Process-Informed Control of NDSRI Risk in Oral Tablet Manufacturing: A Unit Operation-Based Framework

Nitrosamine drug substance-related impurities (NDSRIs) remain an important quality and regulatory concern in oral tablet drug products because they may form or accumulate during manufacturing and storage. Current control strategies emphasize API structural susceptibility, excipient nitrite burden, acceptable intake limits, confirmatory testing, and stability monitoring. However, these factors may not fully explain differences in NDSRI formation among formulations manufactured through different process routes. This review examines oral tablet unit operations as potential modifiers of physicochemical conditions relevant to NDSRI formation. Blending, wet granulation, drying, milling, roller compaction, compression, coating, packaging, and storage may influence moisture availability, thermal history, surface area, molecular mobility, API-excipient contact, and the local reaction microenvironment. For several unit operations, direct NDSRI-specific evidence remains limited, and proposed relationships are supported mainly by indirect nitrosamine observations, mechanistically supportive process evidence, or hypothesis-generating considerations that require product-specific confirmation. To integrate these factors, this review proposes a Unit Operation-NDSRI Control Matrix and an accompanying NDSRI-by-Design strategy for use across formulation development, process-route selection, scale-up, validation, stability assessment, and lifecycle change control. The framework is intended to complement end-product testing by supporting earlier identification and prospective control of formulation-process conditions that may contribute to NDSRI formation.