Risk Assessment and Management Strategy of Two New Nitrosamine Drug Substance Related Impurities (NDSRIs) in a Pharmaceutical Drug Product for the Treatment of a Rare Disease- from Prediction to Control

Several sources can contribute to the formation of small nitrosamines including the drug substance or API, excipients, manufacturing process and associated utilities, and packaging (Fig. 1). In the last 2-3 years, excipients have come under surveillance of HAs as they could introduce nitrites as impurity precursors for nitrosation of amine containing APIs (and impurities in API). For solid oral dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents). The challenges, however, are the following: (1) limited validated information on nitrite levels in excipients, (2) average nitrite content and batch-to-batch variance differ among excipients, and (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing.¹³ All excipient vendors are now required to provide a Certificate of Declaration to report the presence (and amount) or absence of such species in their materials. In Feb 2023, IPEC (International Pharmaceutical Excipient Council) Europe published a list of questionnaires for excipient screening for nitrosamines.¹⁴¹⁵ A nitrite Excipient Database has recently been introduced by Lhasa Limited (June 2023), which constitutes a central platform to hold the data donated by the pharmaceutical company members regarding the nitrite concentrations in common excipients measured with validated analytical procedures.¹³

The EMA is particularly active in updating the AI limit requirements and expanding the list of nitrosamines with their reported AI limits on a routine, often quarterly, basis. The establishment of AI limits for new nitrosamines undergoes strict technical, scientific, and quality scrutiny from the Rapporteurs and Co-rapporteurs, followed by a final safety endorsement of the AI limit by Non-Clinical Working Party (NCWP).

This manuscript describes the comprehensive nitrosamine risk evaluation and mitigation strategy for a case example, miglustat 65 mg capsules (Fig. 2). This work originated as a proactive readiness strategy to comply with the dynamic and stringent nitrosamine detection recommendations being communicated by key regulatory authorities. While executing the work described herein, it became evident that there is a gap in the published literature with regard to development of robust life cycle management strategies for nitrosamine detection. We address this gap with the present publication by exploring several themes, which, to our knowledge, have not yet been disseminated in a research manuscript:

• The complete life cycle management story of an NDSRI including potential formation mechanisms, a comprehensive chemistry risk assessment followed by an in-silico toxicological risk assessment to establish AI limits, and application of a highly sensitive analytical method for confirmatory testing in drug product batches.
• A unique approach for combined quantification of two diastereomeric NDSRIs potentially derived from the same API, with the corresponding scientific rationale.
• A novel risk assessment strategy that complies with all three commonly employed AI Limit calculation approaches- (1) the most conservative and default TTC approach, (2) a read-across surrogate SAR and point of departure approach, and (3) the latest carcinogenic potency categorization approach (CPCA) recommended by regulatory authorities.
• Development and application of an NDSRI risk management strategy that was subsequently approved by key global regulatory bodies including the EMA and FDA.

This approach was aligned with the EMA’s three step nitrosamine evaluation: 1) assessment, 2) remediation, and 3) reporting.⁷ The risk evaluation includes assessment of theoretical formation of NDSRIs from excipients (microcrystalline cellulose [MCC] and starch), the tertiary amine-containing API (Miglustat), and its tertiary amine impurity (L-Ido miglustat) in miglustat capsules. The risk evaluation was conducted using quality risk management principles, as outlined in the ICH Q9 and ICH M7 guidelines. A robust control strategy is also described, which includes the application of a highly sensitive method for confirmatory testing in Miglustat DP batches. Details of the analytical method development, validation, and confirmatory testing will be described in another publication.