Proceedings of a Workshop

Innovations in Pharmaceutical Manufacturing on the Horizon

Proceedings of a Workshop—in Brief

Emerging technologies have the potential to modernize pharmaceutical manufacturing and advance the quality of drug products. A 2021 report from the National Academies of Sciences, Engineering, and Medicine (the National Academies) identified these innovative technologies, including manufacturing processes, control and testing strategies, and product technologies.¹ The report, Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations, sponsored by the Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) and hereafter referred to as the “2021 National Academies report,” also discussed technical and regulatory challenges to implementing these technologies and provided suggestions for overcoming some of those issues. A virtual dissemination workshop titled Innovations in Pharmaceutical Manufacturing on the Horizon was hosted by the National Academies on October 28–29, 2021, and provided a venue for discussing the 2021 National Academies report’s recommendations and a platform for members of the report committee to reflect on the study. This Proceedings of a Workshop—in Brief summarizes the presentations and discussions that took place during the dissemination workshop. In addition to the community discussion during the workshop, responses to polling questions using Slido were also collected from participating audience members.² The workshop videos and presentations are available online.³

FDA PERSPECTIVE: ADVANCED MANUFACTURING AND THE FUTURE OF PHARMACEUTICAL QUALITY

In the opening remarks, Michael Kopcha, Director of the Office of Pharmaceutical Quality (OPQ), offered CDER’s perspective on advanced manufacturing and pharmaceutical quality. He began the presentation by defining pharmaceutical quality as an assurance that every dose of a drug is safe, effective, and free of contamination and defects. Then, he elaborated on four key themes: innovation in a changing world, challenges and opportunities within that endeavor, importance of advanced manufacturing, and regulatory framework.

Kopcha described CDER’s definition of a changing world as one that is volatile, uncertain, complex, and ambiguous, which may benefit from innovation strategies that will protect against supply chain disruptions causing drug shortages. Kopcha then linked the concept of Industry 4.0 (a term widely used in the manufacturing sector referring to the fourth industrial revolution) to pharmaceutical manufacturing.⁴ “Whereas Industry 3.0 [a term that was coined to describe the third industrial revolution] saw rapid advancements of individual operations and tools, Industry 4.0 promises advancements of entire manufacturing systems,” said Kopcha. Theoretically, in Industry 4.0, autonomous systems would

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be capable of self-optimizing, making decisions, moving materials, and performing adaptive controls in real time. These processes and functions would be managed through a network composed of manufacturing and digital technologies, internal and external data collection, analysis, and cloud storage. Kopcha emphasized that significant changes in conventional manufacturing practices within the pharmaceutical industry may be needed in order to achieve these processes.

Next, Kopcha stated the challenges and opportunities faced by FDA in circumventing drug shortages resulting from poor pharmaceutical quality. OPQ created a framework to measure and provide transparency into a pharmaceutical manufacturing facility’s quality management, known as quality management maturity (QMM).⁵ QMM is a state attained through having consistent, reliable, and robust business processes that permit quality drug product objections and promote additional improvements. In short, FDA aims to create a rating system that accounts for pharmaceutical quality and business incentives to innovate based on QMM. Kopcha said, “We need these ratings that recognize and reward manufacturers for having more mature quality systems that achieve sustainable compliance and focus on continual improvement.”

Kopcha then listed the importance of advanced manufacturing to (1) produce better quality medicine, (2) re-shore drug manufacturing facilities, (3) develop drugs rapidly, (4) prevent drug shortages, and (5) improve emergency preparedness. He also highlighted current FDA advanced manufacturing initiatives such as the Emerging Technology Program (ETP), the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), and Advanced Manufacturing Science and Research. These programs would be discussed in depth later in the workshop. Lastly, he summarized key activities supported by FDA, such as funding more than 60 science and research projects, spearheading the International Council for Harmonization (ICH) Q13 guideline, offering pre-submission support for applicants, forming a regulatory framework for advanced manufacturing, and forming collaborations between CDER and the Center for Biologics Evaluation and Research (CBER). In closing, Kopcha said, “Let’s continue working together to use innovation to handle an ever-changing world.”

2021 NATIONAL ACADEMIES REPORT SUMMARY: FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS

Gintaras Reklaitis, Gedge Distinguished Professor of Chemical Engineering and Professor of industrial and physical pharmacy at Purdue University and Chair for the 2021 National Academies report committee, summarized the motivation for the 2021 National Academies report, Statement of Task, committee’s approach, findings, conclusions, and recommendations.

Motivation for the Study

Innovation in pharmaceutical manufacturing will require the identification of ways to fulfill the desire for an agile, flexible manufacturing sector that can produce high-quality drugs reliably without extensive regulatory oversight.

Statement of Task

• Identify emerging technologies that have the potential to advance pharmaceutical quality and modernize manufacturing for CDER-regulated products,
• Describe technical and regulatory issues associated with innovations, and
• Recommend how to overcome regulatory issues to facilitate adoption of novel technologies.

Committee’s Approach to the Statement of Task

Reklaitis mentioned that the committee identified innovations that FDA is likely to see, not necessarily the innovations that should be pursued by FDA. To stay within the scope of the study, the committee focused solely on the role FDA has in preparing for and facilitating innovation and considered other stakeholders’ expectations in this area to be beyond the scope of the charge. However, the committee emphasized the need for all stakeholders to play a role in achieving the goal of a flexible, agile pharmaceutical sector.

2021 National Academies Report’s Findings and Conclusions

Reklaitis provided an overview of key directions for manufacturing innovations within specific technology categories as identified in the 2021 National Academies Report.

Five Major Challenges Imposed by the Existing Regulatory Process

The five challenges listed in bold below were identified by the committee of the 2021 National Academies report. Additional commentary on each challenge was provided by Reklaitis during his presentation on the summary of the report’s findings.

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1. Product and technology review process: Reklaitis emphasized that under the existing regulatory process, the only way a new technology is reviewed is through the context of an individual product review. He stated that this process places a significant burden on the manufacturer because of the double risk associated with obtaining approval for the new technology and the new product. “Unless there is sufficient incentive for a manufacturer to bear the possibility of unanticipated activities, costs, and time on behalf of a particular product, the manufacturer will likely use a conventional technology,” said Reklaitis.
2. Alignment of incentives for manufacturing innovation: While technical and regulatory challenges are hurdles, Reklaitis supported the 2021 committee in stating that none likely presents a greater barrier than the issue of incentives for innovating. He suggested that stakeholders create platforms that align the pharmaceutical manufacturing community’s incentives to spur new manufacturing ideas.
3. Global harmonization: Inconsistent regulatory expectations across international health authorities impede the global installment of new manufacturing technologies, stated Reklaitis.
4. Post-approval change: Reklaitis echoed the 2021 National Academies report that the regulatory requirements for change modifications in the manufacturing process after product approval also delay the advancement of innovative technologies.
5. FDA internal limitations: The role of CDER in accelerating innovation is under developed and jeopardizes its capability to evaluate new technologies for safe and effective drug manufacturing. Reklaitis said capacity constraints, lack of expertise, and organizational culture are obstacles blocking CDER’s success. A dissonance exists between oversight to ensure safe products and the enablement of new technologies. He mentioned that finding ways to break down that dissonance would be helpful.

Based on its findings (including these five challenges) and conclusions the committee for the 2021 National Academies report provided the recommendations listed in the Box 1.

Reklaitis concluded by highlighting the important role of the broader community in moving new manufacturing technology forward and stressing the importance of FDA’s leadership role in driving that change.

FDA’S REFLECTION ON THE COMMITTEE’S RECOMMENDATIONS

Sau (Larry) Lee, Deputy Director of Science, Office of Pharmaceutical Quality, CDER at FDA, and Joel Welch, Associate Director for Science and Biosimilar Strategy at FDA, responded to the recommendations in the 2021 National Academies report by describing the efforts under way in ETP 2.0. Established in 2014, ETP was designed to promote and facilitate the adoption of innovative approaches used in pharmaceutical product design and manufacturing. ETP 2.0 is the result of an internal road mapping exercise to improve the current ETP. Lee and Welch indicated that the changes identified in the roadmap have been prioritized and are being implemented. The team has 30 members who represent

the OPQ, the Office of Compliance, and the Office of Regulatory Affairs (ORA). ETP also invites ad hoc subject-matter experts to join when specialized knowledge is needed to evaluate a specific technology. ETP’s major objectives are to:

• Serve as a centralized location for external inquiries on novel technologies;
• Provide a forum for engagement and early dialogue with ETP to support innovation;
• Aid the consistency, continuity, and predictability of the review practice;
• Engage with international regulatory agencies to share learnings and approaches;
• Identify and evaluate roadblocks related to existing guidance, policy, and practice;
• Facilitate knowledge transfer relevant to CDER and the ORA review and inspection program; and
• Help establish scientific standards and policy as needed.

Furthermore, Lee listed the National Academies recommendations and outlined ETP’s existing efforts in response to them as shown in Table 1.

TECHNOLOGIES AND ADVANCES IN MANUFACTURING INNOVATION

Narendra Bam, Senior Vice President, Biopharm Product Development and Supply at GlaxoSmithKline (GSK), and Jessica Settimi, Senior Director of Continuous Manufacturing, Patheon by Thermo Fisher-Scientific, presented their perspectives on innovative technologies in pharmaceutical manufacturing.

TABLE 1 CDER’s Efforts in Relation to the Committee’s Recommendations from the 2021 National Academies Report

^a For additional information on ICH 13, see https://www.ema.europa.eu/en/ich-guideline-q13-continuous-manufacturing-drug-substances-drug-products#current-version-section.

^b For a complete list of ICH Quality Guidelines, ICH Q2 (R2) and Q14, see https://www.ich.org/page/quality-guidelines.

^c For a complete list of ICH Quality Guidelines, ICH Q2 (R2), Q14, and Q5A (R1), see https://www.ich.org/page/quality-guidelines.

First, Bam described three biopharmaceutical manufacturing technologies employed at GSK-AGILE, Polychaeta technology, and Digital Twins. He also indicated that these technologies are “on the cusp of being industrialized.”

Bam elaborated further that he envisioned the Digital Twins technology evolving from a monitoring approach into a feedback control. But, he cautioned the current empirical models are not first-principle (which are models reflecting physical laws rather than models built primarily on data). By addressing these two points, he said, “[if] we can enable [and] predict first design and in-silico optimization for our manufacturing processes, then we can ultimately support the vision of Industry 4.0.” From Bam’s point of view, industry wants more clarity and direction from the regulatory authorities on matters related to the delivery of the digital transformation. He stated that there is a need for clear guidance on model verification and validation; maintenance and life cycle management, including post-vial model optimization; and updates. Bam posed the questions: How will these data be inspected? What type of data are needed?

After describing GSK’s key innovative technologies, Bam acknowledged that global regulatory divergence may be a significant barrier to facilitating innovation. Therefore, he echoed the recommendations from the 2021 National Academies report, calling for greater alignment among global regulatory authorities. He highlighted that acceptance of advanced model-driven approaches is an area that needs more attention from international regulators. He proposed that FDA could leverage its leadership position in enabling emerging technologies and extend it into developing international regulatory norms and guidance, such as the ICH Q3D.

Finally, Bam reflected on GSK’s lessons learned from developing COVID-19 therapeutics alongside regulators. Through frequent and open communications, “The agencies have allowed us to take very smart scientific regulatory risks and provide the data as we go. I think we need more of that in the innovation space,” said Bam. During the pandemic, the company faced raw material supply shortages, which delayed its lead times for production. Bam posed the following question to regulators: What regulatory mechanisms can be put into place to qualify alternative raw materials? He also claimed there is a need for easier post-launch change mechanisms that would enable site transfers for increasing production in order for companies to meet unexpected demand for existing products. Lastly, travel restrictions due to the pandemic forced regulators and companies to adopt virtual and digital technologies as a way of conducting virtual inspections. He suggested that both the process and capabilities could also be standardized. In addition to using these technologies, Bam suggested that developing good practices, having cooperation across global regulatory agencies, and sharing mutual recognition of inspections could enable successful remote inspections.

Next, Settimi provided commentary from the perspective of a contract development and manufacturing company (CDMO) on how technologies can drive innovation. She presented three criteria that she believes these technologies should possess: speed (to clinic, to market, and to agility), flexibility (in relation to scale and geography), and reduction of risk (by increasing supply chain resilience and process reliability). The pandemic increased the pressure to meet these metrics. Settimi listed process intensification, advanced process control and automation, and modular systems as innovative technologies identified in the 2021 National Academies report that met all three criteria. “These will have a path forward for adoption or commercialization because there is a tangible business impact,” said Settimi. Other technologies not included in the report, but Settimi emphasized were equally important, were traceability of starting materials, platform technologies, digital technologies used for modeling, and digital technologies applied in knowledge sharing and management.

Informal polls were conducted during the meeting,⁶ and about 70 percent of the responding audience members indicated that continuous manufacturing, process intensification, or modeling and digital designs are innovations that may have an opportunity to advance pharmaceutical manufacturing.

EXISTING MECHANISMS TO SUPPORT INNOVATION

In addition to the existing efforts implemented by CDER, representatives from the pharmaceutical manufacturing community also shared their perspectives on mechanisms to further support innovation.

Rohin Mhatre, Senior Vice President of Pharmaceutical/Biopharmaceutical Development at Biogen, presented a perspective on a mechanism that may facilitate innovation in industry. Prior to discussing the mechanisms, Mhatre mentioned several technologies that were also identified in the 2021 National Academies report, including multivariate modeling and condition monitoring that may be important in enhancing process control for the next generation manufacturing of drug substances.

First, he focused on building a culture of innovation, where every member of the staff is empowered to evaluate and drive new processes, initiatives, and new ways of working. He believes that the core of innovation is being able to anticipate the business needs and to plan to stay ahead. Mhatre outlined the innovation pathway at Biogen. Again, he stressed that business and process needs would be the driving force throughout this pathway. The categories as outlined by Mhatre follow.

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Fuzzy Front-End of Innovation: Phase 0: The Spark and Phase 1: Feasibility

At Biogen, the initial innovation phase has between 20–30 projects that are funded through small investments or “seed” money. These projects include forming academic collaborations via post-doctoral hires, co-ops, and developing proof of concepts. Biogen also supports a formal PhD program that allows employees to pursue a PhD on a full salary. The student would write their thesis proposals and an internal committee member from the organization would also serve on the student’s thesis committee. Lastly, projects in the first two phases last between a few months to up to 1 year before moving to the next stage.

Concept Development: Phase 2: Development

In the second stage, Biogen works with regulatory agencies and their programs, like ETT, for feedback and guidance on the innovative technology. Here, the company puts a business case around the technology and then identifies what the investment is, what the outcomes are, and where the technology would be implemented. Regarding working with the agencies, Mhatre said, “Through all the innovations that we have put together, I actually have had in my experience very little resistance from agencies particularly if the science has been strong.”

Commercialization: Phase 3: Implementation and Phase 4: Sustainment

In the final stage of the innovation pathway, Biogen continues to work with agencies to seek product approval and to form alignment with inspector expectations. Mhatre ended his presentation with a brief description of the Innovation Hub established in his department. The hub is a central repository for new knowledge and learnings obtained in seven areas of development (pharmaceuticals, antisense oligonucleotide, protein, gene therapy, analytical, device and packaging, and digital development and analytics). He said, “It is the idea that at some point, if you park something, we do not restart and go back to square one.”

Next, Sarah Arden, Director of Global Regulatory Affairs, Discovery and Early Development, US Research and Development Center at GSK, conveyed four major mechanisms practiced at GSK to engage regulators and other stakeholders early in the innovation process.

Direct Sponsor Interaction

The first major mechanism was direct sponsor interaction, where GSK would build relations with agencies through existing programs. Arden listed the following domestic and international platforms as examples: ETP or ETT, CBER, Advanced Technologies Team, Center for Devices Innovation Group, European Medicines Agency’s (EMA’s) Innovation Task Force, United Kingdom’s Medicine and Healthcare Regulatory Agency, and Japan’s Pharmaceuticals and Medical Devices Agency.

Guidance and Innovation Initiatives

The second major mechanism was divided into two subcategories: guidance and innovation initiatives. Arden explained that guidance written by regulatory agencies is helpful in providing a framework for industry to refer to when at a crossroads during the decision-making process. Examples of these types of frameworks include the PAT guidance “A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,” quality considerations for continuous manufacturing guidance, Q13, and the Advancement of Emerging Technology application. She cautioned that this mechanism is one directional and is not interactive. In contrast, innovation initiatives are platforms that allow for engagement among regulators, industry, and the public. Arden also provided examples of the type of initiatives employed by FDA to generate discussions and ideas, such as dockets for public comments (e.g., Federal Register for quality management maturity used by CDER and FDA’s Center for Devices and Radiological Health), collaboration centers (e.g., Duke-Margolis Center for Health Policies, Digital Health Center for Excellence), and workshops (e.g., FDA and Duke-Margolis Public Meeting: Establishing a High-Quality Real-World Data Ecosystem).

FDA Extramural Funding

The third major mechanism was FDA extramural funding, which appears in the form of contracts and grants used to support new technology development. The agency reviews the submitted proposals and determines how to distribute the funds and define learning goals for the regulatory review side, policy side, and commercial side to expedite the innovation process. Arden cautioned the mechanism’s overall impact on the technology’s commercial success and the private sector remains unclear.

Public–Private Partnerships

Finally, the fourth major mechanism was public–private partnerships, which allow for various stakeholders to engage in discussions. Arden provided the following as examples: Manufacturing Extension Partnership National Network, the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), BioFab, BioMADE, the Medical Device

Innovation Consortium, Manufacturing USA. Arden also highlighted recent GSK experience with ETT for integrating novel manufacturing and testing platforms into pharmaceutical manufacturing processes. She provided an example, for which GSK submitted a meeting request with ETT to discuss microbiological testing platforms. The discussion focused on leveraging prior knowledge for method validation; an approach for product-specific method validation and verification following method transfer; sample preparation and bracketing of evaluated species; and comparability to compendial methods. She mentioned that subject-matter experts from various FDA divisions were included in the meeting package review. Through these interactions, GSK also received feedback and discussion, as well as actionable responses provided by FDA. Lastly, Arden also shared her perspective on areas within the existing mechanisms that could be improved as noted below.

Improving direct sponsor interactions: Arden mentioned that an area that could be improved in this category is to ensure consistency across the centers by using a formalized pre-Investigational New Drug or type C process as well as having a Technology Master File that can be reviewed in the absence of application cross-reference. A well-publicized point of contact or office for sponsor relations within each center was proposed by Arden as a way to facilitate stronger sponsor interactions. Arden also reiterated it is important to have a global alignment between international and national regulatory agencies to allow parallel scientific advice consultation. She said that having a Memorandum of Understanding (MOU) between the agencies is one way of achieving alignment, which may impact various stakeholders’ perspectives, risk assessments, and commercial strategies related to the innovation.

Improving public–private partnerships: Arden stated that more collaboration between agencies and private-sector research and development in the pre-competitive space could be helpful in improving public–private partnerships. She suggested that the efforts can be executed via a Cooperative Research and Development Agreement or innovation test beds.

Another informal poll was conducted, and about 80 percent of the responding audience members indicated that innovation in pharmaceutical manufacturing may be accelerated by changes in regulatory policy, procedures, practices or cultures. On the other hand, approximately 70 percent of those who responded, noted that pharmaceutical innovation can be enabled by industry practices. Changes to guidance, regulations and workforce training were suggestions that may enable innovation.

POTENTIAL CHALLENGES AND OPPORTUNITIES

The speakers in session three examined both the challenges and opportunities within the various mechanisms presented in the previous sessions. Timothy Charlebois, Senior Fellow at NIIMBL and retired Vice President of Technology and Innovation Strategy for BioTherapeutics Pharmaceutical Sciences at Pfizer, moderated this session. Thomas C. Ransohoff, Co-Head of the Biologicals Franchise at Resilience, Dolores Hernan, Chemical Manufacturing Control Regulatory Specialist at EMA, Malcolm Barratt-Johnson, Managing Director at PharmaMedic Consultancy Ltd., and Mike Hourigan, Founder and Managing Director at Horizon Controls Group and Founder and President at International Academy of Automation Engineering, all spoke on this topic.

Ransohoff stated that one of the biggest challenges to deploying innovative technologies is in the perception of risk. From industry’s point of view, this risk is the potential delay and setback for product development caused by new technology adoption. Hourigan also supported the statement and emphasized that companies do not want to be the first to introduce the technology because they fear taking on the double burden of the approval process.

Ransohoff stated that the timing to adopt innovative technology poses another challenge. In general, to implement the adoption of innovation like single-use bioreactors takes about 10–20 years. This timeline is much longer than other industries; thus, he argued that there is no real “good time” to introduce a new technology because there are obstacles at all stages of product development. As a result, little upfront capital investment is dedicated to these activities. Ransohoff also added that the benefits of innovating are underappreciated in industry. While cost and timeline benefits are appreciated, the potential to add value to the program and products is often overlooked. However, he also highlighted that benefits need to be consistent with the level of effort necessary for deploying the technology.

Intellectual property (IP) uncertainty poses another obstacle for innovation in pharmaceutical manufacturing. Ransohoff emphasized that freedom to operate is paramount and Hernan also agreed with this statement. Due to IP and confidentiality restrictions, regulators are constrained by the kind of information they can share with proposal applicants who may have similar technology applications and problems. He noted that this limitation impedes the agency’s ability to refine the regulatory framework and prevents industry groups from solving technical problems together, thus slowing the technology adoption process. Ransohoff concluded by offering several strategies to improve industry’s ability to innovate, including the use of consortia to enable precompetitive collaboration in innovation, reinforcing the message offered by several of the speakers.

Next, Hernan listed technical and regulatory challenges to moving pharmaceutical manufacturing innovation forward. Some of these challenges include the difficulties of evaluating more complex systems or technologies such as

additive manufacturing, platform technologies, performance-based approaches; portable modular systems, bedside manufacturing, and decentralized manufacturing; companion diagnostics; and borderline products.

Shifting the discussion, Barratt-Johnson focused on the challenge of ensuring supply chain robustness and its connection to agile manufacturing. This need was apparent during the COVID-19 pandemic and will likely be increasingly important during future health emergencies. He referred to the European Health Emergency Preparedness and Response Authority (HERA), an initiative established by the European Commission as an organization that worked on this concept.

Hourigan expanded on the issue of pharmaceutical manufacturing supply chain resilience by focusing on the challenges of implementing digital technologies. He discussed the four levels of digital mastery (which considers both leadership capabilities and digital capabilities) and its relationship to pharmaceutical manufacturer’s proficiency, confidence, and vision in employing digital technologies. According to survey results conducted by Hourigan and coworkers, few manufacturers were considered digital masters.⁷

Potential Opportunities Within Existing Mechanisms

Possibilities toward reducing business hesitancy in approaching regulators: Hernan proposed that one way to overcome the risk-adverse mindset is to have companies alert regulators to their innovation in the early stages of the technology development. In doing so, regulators can prepare the appropriate framework to evaluate the new technology. Additionally, she conceded that regulators need to increase personnel trainings to expand the organization’s knowledge of new technologies. Hourigan and Barratt-Johnson agreed that training the inspection regulatory staff in agencies like FDA, EMA, or the Material Handling Industry of America to have the understanding of the technology and best practices in their applications was critical to the adoption process.

Addressing IP uncertainty: Ransohoff expanded on Arden’s previous comment by proposing that industrial collaboration in the pre-competitive space may enable innovation.

Possible approach to addressing supply chain resilience for delivering medicine: Barratt-Johnson discussed one of the strategies proposed by HERA to improve manufacturer’s capability to deliver medicine to patients is by using Portable on Demand (POD). PODs are pharmaceutical units consisting of one or more integrated pharmaceutical operations that can be placed within an existing facility or be fully autonomous. These pharmaceutical operations can be copied several times. In theory, both the process and the quality of the POD could be replicated and be identical regardless of geographic location. He emphasized that the key point was that good manufacturing practice (GMP) compliance of a POD would be retained when it is replicated or relocated because the original GMP compliance was based where the POD was first located and approved. “This should lead to consistency, high production volumes, and greater patient responsiveness, whether that be local or global,” said Barratt-Johnson.

A final informal poll revealed that 90 percent of the responding participants felt that risk of disrupting timeliness or risk in extensive and expensive efforts to gain regulatory approval were two key considerations in relation to implementing innovation. When asked about regulatory risks in business decisions related to innovations in manufacturing processes, some audience members highlighted protracted regulatory reviews, whereas others highlighted either clarity and consistency in the evaluation of residual risk to product quality or satisfying regulatory requirements across different geographic areas.

POSSIBLE SOLUTIONS AND ACTIONS

In session four, speakers shared viewpoints on possible actions that can be taken by stakeholders to introduce innovative technologies in pharmaceutical manufacturing. This session was moderated by Saly Romero-Torres, Senior Director of Digital Quality Systems at Thermo Fisher Scientific. First, Adam Fisher, Associate Director of Science and Outreach (Acting) in the Immediate, and Thomas O’Connor, Director of the Division of Product Quality Research Office of Testing Research, both from OPQ, CDER, FDA, discussed FDA’s initiative for evaluating technologies that may impact industry in the next 5–10 years, FRAME. Fisher and O’Connor noted that FRAME is in Phase III of its implementation. This phase will lead to the generation of white papers that will serve as vehicles for obtaining continuing input from the community of FRAME. They also emphasized the importance of science and research programs at OPQ in moving technologies through the innovation and regulatory pipeline.

Activities of FDA to improve the regulatory oversight of advanced manufacturing: FDA is aligning OPQ’s science and research programs’ agenda with the needs of ETP 2.0 and FRAME. It is also continuing investments in

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research programs for advanced manufacturing. Since September 2021, five collaborative projects were added to its portfolio. Additionally, training CDER and ORA staff in innovative technologies at CDER’s Research Manufacturing Pilot Plant are actions taking place. Finally, collaborating with stakeholders outside of CDER is also an activity FDA is conducting to improve regulatory oversight of advanced manufacturing.

Kelvin H. Lee, Institute Director at NIIMBL and Gore Professor of Chemical and Bimolecular Engineering at the University of Delaware, stressed that the desire to deliver safe medicine to patients is a mission shared among all stakeholders in pharmaceutical manufacturing. When considering factors that drive innovation, he argued that the business risk, such as delays in time to market and uncertainty in regulatory response due to a fragmented global regulatory environment, is more decisive than the technology itself.

Lee proposed potential options to mitigate business risks. First, increasing appropriations may encourage more engagement from the community in advanced manufacturing. Lee also proposed that considerations of a tax incentive for products and processes that adopt “advanced manufacturing” approaches may reduce business risks. Lee also acknowledged that defining “advanced manufacturing” is not a trivial task. Next, considerations for extending the period of exclusivity for products that are first to adopt “advanced manufacturing” approaches could also reduce these risks. Lee mentioned that this strategy may encourage innovators to debate the business benefits and risks of adopting new technologies relative to the product development timeline. Finally, NIIMBL announced it is prepared to host a workshop focused on lowering the risk barriers to introducing innovative technologies.

Fernando Muzzio, Distinguished Professor of Chemical and Biochemical Engineering at Rutgers University, reflected on the steps taken by FDA and Rutgers to graduate the first technology, continuous direct compression (CDC), from ETP. He summarized the mechanisms previously taken or that could be taken by FDA to allow for future adoption of other technologies. He shared tips for graduating new technologies. Muzzio mentioned that building on CDC success to create momentum may enable widespread implementation of CDC by creating technology transfer laboratories that would lower upfront costs and lead time for process implementation, enabling rapid approvals based on 100 percent inspection capabilities, creating platform formulations and processes, and facilitating process transfers between similar lines. Muzzio stated creating pathfinder programs through the activities below may help graduate new technologies by identifying manufacturing problems that need technology solutions, providing seed funding for technology, and engaging more industry and more academics at all career stages. Furthermore, funding for technology demonstration and commercialization that may help innovators cross the valley of death.⁸ Muzzio highlighted that funding technology implementation toolboxes may generate widespread technology adoption. He noted tools like established knowledge, material property database, equipment performance database, technology standards (e.g., sensors), modeling libraries and digital design tools, and process control method that could be improved. Lastly, he emphasized that inviting more groups to be involved in conversations about innovative technologies could drive more technology adoptions.

Gillian Sanders Schmidler, Deputy Director of Academics, Duke-Margolis Center for Health Policy, and Stephen Colvill, Research Associate at the Duke-Margolis Center for Health Policy and Executive Director and Co-Founder at RISCS, Inc., highlighted obstacles that are impeding biomedical innovation. For example, lack of incentives and small margins can result in undesirable foreign dependencies and supply chain risks (e.g., risk of natural disasters, international trade disputes, etc.). They listed the following considerations to improve biomedical innovation.

Considerations for improving biomedical innovation: Regulators could set a future date when older technology will no longer be approved. This strategy can be achieved using a method like track and trace, where dates for technology approvals are monitored in conjunction with their development. Setting this type of approval status for older technologies may incentivize competition in manufacturing. For example, manufacturers may be asked to present a plan on how they will move the new technology forward. However, if a competitor enters the market with the new technology to supply the demand, then the approval for the existing manufacturer using the older technology will be revoked. Next, FDA could also collaborate with international regulators to promote the standardization of platforms. Schmidler and Colvill also stated that including types of technologies in FDA’s QMM Model may increase biomedical innovation, accelerate product reviews, and provide filing fee waivers for products with innovative technologies.

Potential ways to increase impact ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Life Cycle Management: Reklaitis mentioned that the ICH Q12 initiative is directed explicitly to the commercial phase of the product life cycle. He emphasized that in order for the program to have a lasting impact, a consistent support and genuine sense of partnership, experimentation, and continuous adaptation must be employed.

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COMMITTEE REFLECTION AND WORKSHOP DISCUSSION

Committee Reflection

Reklaitis invited members of the 2021 National Academies report committee to offer their comments on the report. The members reflected on impacts from the pandemic, the role of continuous processing and product quality, and change management.

Initiating the reflection period, Kelley Rogers, Technical Program Manager at the National Institute of Standards and Technology, reminded the audience that the Statement of Task was written before the pandemic, hence the technologies and innovation timeline considered by the committee may have changed due to this historic event. For example, the rapid implementation of mRNA vaccines was a scenario where the pandemic accelerated technology deployment to commercial applications. Arlene Joyner, Branch Chief at the Biomedical Advanced Research and Development Authority of the U.S. Department of Health and Human Services and Deputy Director of the Pharmaceutical Countermeasure Infrastructure Division, added to Rogers’s comments by stating that two major outcomes resulted from this public health emergency. First, the large collaboration among private-sector companies and research communities allowed FDA to work with a group rather than an individual company. As a result, Joyner said, “[FDA can] develop regulations and policies that address a group of companies as opposed to one at a time.” Second, the pandemic showed that FDA can be cooperative with having frequent conversations regarding new vaccine technologies, expediting development processes, and reviewing extra requirements with technology teams. On the other hand, Todd Przybycien, Professor in the Howard P. Isermann Department of Chemical and Biological Engineering at Rensselaer Polytechnic Institute, balanced the previous two perspectives by underscoring how the extreme pressure and time constraints placed on manufacturers to move products out faster may also inadvertently increase the barrier for innovation.

Shifting the discussion, Paul Mort, Professor in the Department of Materials Engineering Center for Particulate Products and Processes at Purdue University, talked about CDER’s role in encouraging the use of continuous processing and suggested that the perspective be expanded to include a more end-to-end view of continuous flow. This change would consider both drug substance and drug product regulations, which Mort noted, can be difficult. He also proposed that in areas concerning product quality, the broader community could focus less on the word “continuous” and more on concepts such as process, stability, and control in order to consider other methods like small batch and fast batch.

Romero-Torres broadened the discussion further by sharing her perspective on change management. She called for the community to organize and transmit concepts and language in a way that can fit inside the quality system. She mapped the process by asking a few questions “what is going to be [the organization’s] value proposition? What is going to be the end goal for customers and patients? And how do [organizations] get there by leveraging new technologies and perhaps learning from each other?”

Community Discussion

Later in the workshop, during session five, Reklaitis moderated an open discussion with the workshop’s audience, where the group reflected on topics heard in the previous sessions. Highlighted below are questions and responses from various audience members on ways they believe the pharmaceutical manufacturing community could progress in the next 5–10 years.

Q1. What could the community do collectively to enable new technologies?

Reklaitis started the conversation by stating that implementing new technologies does not always rely on the government to move the process forward; industry is also capable of doing so. Additionally, he emphasized that globalization will continue to promote communications among regulators, which will accelerate the adoption of new technologies. To unify international collaborators, he suggested an MOU could be created. Following Reklaitis’s comment, Charlebois said that the community could outline a strategic plan that could then be executed. He encouraged the community to capitalize on the current momentum and called on groups involved in pharmaceutical manufacturing to take collective action. Muzzio expanded on this idea and proposed that the map or strategic plan could include defined goals and pathways to implement technologies. These routes could leverage everyone’s contributions (e.g., academic researchers, industry, regulators, etc.) and interests, as well as ensure the plan would be outcome driven. Additionally, a representative from International Pharmaceutical Quality remarked that the organization was willing to help enable future dialogue and ideas that were discussed in the workshop.

Q2. What do you think are productive ways to move forward in advances in manufacturing?

Reklaitis referenced Muzzio and Kelvin Lee’s talks, where the impetus for moving technology forward should be focused on the patient’s interest. Rogers stated that while there is significant effort within FDA to enable new technologies, a misalignment between the pharmaceutical manufacturing community’s incentives and FDA is evident. For

example, she mentioned that specific partnerships between FDA and a single university may be more limited than from direct engagement with industry consortia. Therefore, she suggested the community could focus on the incentives, existing mechanisms, and assets to reach an alignment. Moreover, Romero-Torres acknowledged that the vision and support to enable new technology development is evident, however, from her perspective, the business case to incentivize adoption remains unclear.

Q3. What is the business case to support advanced manufacturing?

Stelios Tsinontides, Director of Office of Pharmaceutical Manufacturing Assessment at FDA, stated that the community needs a business case to support why advancement in manufacturing makes sense. For example, he said businesses need to assess the cost associated with the loss of products (e.g., beyond expiry dates) and defects. If businesses can estimate the costs and identify specific manufacturing technologies that may minimize loss, then that could be a stronger business argument for implementing new technologies beyond pure novelty. Tsinontides further mentioned that the compilation of information on these types of costs and ways specific manufacturing technologies could reduce or eliminate them could be of interest for an industry–university collaborative study.

Q4. What are the various benefits for stakeholders (federal agencies, companies, academia, etc.)?

From her observation, Romero-Torres stated that a diverse set of benefits that argues for the adoption of new technologies would be more appealing to various stakeholders because each group would benefit differently from the same technology. Examples of different benefits include (1) saving a batch or (2) having fewer inspections. She highlighted that stakeholders (e.g., agencies, society, companies) have different reasons for why new technology adoptions would benefit them, and if these incentives are tailored to each involved party, then the adoption may be met with greater success.

Q5. What are ways ETT is demonstrating that it is actively participating in discussion with other industry groups to understand new technologies?

Larry Lee explained that FDA has existing forums and consortium to facilitate discussions between technologists and pharmaceutical groups. However, the problem does not lie in the facilitation medium, but rather in the lack of cross-collaboration between industry–industry and between FDA–industry. Due to the confidentiality agreement restriction, FDA relies heavily on the actions of industry partners to work together and decide on how they can share information. For example, industry could come together to create a collective and shared data set. Lee reiterated that although FDA can only approve products, ETP is the vehicle available to discuss technologies independent of specific products.

Q6. Why are some groups hesitant in approaching FDA?

Fisher stated that programs like ETT must adhere to rules of confidentiality, which restrict agencies from revealing to the broader pharmaceutical manufacturing community the type of technologies and activities that are ongoing. In other words, FDA must maintain confidentiality until the companies publicly share their experience. Therefore, to raise awareness about the program’s support role and capabilities, FDA relies on participating companies to share their experience of working with ETT and to describe their technology to the community. Fisher suggested that ETT work closely with these companies on more public engagement to increase the program’s visibility and help increase business risk tolerance.

Furthermore, Fisher, shared his perspective as a scientist and said he sees opportunities for innovations within the pre-competitive space. In this area, people with different intellectual property can come together to build a collective portfolio that will enable the creation of new technologies.

Q7. What are other obstacles for implementing new manufacturing technologies?

John Erickson from NIIMBL brought up two key points. First, the problem with moving technologies forward is less about the actual approval process or even timing of approval, and more about the lack of confidence that some technology practitioners have in approaching FDA. Due to this hesitancy, new and potential technology does not actually come forth to ETT or other approval platforms. He encouraged the community to think of ways to increase this confidence. Second, understanding strategy roadmaps may not be the hurdle to moving manufacturing technologies forward, rather, companies and consortia may be struggling with identifying specific projects that they could work on together. Next, Jack Prior, Head, MSAT Digital, IA Specialty Care MSAT at Sanofi, said the pharmaceutical manufacturing industry’s main priority is to bring drugs to market fast. Because of this objective, he argued that incentives for innovation could be further discussed and posed the question: Are there examples of innovations that could be incentivized?

Q8. How can change be managed within a complex dynamic system?

Rob Guenard, Head of Digital Realization at Biogen, spoke on managing change in a complex system. He said in order to implement meaningful change within a well-established and dynamic industry such as the pharmaceutical manu-

facturing sector, the concept of change needs to be managed methodically. Guenard suggested that taking a social science approach in answering key questions to this problem may provide more clarity because the current capabilities (incentives, investments, technologies, etc.) used to manage change are diluted and fragmented. Rather than employing the “shot-gun” approach currently being pursued, he urged the community to unify its resources and capabilities.

CLOSING REMARKS

In the workshop’s closing remarks, Kopcha informed the audience that CDER and CBER have partnered together to establish the Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals. He also encouraged more dialogue among ETP and industry and manufacturing groups. Kopcha proposed that to increase participation in ETT and decrease hesitancy, companies can approach ETP as a team sharing a common technology, instead of individual companies. He reminded the audience of FDA’s primary role in protecting the American public, where its job is to ensure only safe, effective, quality medicines are available to patients and consumers. At the same time, Kopcha acknowledged that there are possibly unnecessary regulations or regulatory barriers to implementing new technologies that could be addressed. ”But the way to minimize that oversight by us is to make sure that we’re at a quality level or a quality management maturity level that allows us the ability then to inspect companies less,” said Kopcha. In the end, he emphasized the importance for different stakeholders to come together and work toward a common goal of using advanced manufacturing to deliver safe products. He said, “Let’s take what we’ve learned and use manufacturing innovation to give patients and consumers more confidence and better quality in their next dose of medicine that they take.”

DISCLAIMER: This Proceedings of a Workshop—in Brief was prepared by Linda Nhon as a factual summary of what occurred at the workshop. The statements recorded here are those of the individual workshop participants and do not necessarily represent the views of all workshop participants, the planning committee, or the National Academies. To ensure that this Proceedings of a Workshop—in Brief meets institutional standards for quality and objectivity, it was reviewed in draft form by Gintaras Reklaitis, Purdue University, and Kelly Rogers, National Institute of Standards and Technology. We also thank staff member Jennifer Cohen for reading and providing helpful comments on this manuscript. The review comments and draft manuscript remain confidential to protect the integrity of the process.

The workshop planning team members were Gintaras V. Reklaitis (NAE) (Chair), Purdue University; Timothy Charlebois, National Institute for Innovation in Manufacturing Biopharmaceuticals; Kelley Rogers, National Institute of Standards and Technology; and Saly Romero-Torres, Thermo Fisher Scientific. National Academies’ staff were Linda Nhon, Jessica Wolfman, and Brenna Albin.

This activity was supported by the Food and Drug Administration and the U.S. Department of Health and Human Services under Grant 10004526. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. Innovations in Pharmaceutical Manufacturing on the Horizon: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/26539.

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