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FDA is moving to shift industry away from step-wise batch production.
Regulatory authorities in the United States and other regions are encouraging investment in continuous manufacturing (CM) processes to better ensure quality drug production, avoid shortages, and ultimately lower the cost of medications for patients. The aim is to support an industry shift away from step-wise batch production, which is vulnerable to contamination, errors, and stoppages, to the use of automated modular systems better able to reduce human error, waste, and delays.
As of January 2019, FDA has approved five products from four manufacturers that use CM systems. These involve small molecules, but more comprehensive CM processes are in development for proteins and biologics. FDA reports that approximately 20 companies-both brand and generic-are talking to agency staff about developing and implementing CM processes.
To spur more manufacturers to join the trend, FDA published new draft guidance in February 2019 that clarifies its policy regarding CM approaches (1). The aim is to address manufacturer concerns that adoption of CM technology could delay approval of new drug applications or complicate switching from a batch to a CM process for marketed products, explained then FDA commissioner Scott Gottlieb and Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), in a statement highlighting agency efforts to expand industry investment in modern manufacturing systems (2).
The new guidance provides advice on what process and control strategy designs, including equipment, are needed to meet regulatory considerations. The guidance applies to CM for drug substances of all finished dosage forms, including drugs, generic drugs, and over-the-counter products, but not to biologics. It aims to clarify definitions of batches, process validation, and quality systems considerations for CM and to provide recommendations for scaling up production and demonstrating stability for finished drugs produced with CM systems.
To overcome company concerns about the cost of investing in new production technologies, FDA emphasizes that CM platform technology can be used to manufacture multiple products, which can help reduce the risk of drug shortages and facilitate scale-up of production when needed. An added benefit is the smaller footprint for CM systems, along with greater efficiency and consistency in these operations.
Gottlieb and Woodcock also cite increased FDA funding for private organizations assessing CM technology in laboratories, as well as support for internal agency investigation of CM and other technologies. CDER’s Emerging Technology Team (ETT) also is providing additional help for early adopters of CM in implementing new technology and navigating the application review process for products made with these modern methods. Additional funds in FDA’s 2019 budget will support further development of a standard operating approach for CM and advanced manufacturing, with the overall aim of reducing dependence on the import of pharmaceutical ingredients and products to better assure quality and supply.
At the same time, the International Council for Harmonization (ICH) is moving forward to establish standards for continuous manufacturing of drug substances and drug products, with the aim of developing a common framework for regulating and approving products that utilize CM methods. ICH approved a concept paper on the topic at its November 2018 meeting, and a panel of experts is mapping plans for developing a new quality guideline (Q13) on this topic. The aim is to establish common definitions for CM, articulate key scientific issues, and harmonize regulatory concepts and expectations across the regions. Participants hope to complete the project by the end of 2021, after conducting a series of site visits to CM facilities for both small and large molecules and learning more about state-of-the-art technologies. The expert working group includes representatives of industry and regulatory authorities in the United States, Europe, Japan, Canada, China, Korea, Singapore, and other nations.
While most CM operations so far have involved small molecules, manufacturers of biologics also are assessing how CM may apply to both upstream and downstream biotech production. This topic was examined in depth at the January 2019 CMC Strategy Forum on Continuous Manufacturing for Biologics organized by CASSS (3). Industry experts discussed advances in implementing CM for small molecules, noting that adoption of this approach in biomanufacturing has been limited largely to upstream “hybrid” approaches. BioMarin Pharmaceutical vice-president, Novato Operations, Erik Fouts noted that equipment manufacturers are offering small and pilot-scale CM systems for integrated continuous upstream and downstream processes and that these approaches are drawing interest as ways to boost productivity, lower the manufacturing footprint, and avoid waste in raw materials.
Participants at the Forum supported the ICH effort to develop the Q-13 guideline on CM as important in encouraging flexible approaches for implementing CM in manufacture of small molecules and therapeutic proteins. The aim is to clarify regulatory concepts, such as batch, process validation, and continuous process verification. While CM has the potential to increase flexibility and robustness in biomanufacturing, and to reduce costs and product heterogeneity, challenges remain in assuring sterility and advancing process controls.
These issues were addressed more broadly at the CASSS WCBP 2019 Scientific Program (4). The three-day program concluded with a review of initiatives to achieve flexible and modular facilities and the use of process analytical technology (PAT) in continuous manufacturing. PAT for an integrated continuous biomanufacturing platform is “becoming a reality today,” the experts concluded, noting that there remain many questions to consider in the journey to flexible and modular facilities.
1. FDA, Quality Considerations for Continuous Manufacturing Guidance for Industry, Draft Guidance (CDER, February 2019).
2. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., and Director of FDA’s Center for Drug Evaluation and Research Janet Woodcock, M.D., on the FDA’s Continuing Efforts to Maintain Its Strong Oversight of Generic Drug Quality Issues Domestically and Abroad,” Press Release, Feb. 22, 2019.
3. CMC Strategy Forum, Welcome to the CMC Strategy Forum Continuous Manufacturing for Biologics, Jan. 28, 2019.
4. WCBP 2019 Scientific Program, Jan. 29-31, 2019.
Volume 43, No. 4
When referreing to this article, please cite it as J. Wechsler, "Continuous Manufacturing Gains Major Push from FDA," Pharmaceutical Technology 43 (4) 2019.