Pharmaceutical continuous manufacturing (PCM) is suitable for some medicines, but not every product or situation, and potential hurdles abound, participants generally agreed at USP’s workshop on “Identifying and Addressing Barriers to Continuous Manufacturing Adoption” July 18-19 in Rockville, Maryland. USP convened representatives from industry, academia, and FDA to facilitate knowledge sharing among those interested in the implementation of PCM. While not yet widely adopted, PCM can enable potential efficiencies that can help achieve geographic diversity in manufacturing and supply chain resilience to improve global health, according to stakeholders.
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. The U.S. FDA has approved 20 regulatory submissions for drug products and drug substances utilizing the advanced manufacturing technology since 2015.
[Editor’s note: The following is a snapshot of take-aways from the workshop. It is not intended as a comprehensive summary or report.]
PCM not ideal for every drug
Continuous manufacturing “may not be fit for every pharmaceutical manufacturing process, but it can bring some advantages in some cases” compared with traditional batch manufacturing, summarized FDA’s Adam Fisher, Ph.D., Director, Science Staff - Office of Pharmaceutical Quality, Center for Drug Evaluation and Research. “One pharmaceutical company switched to continuous manufacturing and reported a 50% reduction in operating costs, 33% reduction in waste, 80% reduction in manufacturing and testing cycle time, and a 66% reduction in time from testing to release,” Fisher highlighted at the USP workshop.
However, such benefits can be out of reach in other instances. These include cases impacted by financial challenges of switching to PCM, such as the costs of capital equipment; technical challenges; regulatory considerations; and the organizational mindset shift needed to recognize long-term benefits of PCM, according to some workshop attendees.
Regarding cost effectiveness over time, “is [PCM] always better for every asset? It’s hard to say because they are so individual,” said workshop participant Matthew Beaver, Ph.D., Director, Process Development, Pivotal and Commercial Synthetics, at Amgen. “It’s very hard to compare directly a [PCM] process and a batch process…. It’s never an apples-to-apples comparison,” Beaver suggested.
The potential for production efficiencies and related cost savings with PCM was among the top motivators for global generics manufacturer Dr. Reddy’s Laboratories’ interest in PCM, according to workshop presenter Srividya Ramakrishnan, Ph.D., Vice President and Head - API Process Engineering at Dr. Reddy’s Laboratories. However, early experience showed “the capital investment ended up being more than our initial estimate,” Ramakrishnan reported. “Rationalizing this return on investment was quite a bit of a challenge.”
“There is a lot of sunk capital” in existing batch manufacturing facilities, Ramakrishnan continued, “which makes it difficult to justify the investment into a continuous plant if batch is working just as fine.” For one product, the firm calculated switching to PCM would take “22 years” to payback the investment, Ramakrishnan reported. Related considerations can include the uncertainty of future demand for a particular active pharmaceutical ingredient (API) and a lack of published “business cases” showing where PCM is cost effective over time, especially for generics where margins can be slim, some workshop attendees suggested.
Excess batch manufacturing capacity and infrastructure following major industry capital investments in the 1990s and early 2000s has limited interest in investing in new capacity, attendees suggested. U.S. generic drug manufacturing sites surveyed have existing, aggregate excess capacity of “nearly 50%,” according to a September 2022 report by Anthony Sardella, Senior Research Advisor at the Center for Analytics and Business Insights, Washington University in St. Louis.
For this reason, pharmaceutical companies considering PCM in either their API production or finished dosage form lines should conduct early, thoughtful, technological and economic analyses of specific products and circumstances, conference presenters suggested. Such analyses can reduce risks of over-investment in related capital assets while boosting confidence that anticipated benefits can be achieved. Describing this type of analytical process as part of Amgen’s select use of PCM, Beaver noted that “Amgen’s approach really has been a hybrid approach.” The firm has “developed platforms, knowledge [and processes] around each individual unit operation required for drug substance continuous manufacturing…and as we look at an individual molecule or an asset we think ‘how would we deploy these…in a hybrid manner to drive the maximum benefit?’”
Quality in focus
For solid oral drug products, PCM can facilitate blending of ingredients and enhanced assurance of quality compared with batch manufacturing, though not necessarily improved quality, according to several workshop participants.
“Why is continuous better? If I could take everything and boil it down into one statement, the statement is: superior blending,” opined workshop presenter Eric Jayjock, Ph.D., Director, Process Engineering, Technical Operations Drug Product, at Vertex Pharmaceuticals. This feature of the technology also facilitates a more direct pathway to production scale-up, Jayjock suggested.
On the API manufacturing side, PCM utilizes flow chemistry, which allows reactants and reagents to be fed into a process pipeline simultaneously as the transformed output is collected on the other end in a continuous stream. At the same time, PCM leverages process analytical technology (PAT) to help control manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring high product quality.
As a result, PCM provides “additional means of understanding” quality attributes, with “rich” data and “extra information” that enables companies to “accelerate through your testing levels quicker because you have a higher assurance of quality,” Jayjock said. PAT can also help minimize the need for “human intervention” to review production samples in a commercial scale process, providing important efficiencies, noted workshop presenter Todd Maloney, Ph.D., Executive Director at Eli Lilly.
Such advantages in understanding processes do not necessarily equate to better quality, however, some workshop attendees suggested. “It is true in some cases” that PCM allows improved quality for drug substances, but “it’s not true for every case that the quality is better,” Ramakrishnan noted.
“I think it’s important that we acknowledge that quality of batch manufacturing is held to an incredibly high standard, and so I don’t think operating in [PCM] is inherently higher quality,” Beaver agreed. “The quality considerations for [PCM] I think are just different, and our ability to probe, build models, add additional PAT, is helping us understand the processes better.”
There are “uneven expectations for assurance of quality” between PCM and batch manufacturing that may be a contributing factor to the slow pace of PCM adoption to date, Jayjock suggested. For example, while regulatory expectations all but require “real time” quality assurance with PCM, simply performing end-product testing can be deemed sufficient to release a batch. With PCM, “we have a higher capability, yet at the same time we have a higher onus to demonstrate it within a regulated environment,” Jayjock said.
Plusses and minuses
When it came to pharmaceutical manufacturer Merck’s pursuit of PCM as an alternate manufacturing process to an existing batch process for one of its drug products, “the focus was really on flexibility to meet product demand,” explained workshop presenter Frank Witulski, Director of Engineering at Merck. Global supply chains are more favorable with a mix of batch and continuous manufacturing, Witulski suggested. “To meet patient needs is why we need this flexibility. It’s not just about the companies, it’s about the patients. Having that flexibility will reduce supply chain shortages, it will increase access to medicines,” Witulski said.
Nevertheless, “cost is a big factor” impeding faster PCM adoption by industry, Witulski agreed. “There is so much batch equipment out there.” PCM “is more cost effective if you have to build a new plant, but you don’t have to build a new plant in many cases. So, it’s that challenge of, ‘when is the investment worthwhile?’ I think that’s the biggest thing that would keep…companies that have already done a lot of work in [PCM] from moving to more [PCM] more quickly.”
Beyond financial concerns, technical challenges of PCM adoption cited by workshop attendees include workforce capacity challenges and the level of training and capability required, especially for those comfortable with the status quo; and a lack of knowledge within some companies about how best to bring PCM to fruition, with a need for lower-level guidance within the industry.
There remains a need for “practical guidance” to help clarify how best to implement PCM, Ramakrishnan suggested. Publication of “success stories” on PCM implementation “would be really helpful.”
For some companies, other hurdles include navigating global regulatory challenges, including the difficulty of changing existing regulatory filings, change management, and protectiveness around prior processes, some workshop attendees said. Though the U.S. FDA has worked to mitigate regulatory challenges to PCM – through the agency’s Emerging Technology Program, development of internationally harmonized guidance, stakeholder engagement, and other efforts – differences in regulatory approaches across geographies can contribute to uncertainties, some workshop participants suggested. (See related Quality Matters blog on regulatory considerations.)
Flow chemistry insight
The workshop included discussion of various technical aspects of PCM, including flow chemistry processes that are of interest to chemical engineers, process chemists, and others involved in manufacturing.
The benefits of flow chemistry as an enabling technology for PCM, highlighted by several presenters, include the potential to facilitate safer handling of hazardous or challenging chemical transformations and separations, lower waste production, reduced facility footprint, easier on-demand manufacturing, shorter production times, as well as consistent quality. However, from the perspective of contract development and manufacturing organizations (CDMOs), there is an inherent challenge in flow chemistry because reactors for flow chemistry are often “process-specific” while batch manufacturing reactors are designed to be “multi-purpose,” reported workshop presenter Olivier Dapremont, Ph.D., Executive Director for Process Technologies at CDMO firm Ampac Fine Chemicals.
The need for process-specific reactors for PCM, as well as often process-specific automation, control strategies and recipes, can add time and capital investment requirements that represent an added barrier to entry for PCM, Dapremont continued. For CDMOs “it’s very difficult to develop a [PCM] process because we don’t necessarily have all the tools” at the onset of a project, he summarized.
Solutions to break through
When asked to provide one bit of advice to organizations beginning to think about PCM adoption, workshop presenters offered the following take-aways:
- Start small: “Just start small at first and get those quick wins,” Ramakrishnan offered. Look at “hybrid processes for APIs and finding those few specific reactions where maybe there is an advantage, and also collaboration, reaching out to experts or consultants who could help guide [you] through the process.” Getting a “quick win…builds a lot more confidence in the organization that this is something that is beneficial and doable” and worth investing in, Ramakrishnan said.
- “Build small, organically” in stages, Jayjock recommended. “You figure out [the] business opportunity…you go through that design phase, you do your R&D – which is cheap compared to the capital expense – for a couple of years, and then when you know what you’re going to build, you go and you build exactly what you need to build,” Jayjock said.
- Build the right team: “The first thing is to build a team that is robust,” Dapremont suggested. “Get individuals that really understand the process, not just the chemists and the engineers, but also the quality group, the analytical” people, Dapremont continued. It’s also important to get “top-down acceptance through the company, so it’s not just a small group in a corner developing process and doesn’t go anywhere. You need to really embrace it as a technology but have a core of individuals that really believe in it, and knowledgeable.”
- “When we started [with a] drug substance, probably the most beneficial thing was: One, we had executives who were for the initiative,” Eli Lilly’s Maloney said. “Two, we pulled together a team of scientists…across all scientific disciplines, quality, etc., but we were allowed to immerse ourselves and try to get from ‘A’ to ‘B’ as fast as possible…. Having that freedom to do that, and invest, and develop that core, was really important for us and enabled us to grow and share what we learned with the rest of our company so that they could also become enthusiastic and help drive and deliver it for other areas of our business,” Maloney said.
- “Build that cross-functional team of everyone, and then think and be honest,” Witulski suggested. “Think about what you already know how to do…. Be honest about things that you don’t know how to do yet. And then reach out for others and figure those out together…. A lot of it is easier than you think,” Witulski said
Looking ahead
Ongoing development and research, as well as engagement among industry, academia, regulatory authorities and other stakeholders, likely will continue to help manufacturers unlock approaches for PCM, where appropriate. “There is a lot of potential for further adoption” of PCM, and “further collaboration through forums like this will really help to meet that potential,” Witulski said.
USP aims to keep the conversation going through the on-line Continuous Manufacturing Knowledge Center (CMKC), which launched in July 2023 to facilitate access to available information on PCM. 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.
