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Antibody–drug conjugates (ADCs) and N-nitrosamines are two topics that have seen a surge of interest in recent years. ADCs are increasingly prevalent as oncology therapeutics in clinical development and on the market. Concerns about the potential presence of N-nitrosamines in pharmaceutical products have led to increased regulatory scrutiny and implementation of robust control strategies by the industry. This article, the first in a two-part series, provides visibility into current industry practices for risk assessment and control of N-nitrosamines in ADCs with results and analysis from a benchmarking survey of member companies of the IQ Consortium. Items covered include assessment methodology, identification and characterization of risks, control limits at the drug-linker intermediate and drug substance, and specific factors related to the ADC modality that can be considered. Simpler N-nitrosamines (e.g., NDMA) and more complex N-nitrosamine drug-linker-related impurities (NDLRIs) are discussed. Areas where there are greater or lesser degrees of consistency across companies are highlighted. The second paper builds on these survey results by presenting a comprehensive set of recommendations for the risk evaluation and control strategy of N-nitrosamine impurities in drug-linkers and ADCs. Taken together, these papers provide a perspective on the current state and encourage further development of scientifically sound approaches in this field.

This position study provides a science-based, holistic approach to evaluating the risks of nitrosamine presence in drug-linkers as intermediates toward antibody–drug conjugate (ADC) drug substances. The evaluation of 47 different ADC drug substances, which have a recommended dose available in the public domain, supports the conclusion that the chemically synthesized fragments of ADCs are unlikely to lead to nitrosamine presence in the final drug product. Hence, it can be concluded that for most ADCs there are few nitrosamine risks introduced by the drug-linkers and their impurities. An abbreviated workflow for quality risk management of nitrosamine in drug-linkers is therefore proposed.

The nanoemulsion‐based 10% aminolevulinic acid (ALA) hydrochloride gel BF‐200 ALA optimizes epidermal penetration of its active ingredient and is approved for topical photodynamic therapy (PDT) for the treatment of actinic keratosis in the United States and Europe. To characterize systemic absorption from dermal application during PDT, ALA and its key active metabolite protoporphyrin IX (PpIX) were analyzed in 2 maximal usage pharmacokinetic trials (MUsT) in patients severely affected with actinic keratosis. The primary objective of both MUsTs was to assess baseline‐adjusted plasma concentration–time curves for ALA and PpIX after a single PDT treatment applying either 2 g (1 tube) of BF‐200 ALA on the face (MUsT‐1) or applying 6 g (3 tubes) of BF‐200 ALA on the face/scalp or body periphery (MUsT‐2), to 20 or 60 cm2, respectively. All PDTs were performed using red light at around 635 nm wavelength. Safety and tolerability were documented along with pharmacokinetics. In both MUsTs, ALA plasma concentrations were transiently increased to a maximum concentration at about 2.5 to 3.3 times above endogenous baseline with time to maximum concentration at ≈3 hours after dosing. Plasma levels subsequently returned to baseline within 10 hours after dosing. Overall baseline‐adjusted mean area under the baseline‐adjusted plasma concentration‐time curve from time zero to the last sampling time point at which the concentration was at or above the lower limit of quantification ranged from 142.8 to 146.2, indicating that a similar, minor fraction of topical ALA is systemically absorbed under both dosing regimens. Systemic PpIX exposure after administration of either dose of BF‐200 ALA was equally minimal. Application site skin reactions were treatment area size‐related, albeit transient and consistent with the known safety profile of BF‐200 ALA.