Real-time release testing: a review of global regulatory frameworks and application by the industry

Real-time release testing is defined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8(R2) as “the ability to evaluate and ensure the quality of in-process and/or final drug product based on process data, which typically includes a valid combination of measured material attributes and process controls”. The purpose of this review is to present the evolution of the real-time release testing regulatory framework, current health authority guidance and expectations, and possible regulatory burden and rationale of why the industry has been reluctant to more aggressively implement this concept. Overall, there remains a harmonized approach and wide acceptance of real-time release testing by global health authorities thanks to international cooperative agreements such as the Pharmaceutical Inspection and Convention Pharmaceutical Inspection Co-Operation Scheme (PIC/S). The most mature and successful application of real-time release testing remains the manufacturing of pharmaceutical tablets. The literature mainly features hybrid approaches of real-time and traditional release testing, and often within the context of continuous tablet manufacturing. The implementation of real-time release testing for large molecule modalities remains a challenge, as the limitations in current in-line, on-line, or at-line analytical technologies would likely not support all biologic CQA testing resulting in hybrid real-time/conventional release testing. Additional potential causal factors toward the industry’s slow implementation include the challenging regulatory issues managing out of specification results, analytical technology limitations, the high data and modelling required to support regulatory approval, and the regulatory burden associated with maintaining the control strategy post-approval. However, as analytical and modelling technologies continue to improve, these technical challenges may become less relevant. Continued discussion between industry and global health authorities will additionally drive new regulatory strategies to help implement these innovative technologies. For example, ICH is currently revising Q6A and Q6B (e.g., specifications) and may facilitate broader adoption of innovative approaches including real-time release testing. Additional discussions through United States Food and Drug Administration’s (US FDAs) Emerging Technology Program (ETP), the European Medicines Agency (EMAs) Quality Innovation Group (QIG), and Japan’s Pharmaceutical and Medical Devices Agency (PMDAs) Innovative Manufacturing Technology Working Group (IMT-WG) remain promising forums for further discussion. Graphical Abstract