// September 15, 2023

Pharmaceutical Continuous Manufacturing: Regulatory landscape in the spotlight at USP workshop

Adam Fisher, Ph.D., Director, Science Staff, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), FDA

The science of pharmaceutical continuous manufacturing (PCM) may not be entirely new but increasing interest in adoption of advanced manufacturing technologies (AMT) including PCM among industry and policymakers in recent years has been accompanied by strong support by FDA. This is due in part to the potential for PCM to enable efficiencies that can help make more medicines in more places, reduce possible drug shortages, and support medicines supply chain resilience, according to stakeholders. FDA representatives emphasized the agency’s commitment to working with industry to mitigate potential regulatory hurdles to PCM adoption during USP’s workshop on “Identifying and Addressing Barriers to Continuous Manufacturing Adoption” July 18-19 in Rockville, Maryland.

[Editor’s note: The following is a snapshot of workshop take-aways focused on the PCM regulatory landscape. It is not intended as a comprehensive summary or report. See also the related Quality Matters blog on industry take-aways from the workshop.]

FDA’s Emerging Technology Program

“Advanced manufacturing as a concept, as an initiative, has been very important to the agency,” emphasized workshop presenter Adam Fisher, Ph.D., Director, Science Staff, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), FDA. For example, FDA established its Emerging Technology Program (ETP) in 2014 to facilitate emerging technologies like PCM and has already marked significant progress, Fisher said.

The ETP facilitates “early engagement” with FDA “before and during submission and assessment” of industry regulatory applications involving an AMT such as PCM, Fisher explained. “Actually, it works better for everyone if we do it before you submit an application. That way…we can do our best to communicate with you about how to best prepare a submission.” In addition, “these early interactions don’t even have to be specific to a product or a regulatory submission,” he continued. “We can have conversations prior to identifying a product.”

Key milestones include FDA’s approval of the first PCM submission for a small molecule drug product in 2015, and approval of the first switch of a drug product from traditional batch manufacturing to PCM in 2016. To date, over fifty PCM proposals have been submitted to ETP, and FDA has approved 20 regulatory submissions for drug products and drug substances utilizing the advanced manufacturing technology, Fisher noted. The agency has also worked with the International Council for Harmonization (ICH) to develop internationally harmonized guidance on PCM to address potential differences in regulatory approaches across geographies that can contribute to regulatory uncertainties.

Addressing “myths” head on

While the need to navigate global regulatory challenges associated with PCM has been cited by some industry participants as a potential obstacle to PCM adoption, Fisher sought to dispel several, related “myths” during the workshop. For example, while some stakeholders may perceive PCM to be primarily for innovators and not for makers of generic medicines or biotech companies, it “can be for generic companies, biotechnology companies, and so on, and we have had engagements with generic drug companies in our emerging technologies program already,” Fisher said.

Despite support for industry participants that may be pursuing PCM adoption, FDA is not “pushing” PCM and it is not mandated by the agency, Fisher asserted. “FDA will approve drugs if they comply with the appropriate standards, regulations, and laws,” Fisher said. “It doesn’t matter how they are manufactured.” Furthermore, “just because an innovator company has used a continuous process, it does not mean that a generics company also needs to use a continuous process,” Fisher said. “Let me be clear…the specification criteria are based on patient relevance and not on process capability,” Fisher emphasized.

Potential benefits of PCM “can be realized in some, but not all instances,” and “we don’t believe everything should be made with an advanced technology,” Fisher noted. For certain drug substance and drug product manufacturing processes, PCM can bring opportunities to enhance flexibility and efficiency, lower production costs, cut environmental footprints, accelerate scale-up when needed, improve process control, and reduce potential quality issues, workshop participants reported. However, such opportunities are not universally achievable and there is no one-size-fits-all approach, in part due to up-front investment costs and other challenges, attendees suggested.

Despite concerns by some to the contrary, FDA regulatory applications for medicines using PCM have not taken longer to review and approve than those for traditional batch manufacturing, Fisher said, noting a 2022 FDA self-audit comparing PCM to batch manufacturing regulatory outcomes. The audit showed that manufacturers that submitted PCM applications actually “had relatively shorter times to approval and market as compared to similar batch applications…translating to an estimated $171-537M in early revenue benefit.” The assessment also found “no substantial regulatory barriers” for PCM applications related to manufacturing process changes or pre-approval inspections.

While there may be certain regulatory challenges, “there are no regulatory barriers to the adoption of continuous manufacturing, only potentially perceived ones,” asserted presenter Riley Myers, Ph.D., Chief, Advanced Pharmaceutical Manufacturing Laboratory, Office of Testing and Research, FDA, during the second day of the workshop. “The nature of innovation is that there’s always going to be challenges that industry and FDA need to face…it’s the nature of evolving technology and science,” Myers acknowledged.

Building PCM knowledge

Beyond the U.S., harmonization efforts to date have sought to address potential differences in PCM regulatory approaches across geographies, though variations in regulatory maturity and capabilities persist among global health authorities that can contribute to hesitation among stakeholders looking to PCM. “That’s feedback we’ve consistently heard…I think this is a challenge for the entire community,” Myers said when questioned about potential industry challenges of working with less experienced regulatory authorities. “I don’t think the FDA alone is able to solve and bring all the countries in the world together to have a harmonized approach.” To support less experienced regulators who do not participate in ICH, Myers pointed to FDA’s published research as an important channel for related information sharing.

AMT such as PCM is employed for less than one percent of human drugs, but accounts for more than ten percent of CDER’s research projects, Fisher reported. FDA supports continued efforts to build knowledge of PCM through intra- and extra-mural research to generate reports and publications, some of which are available publicly for industry stakeholders and regulatory authorities to access. FDA’s intramural research and extramural grants and contracts have generated more than 78 internal reports, including 36 AMT research projects and 28 specifically on PCM. The knowledge generated through this work informs exploration of opportunities for new standards, guidances, policies, and regulatory recommendations to further facilitate product and technology development.

What’s next

Looking ahead, CDER’s Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative – which Fisher leads – will continue to focus on identifying regulatory process-related risks so that AMTs like PCM are not stymied by existing regulatory frameworks, Fisher said. FRAME priority areas include end-to-end continuous manufacturing as well as distributed manufacturing, point-of-care manufacturing, and artificial intelligence (AI).

To continue to facilitate dissemination of knowledge about PCM and keep the workshop conversation going, USP launched in July its Continuous Manufacturing Knowledge Center (CMKC) through collaboration with the National Institute for Pharmaceutical Technology and Education (NIPTE) and supported in part by funding awarded to NIPTE by FDA. Beyond the CMKC and the July workshop, USP’s work to address barriers to adoption of PCM has included development of technical guides on best practices, educational programs, R&D analytical lab services, and other quality-focused solutions.

Consulting services are also provided by Pharmatech Associates, a USP company that operates independently from USP’s standards-setting processes and offers business, technical, and regulatory strategies, equipment and process design services, as well as workforce training to manufacturers seeking to pursue PCM technology. Building on the July PCM workshop, Pharmatech Associates will conduct the PCM Business Summit on Sept. 27-28 in Princeton, New Jersey. The summit will convene pharmaceutical leaders and experts to further discuss the business perspective, business drivers, implementation strategies, and best practices in continuous manufacturing.

Learn more about related USP resources and efforts to advance quality-focused solutions for a stronger medicines supply chain.