. In addition, NAs can form endogenously in the stomach after con- sumption of foods that contain secondary/tertiary amines and nitrites/nitrates (8, 12–16). This effort has identified opportunities for further enhance- ment of existing regulatory documents. First, there are currently eight NAs with regulatory limits; however, additional assess- ment with more robust analyses may enable further refine- Quality Collaboration