FDA and EU push for process data

Drug regulators in the United States and Europe are asking manufacturers to show more of the data behind how medicines are made, not just the test results at the end of production. The shift is tied to continuous manufacturing, process analytical technology and model-based controls that generate real-time information during production. FDA’s 2004 PAT framework and its March 2023 adoption of ICH Q13 already set the regulatory base for that approach, while the European Medicines Agency lists Q13 among its manufacturing quality guidelines with a July 10, 2023 legal effective date. Moo Sun Hong, a chemical and biological engineering professor at Seoul National University, said the practical change is that monitoring tools, mechanistic models, hybrid models and digital twins now give manufacturers “much richer real-time information.” In comments published by Genetic Engineering & Biotechnology News on September 2, Hong said those tools let companies move “from reactive quality testing toward proactive, model-informed process control.” (fda.gov) ### Why are regulators asking for more process data now? ICH Q13 says continuous manufacturing should be managed through development, implementation, operation and lifecycle management, not treated as a one-time validation exercise. The EMA summary says the guideline builds on existing ICH quality standards and adds regulatory considerations specific to continuous manufacturing of drug substances and drug products. FDA’s version says the same guidance covers the scientific and regulatory considerations for continuous manufacturing. (genengnews.com) Hong said regulators have “shifted from emphasizing end-product testing toward encouraging science- and risk-based process understanding throughout the product lifecycle.” He cited validated process models, real-time monitoring and robust control strategies as the elements getting more attention under recent guidance, including ICH Q13. ### What does that change inside a filing? (fda.gov) FDA’s process validation framework defines validation as the “collection and evaluation of data” from process design through commercial production to show a process can consistently deliver quality product. That lifecycle definition matters because it ties approval and post-approval oversight to continued evidence, not only launch data. FDA training material on CGMP and process validation also says in-process controls are used to monitor output and validate processes that may cause variability. (genengnews.com) For companies, that means chemistry, manufacturing and controls packages increasingly need to include control strategy, process models, monitoring plans and data showing the model remains reliable over time. Hong said regulators are likely to become more receptive to advanced model-informed control strategies if there is enough evidence that the models are reliable for their intended use, and if ongoing performance monitoring supports updates with new data. (fda.gov) ### Where do FDA and Europe line up on cross-border reviews? FDA and EMA already run a Parallel Scientific Advice program that lets experts from both agencies engage concurrently with sponsors on key development questions. FDA says the program gives companies a way to discuss procedure timelines, expected outcomes and best practices for joint interactions. The program is formally described for development-stage products, but it shows the agencies already have an established structure for coordinated scientific exchange. (genengnews.com) The LAL-to-recombinant Factor C example sits inside that broader push. FDA’s own research page on rFC says traditional bacterial endotoxin testing relies on horseshoe-crab-derived LAL, while rFC alternatives offer promising specificity, reduced variability and sustainability advantages. EFPIA, in a recent sustainability proposal to European regulators, listed new TAL/LAL endotoxin tests among manufacturing changes companies are pursuing and asked regulators to use tools such as post-approval change management protocols and parallel scientific advice to enable such changes. (fda.gov) ### Why does LAL versus rFC matter here? FDA researchers said their internal evaluation of rFC assay technology was intended to provide data to support agency best practices and guidance while ensuring product and patient safety. That makes the issue a useful case study for the larger regulatory direction: even when agencies are open to a new method, they still want comparability evidence, failure-mode analysis and a clear data package. (fda.gov) European and U.S. regulators are not abandoning end-product testing. But the documents now in force show they are asking manufacturers to prove, with process data and lifecycle evidence, that quality is being built into the process itself. The next practical milestone for companies is the post-approval submission: updated CMC documentation, model support and control-strategy data will be the material reviewed when sponsors seek manufacturing changes in multiple jurisdictions. (fda.gov 1) (fda.gov 2)