6

Advancing Innovation: Observations, Challenges, Opportunities, and Recommendations

The committee received input from a number of experts and stakeholders, many of whom have been advocates, champions, and practitioners of innovative technologies and who have direct experience in the business, scientific, technical, and regulatory factors that affect the rate of progress in the field. A concern commonly expressed was that the agility, robustness, and overall industrial maturity of pharmaceutical manufacturing need attention and investment to guard against the many potential vulnerabilities that could threaten access to products essential to public health. In addition, there is a strong consensus that advanced manufacturing technologies can and must play a central role in moving toward a successful future for the global supply chain.

What became evident to the committee in conducting its analysis is that many stakeholders have a role to play and can influence the outcome of this endeavor. The members of the public who benefit greatly from pharmaceutical products are the ultimate stakeholders and depend heavily on the industry and the regulators to enable and protect the future availability of high-quality medicines. However, reflecting on the various parties and the overall system responsible for delivering this important value to the public, the committee concludes that no single organization or entity—however well-financed, large, powerful, or influential—has either the capability or a mandate to lead the broader community to this future state on its own.

Historically, the pace of improvement arguably has suffered at the whole-system level because of fundamental structural barriers and because of the roles and incentives of the various key participants in the pharmaceutical-manufacturing ecosystem. In particular, the predominant drivers of value for the industry and the public are the pharmaceutical products themselves—not the technologies deployed to manufacture them. That reality has important implications both for industrial developers and manufacturers of products and for regulatory authorities reviewing and overseeing them. Thus, neither pharmaceutical companies nor regulatory agencies are able to take a fully strategic, system-focused approach to the implementation of advanced manufacturing technology. Even if each organization acts responsibly and effectively within the expectations, motivations, and incentives of its own mandate, there is no concerted driving force or “invisible hand” that is guiding the system toward an overall desirable end point. A substantive change in the relationship and collective leadership among entities most able to achieve the outcome will be required. The committee concludes that the Food and Drug Administration (FDA), as a critical participant and node of influence, can and should play a direct leadership role. FDA also needs to support the ability and willingness of manufacturers to lead and drive innovative change.

It is noteworthy that in the case of the COVID-19 pandemic, the incentives of industry, regulators, and society were strongly aligned. FDA was seen from the committee’s perspective as playing a co-leadership role in enabling the rapid advancement of vaccines and therapeutics, including innovative manufacturing technologies. That case provides a clear example of the power of FDA leadership and suggests an important opportunity if it were effectively applied more generally to pharmaceutical manufacturing.

In this chapter, the committee first provides some examples of key innovations likely to be implemented in the next 5–10 years that will be particularly important for both manufacturers and regulators. The discussion is not intended to be a comprehensive summary of innovations covered in Chapters 2–5. Rather, it highlights the importance and opportunity of pharmaceutical-manufacturing innovation and underscores the associated challenges in achieving the desired future state. The committee then discusses the implications of technology review that is confined to product applications, incentives, and disincentives that have affected innovation in pharmaceutical manufacturing and the role that FDA could play in advancing innovation. The chapter concludes with the committee’s overarching recommendations. The commit-

tee emphasizes that its task was to focus on the role of FDA in preparing for and facilitating innovation to reach this future state. Accordingly, this report does not make recommendations to other stakeholders in the pharmaceutical ecosystem, but the committee acknowledges the critical need for them to undertake actions in support of shared goals.

KEY MANUFACURING INNOVATIONS

In this report, the committee has described many innovations for manufacturing drug substances and drug products, to advance new control approaches, and to develop integrated, flexible, and distributed manufacturing networks. The committee is impressed by the wealth of innovative technology in development and the great opportunity for such innovation to benefit all stakeholders, provided that appropriate incentives can be aligned between business and regulatory priorities. This concluding chapter of the report highlights a subset of the innovations discussed more fully in Chapters 2–5. The technologies discussed here are ones that offer the most probable and extensive opportunities to advance pharmaceutical manufacturing within 5–10 years. It should be noted that the committee has deliberately represented many of these innovations by classes rather than individual technologies; it is likely that a diversity of novel technology within a class will be implemented on similar timelines.

New Routes to Produce Drug Substances

As discussed in Chapter 2, innovations in manufacturing technology used to synthesize active pharmaceutical ingredients (APIs) or drug substances are advancing toward implementation. For small- and large-molecule pharmaceuticals, photochemistry, electrochemistry, biocatalysis, cell-free protein synthesis, and cell-based biosynthesis that uses alternative hosts are all gaining traction and likely to be implemented in the next decade. Those technologies are motivated by a combination of process- and product-related needs, including improvements in process efficiency, speed, cost, throughput, safety and environmental sustainability. They also can improve the assurance of product quality by reducing the risk of side-product formation or other undesired variants. These novel synthetic approaches are also driven by product innovations, including higher-complexity small molecules, engineered biomolecules that are difficult to produce in traditional cell-based processes, and such emerging modalities as oligonucleotide and RNA-based therapies.

The implementation of a broad suite of new methods of drug synthesis should not require a fundamental shift in the regulatory system associated with their manufacture. However, the breadth and scope of the products and processes that are contemplated will likely place substantial additional demands on FDA with respect to the volume and complexity of product review. Novel processes and new impurities will likely involve much learning on the part of both industry and regulators: uncertainties will abound, unexpected control issues will arise, and challenges in setting manufacturing ranges and specifications will need to be addressed and overcome.

Co-Processed Active Pharmaceutical Ingredients

As discussed in Chapter 2, innovations in API manufacture might include substantive changes in the traditional boundary between API and drug-product formulation operations. Addition of nonactive excipients or carriers during production of drug substances offers the potential to improve yields and manipulate attributes of a process stream to achieve a desired outcome. Co-processed APIs might be advantageous, for example, in particle formation, crystallization, or drying operations to improve stability of a desired solid state or to tailor physical properties of the APIs.

The regulatory challenge presented by a co-processed API is related to regulatory definitions and has important implications for how the expiry date is determined for such products. Defining a co-processed API as a drug-product intermediate—rather than a drug substance—could have the effect of setting the start of the stability dating period further upstream before a drug product itself is manufactured. That action could lead to the drug product entering the supply chain with an earlier expiry date and thus reduce overall supply-chain agility and robustness.

Process Intensification

As discussed in Chapter 2, process intensification can be achieved through technology-driven changes in manufacturing process flow, thereby increasing performance and efficiency. Expected innovations include the integration or reduction of multiple traditional unit operations (including solution preparation), the replacement of batch processes with continuous formats, and the incorporation of recirculation and recycle approaches. Those innovations are likely to afford a number of improvements that are also foundational in the development of modular systems and flexible, distributed manufacturing networks (discussed in Chapter 5; see also below). Specifically, substantial reductions in the number of unit operations, equipment size, solution volumes, in-process hold requirements, raw-material use, and waste generation can

be achieved. More efficient, higher-yielding processes enable smaller manufacturing footprints and reduced capital and operating costs. For pharmaceutical manufacturers, those improvements will help to overcome some of the most difficult impediments in supply-chain investment and decision-making and make it more feasible to create redundant and surge capacity and thus improve overall capability and security of pharmaceutical supply.

To realize the potential benefits of process intensification, it will be critical to ensure that process control and assurance of product quality are not compromised. Rather than conducting oversight of a discrete set of unit operations, each with its own discrete set of performance and quality expectations, a more holistic demand is placed on an integrated, intensified system. Multiple mechanisms of achieving product-quality objectives might be used simultaneously rather than sequentially. Process intermediates and associated quality-control and quality-assurance data might be eliminated, and this would increase dependence on the sophistication and capability of process-control systems. The use of recirculation and recycle approaches might heighten the potential for process- and product-related impurities to accumulate or for backward propagation of out-of-specification materials, which would further challenge traditional batch definition and control paradigms.

Additive Manufacturing

As discussed in Chapter 3, additive manufacturing or product formation by three-dimensional (3-D) printing is a radical alternative for manufacture of pharmaceutical products in comparison with conventional tablet production. The most promising technologies include powder solidification, liquid solidification, and extrusion-based methods, all of which use precise layering of materials in a successive, specific pattern to arrive at the final dosage form. Those technologies also have the capability of tailoring desired characteristics of a drug product, for example, geometry, porosity, and API composition (including combinations of APIs and excipients) that can be custom-fitted for a specific indication or for individual patient requirements. And additive manufacturing enables monitoring and acceptance or rejection of a product at the individual-dose level and can be scaled down to compact size, potentially supporting highly distributed manufacturing.

To achieve broad implementation of 3-D printed pharmaceuticals, industry and regulators will need to address a number of challenges, including technical challenges that pertain to each method and the essential connection between the additive manufacturing process and the critical attributes of a product. Novel excipients might also be required. Proactive regulatory engagement and guidance will be important for guiding the broad category of additive manufacturing (regardless of variations in technology) and specifically the topic of individualized dose production and whether this should be treated as drug compounding or manufacturing.

Advanced Process Control and Automation

As discussed in Chapter 4, important advances are being made in sensor technology, data analytics, and system modeling, and manufacturers will increasingly rely on these innovations to design, understand, and control complex processes. The combined characteristics of various off-line, at-line, and in-line sensors will create an unprecedented ability to measure process variables and product attributes. To use the enormous quantity and resolving power of such data effectively, sophisticated analytics, models, and artificial intelligence will be required to support advanced process-control strategies, continued process verification, and ultimately real-time process optimization and more automated operation and management of manufacturing.

The innovations will be critical for the future of pharmaceutical manufacturing. As innovative product modalities and technologies to manufacture drug substances (Chapter 2) and drug products (Chapter 3) emerge, there is an increased need to ensure process capability and product quality that must be addressed by advanced control strategies. The expected benefits of innovations in integrated, flexible, and distributed manufacturing networks (Chapter 5) will be extremely difficult to achieve through traditional quality-management systems that were built around large, centralized facilities and supply-chain networks. The ability to achieve consistency of operations and quality in smaller, more modularized operations will depend heavily on integrated advanced process control and automation.

The challenges for regulators and industry pertain to the complexity and sophistication of the technology itself and to the paradigm-changing integration of these capabilities into development and manufacturing. Because control strategy is so foundational, much care, expertise, and experience will be required to ensure that these innovations can deliver on the promise of improving quality assurance and process capability.

Modular Systems

As discussed in Chapter 5, modular systems that leverage innovations in drug-substance and drug-product manufacturing and technologic advances in process control and automation present an opportunity to reshape the very nature of manufacturing facilities and the global supply chain. Unit operations that have greatly reduced footprints can be more readily modularized and lead to a flexible and rapidly reconfigurable capability that can support manufacture of a large array of drugs and biologics. In some cases, fully end-to end manufacture—from input raw materials to finished drug product—might be accomplished with one or a few closely associated modules. In addition, modular systems can be easily replicated and deployed quickly, either in the context of an existing facility or in other locations.

The integrated, flexible, and distributed manufacturing networks that modular systems will make possible constitute a paradigm shift in the industry—away from traditional large, bespoke, centralized facilities that were based on predictable, stable pharmaceutical portfolios and a strong drive to leverage economies of scale. Rapid response to patient and health-care system needs that range from niche and personalized therapies to varying patient needs across geographic and demographic boundaries will be enabled by widespread implementation of modular systems.

To achieve the dimensions of potential supply-chain agility and efficiency afforded by modular systems, innovation in how manufacturing processes, facilities, and networks are designed, defined, validated, operated, and monitored will be required. Indeed, using conventional approaches to many of those aspects would undermine the fundamental attributes that drive the innovations, so adaptations of conventional regulatory models will be needed. A variety of questions about traditional quality-management approaches will have to be addressed, including the degree of redundant qualification and validation that will be necessary for each deployment or redeployment of identical modules and processes and how in-process, release, and stability-testing paradigms and control systems will be integrated and managed among distributed networks.

THE EFFECT OF PRODUCT REVIEW AND APPROVAL AS THE BASIS OF ACCEPTANCE AND IMPLEMENTATION OF MANUFACTURING TECHNOLOGY

An important factor in the pace of manufacturing innovation is the reality that formal regulatory review of technology occurs specifically in the context of individual products. Technology is evaluated with respect to its suitability to deliver a high-quality product consistently and is not approved outright on its own. Although that paradigm might be appropriate for the pharmaceutical regulatory regime, it places a large burden on any manufacturer that seeks to bring forward a novel technology in support of product approval for the first time. Even if regulators have had exposure to and generally support a particular manufacturing innovation, only when a product that uses it has been fully subjected to detailed review and approval can an initial understanding of its genuine regulatory status be achieved. It is entirely incumbent on the manufacturer to satisfy all requirements that regulators need to approve the product, which might include unanticipated activities, costs, and time that could affect the financial viability of the product. In such a context, introducing innovative manufacturing can be a risky proposition. As will be discussed below, unless there is sufficient incentive for a manufacturer to bear the burden of potential cost and risk on behalf of a particular product, it often makes business sense to use more conventional technology for the product. Thus, the overall potential of a manufacturing innovation to influence many products or the global supply chain is not easily built into the value proposition for a single product. That is especially true of older, more established products, such as generics, for which the costs of introducing more modern, efficient technologies are difficult to justify for products that have smaller profit margins. In addition, even when a first such approval is achieved, it will take much time and effort—through the review and approval of other products—for a particular manufacturing technology to be broadly and successfully adopted.

THE NEED FOR INCENTIVES TO ADVANCE TECHNOLOGY INNOVATION

A strong and consistent view expressed during this study pertains to the effect of incentives and disincentives on innovation. Although the technical and regulatory challenges described in this report pose hurdles, none likely presents a greater barrier than insufficient, conflicting, or countervailing incentives. Such forces are relevant—often in different ways—to manufacturers and regulators. A summary of incentive-related challenges and illustrative examples is provided below.

The most obvious strong incentive for manufacturing innovation occurs when a pharmaceutical product fundamentally depends on the technology in such a way that

the therapeutic benefit cannot otherwise be delivered to patients. For example, the development of antibody–drug conjugates for oncology indications created great complexities and challenges in manufacturing and analytics, but the clinical benefits of the products and potential financial returns were sufficient motivation for manufacturers to develop the necessary technology. The incentives of industry and regulators aligned well, and they agreed that a process must be developed to make the products available to patients.

In a more challenging case, a manufacturing innovation itself is being advanced as a central feature of a potentially disruptive business model. Small-scale, automated, integrated, and portable drug-manufacturing systems serve as an illustrative example. As these technologies increasingly demonstrate feasibility, they raise the prospect of a transformation of traditional manufacturing and supply chains, and business enterprises can be launched to pursue commercialization of such opportunities (see, for example, Love 2020). Here, the underlying value proposition is not the “what”’ (a particular pharmaceutical product) but rather the “how” (highly flexible, distributed manufacturing and supply). The business incentive is driven by the potential to create and participate financially in this new drug-supply paradigm. However, for the new technology to be reviewed, approved, and accepted, it needs to be attached to a product. The logical choice is typically not an innovative pharmaceutical product for which speed to patients could be undermined by a slower, more complex, expensive, and riskier development program. The better choice would appear to be advancing the technology with a well-established or generic product because that would entail less risk, but the effort and cost of gaining approvals for such products manufactured with novel technology might not be sufficient to generate a positive return on investment. Such an innovative enterprise might need exceptionally strong financial backing, faith in the viability and long-term impact of both the technology and business model to succeed, and the wherewithal to improve and adapt as needed. Those challenges are not trivial and will prove too great for some aspiring enterprises to overcome; some will simply fail, be sold, or sell the technology to other businesses. Even if the technologic and transformational potential exists, the business realities in the manufacturing ecosystem of innovators, suppliers, and end-users are not set up for a transformational pace of change. Implementation stalls because the incentives to finance, drive, or accelerate the transformation are insufficient. A final complication is that the fundamental direct role of the regulator occurs at the product-review stage in which attention is appropriately focused on ensuring the suitability of the novel manufacturing system to deliver a high-quality product reliably and is indifferent to business models or manufacturing costs.

Manufacturers of pharmaceutical products have extensive experience with the constraints and burdens of existing manufacturing technologies. They have had to learn to adapt and live with any adverse attributes and have invested to mitigate issues with supply reliability and business exposure. Those companies are generally aware of and interested in the opportunities afforded by manufacturing innovations to overcome and move past the burdens of legacy processes and facilities. However, under what circumstances are there sufficient incentives to invest? If the objective is to introduce new technology as a replacement for older technology in the same supply-chain model, favorable circumstances occur typically when additional, expanded capacity is needed or existing capacity has reached the end of its useful life. Even when such conditions exist, the implementation of innovative technologies must be carefully considered in relation to the portfolio of products for which they would be intended and the reality that each product must be successfully transitioned to the new technology. In the case of generics manufacturers, multiple products must often be transitioned simultaneously. Attendant risks and costs associated with undertaking such an implementation could include the need to increase the redundancy of capacity, to expand inventory stockpiles to ensure continuity of supply, and to address new and unexpected vulnerabilities of manufacturing processes and critical quality attributes discovered during implementation. Those risks and costs are substantial for large pharmaceutical manufacturers and can be insurmountable for smaller manufacturers or contract manufacturing organizations (CMOs).

For manufacturers of commercial products, such risks and costs, coupled with the uncertainties of managing global regulatory acceptance of post-licensure changes, are strong disincentives to pursue innovative manufacturing technology aggressively. For developers of innovative products, it is conceivable that novel technologies can be introduced early in clinical development and track with new product candidates as they mature in the pipeline toward commercialization. That approach has been undertaken by some manufacturers (NASEM 2020a,b), but the timing, success, and breadth of implementation in such cases are inextricably linked to the clinical advancement of the product candidates and therefore fraught with uncertainty: if a product fails in clinical trials, the

manufacturing innovation similarly does not advance. For manufacturers of generic and biosimilar products that were designed and produced by originators many years ago, the challenge of modernizing technology is particularly acute if doing so would increase risk and cost. Given the enormous preponderance of such drugs in the global pharmaceutical landscape, the implications for the overall supply-chain robustness and product quality of having too few incentives are concerning. In the absence of a substantial effort to rebalance incentives, circumstances do not suggest a rapid shift toward adoption of cutting-edge technologies.

The above discussion focuses primarily on incentives from the industry point of view, and this is due to a general perspective that the responsibility for proposing and justifying innovative technologies rests entirely on manufacturers. As the examples above illustrate, the realities of evaluation and approval of pharmaceutical products and associated manufacturing technologies seriously limit the value proposition—and therefore capability—for industry to advance and implement the broad spectrum of potentially available improvements necessary to achieve the future state of a mature, agile, and flexible manufacturing sector in which drug shortages are minimized. Although the need to shift the balance in favor of innovation has been vigorously articulated by FDA leadership, visible actions to propagate that view through the full regulatory network are less evident. Ultimately, it will be essential for incentives to be sufficiently aligned among all stakeholders—otherwise, innovation will continue to advance slowly and haphazardly. The committee concludes that the work of aligning incentives needs to be broadly shared and cannot afford to wait for industry-centric drivers alone to evolve and prevail. A more active, strategic, system-focused effort will be required.

THE NEED FOR GLOBAL CONVERGENCE AND HARMONIZATION

A strong and recurrent theme encountered during this study is the challenge posed by differences in regulatory expectations and requirements of international health authorities. Pharmaceutical companies often aspire to register and commercialize their products in multiple geographic regions or globally, and the cost, effort, and complexity of the endeavor can be daunting or even insurmountable for small manufacturers. To meet chemistry, manufacturing, and control requirements, an extensive dossier must be prepared that provides assurance that the manufacturer can reliably supply a high-quality product that meets accepted quality standards. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Quality Guidelines¹ represent an enormous effort to achieve greater worldwide harmonization of regulatory requirements. Indeed, the principles outlined in the various guidelines constitute a common, aligned framework that has generally supported more uniform quality standards and improved the efficiency of pharmaceutical regulation and the caliber of medicines approved and distributed around the globe. However, even in the case of well-established product categories that are manufactured by using proven technologies, companies regularly experience substantial differences in how guidelines are interpreted by regulatory authorities.

Navigating a path to timely approvals in multiple geographic areas inevitably is an immense accomplishment subject to many twists and turns. The industry experience is that queries, interests, and concerns of individual reviewers and institutional health authorities are still variable and seemingly often arbitrary and inflexible. In the best case, the process can be resource- and time-intensive; manufacturers are often trying to achieve business-critical approvals without creating a patchwork of commitments and quality standards to suit different markets. Such a situation should be avoided whenever possible because it creates logistical challenges and results in a more-complex and less-flexible supply chain if products are made and released to meet the requirements of specific countries. In those cases, manufacturers typically will default to the most conservative and rigorous standard applied by any regulatory authority worldwide even if other authorities would apply different risk algorithms for any given quality or control attribute.

The burden of seeking approvals for multiple geographic areas is great, and including novel manufacturing methods in the approval process increases the effort and cost and carries a greater risk of delays or an inability to register products in some countries. Any progress that can be made to enhance or accelerate regulatory harmonization and consistency will clearly reduce current disincentives for global implementation of innovative manufacturing technology. It should also be noted that the ICH mission does not involve an overt mandate to support and enable manufacturing innovation; such organizations as FDA and the European Medicines Agency should help global health authorities to appreciate the connection between advanced technologies and the resource-efficient supply of safe, effective, high-quality medicines.

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¹ See https://www.ich.org/page/quality-guidelines.

POST-APPROVAL CHANGES: ESSENTIAL FOR ACCELERATING INNOVATION

Another important global regulatory opportunity to support manufacturing innovation pertains to post-approval changes. To create wide-scale change, advanced technology must be applicable to approved products—those being manufactured and supplied to patients. The full complement of commercial pharmaceutical products (including generics)—many of which were developed and registered years or even decades ago—should have legitimate, viable access to post-licensure improvements. Otherwise, the actual implementation and impact of innovation will lag profoundly behind the state of technology with little overall effect on the stability and security of the global supply chain. Conversely, if innovations in manufacturing technology can be expected to apply only to future products, the ability to realize value and return on investment will be constrained by the risks and potentially long timelines associated with research and development. Moreover, there are strong pressures to accelerate development to bring the most promising products to patients faster, and this pressure inevitably leads to a situation in which, even for newly launched products, implementation of cutting-edge technology must be deferred until after initial product launch. Those considerations emphasize that the regulatory path to post-approval changes will be critical in enabling and accelerating manufacturing innovation.

As discussed in the context of incentives and global harmonization, industry’s ability and willingness to pursue post-approval changes have been constrained by several factors. In response, global regulators have recognized the challenges and have sought to develop guidance documents to provide a framework for post-approval changes, of which the most recent and notable is ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.² The guidance is explicitly directed toward the commercial phase of the product life cycle and represents a major effort to address issues that have hindered the full realization of the vision of a more flexible and agile pharmaceutical manufacturing sector that has been advocated for the last 2 decades. The harmonized regulatory tools, enablers, and guiding principles described in ICH Q12 include categorization of post-approval chemistry, manufacturing, and control changes; definition of established conditions; post-approval change-management protocol; and product lifecycle management. They are intended to support innovation and continuous improvement by enabling industry to implement desired post-approval manufacturing changes more efficiently and effectively. With the combination of an effective pharmaceutical quality system, a strong and complementary relationship between regulator assessment and inspection, and detailed guidance for analytic changes made in marketed products, a solid toolkit appears to be in place.

The ultimate success of ICH Q12 will, however, depend not only on the specific merits and comprehensiveness of the guidance itself. It will require an intensive, sustained effort on the part of the industry and regulators to agree on how the guidance will be used in practice. With consistent support and a genuine sense of partnership, experimentation, and continuous adaptation and improvement of the process, the initiative has a chance to make a lasting difference. However, the committee emphasizes that there are important challenges for this guidance to support and affect the full spectrum of pharmaceutical manufacturing enterprises, including not only product originators but also generics manufacturers and CMOs.

CHALLENGES WITHIN THE SPHERE OF FDA INFLUENCE IN SUPPORTING AND ENABLING INNOVATION

FDA is a public-health agency that oversees the quality and efficacy of marketed drugs to ensure patient safety. Its oversight role also includes ensuring patient access to safe therapies, and this means that the agency has a critical role in supporting and enabling manufacturing innovation that can improve product quality and lessen the risk of drug shortages. The importance of that role in supporting innovation is acknowledged and emphasized as mission-critical by FDA leaders in the Center for Drug Evaluation and Research (CDER) in public presentations and various reports.³ CDER has also taken an important step in supporting innovation through the establishment of the Emerging Technology Program in 2014.⁴ Yet the totality of stakeholder experience that has informed this committee indicates that the role of CDER in enabling innovation is underdeveloped, and this underdevelopment jeopardizes the center’s ability to meet its full public-health mission. The themes described in this section were identified as challenges within the sphere of CDER’s authority or influence that affect the implementation of innovative technology by manufacturers. It is

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² See https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf.

³ See https://www.fda.gov/media/93524/download and https://www.fda.gov/media/95444/download.

⁴ See https://www.fda.gov/media/95444/download.

worth re-emphasizing that the committee is fully aware that CDER cannot advance innovation without efforts by other stakeholders in the pharmaceutical manufacturing ecosystem. Success depends on the concomitant actions of other critical stakeholders, especially the industry and policy-makers. However, the committee’s task was to recommend actions that FDA should undertake to prepare for and accelerate adoption of innovative technology in pharmaceutical manufacturing.

Expertise, Capacity, and Culture in the Center for Drug Evaluation and Research

The capability of CDER to evaluate risk to patient safety associated with novel manufacturing technology is linked to technical expertise, capacity, and a culture that actively incentivizes the center’s role in alleviating the risk associated with the implementation of innovation. Several challenges to that capability are described below.

• Breadth of innovative technology. The breadth of innovation in products, manufacturing processes, analytic technology, and control approaches presents staffing and training challenges to ensure that CDER has the expertise necessary for evaluating new technologies. Widely acknowledged shortages of skilled workers in the pharmaceutical industry contribute to the challenge and create competition between the agency and the industry for recruitment and retention of talented staff who have the needed expertise.⁵
• Capacity constraints that affect consistency in evaluating innovative technology. The CDER Emerging Technology Team (ETT) is designed to be a knowledge interface between sponsors of innovative technology and reviewers and inspectors in their evaluation and oversight roles.⁶ The views expressed in the committee’s workshops indicate that although the ETT is valued in its external-interface role, the stakeholder experience has been that internal dissemination of expertise throughout the agency is inconsistent. That suggests that the capacity of the ETT to sustain external engagement with industry, cultivate the internal expertise necessary to inform that interaction, and support the transfer of the expertise to reviewers and inspectors is constrained. The inconsistencies lead to industry’s hesitation to implement innovative technologies because of the expectation that reviewers and inspectors will need to be educated through iterative information requests throughout the life cycle of the product.
• Dissonance between oversight and facilitation roles. CDER’s role in ensuring that industry practices do not lead to unacceptable risk to patients is appropriately and deeply embedded in the culture and practices of the center. However, that posture presents challenges for CDER to support and enable innovation because the regulator and the regulated industry are primed to approach all interactions with formality and caution and thus constrain the shared learning opportunities. The perspective of the stakeholders that informed this committee is that although FDA leadership has encouraged the use of novel technologies to strengthen the robustness of the manufacturing processes for pharmaceuticals, a disconnect between the podium and the practice of front-line regulators erodes the industry’s confidence that an investment in innovative technology will not derail planned regulatory review timelines. The user fees paid by industry provided through the Prescription Drug User Fee Act (PDUFA) provide the agency with substantial funding, and PDUFA requires reviewers to conform to aggressive review timelines to meet performance benchmarks.⁷ The iterations of information requests and reviewer education associated with the first use of an innovative technology create a highly stressful environment in light of PDUFA deadlines for both industry and regulator. Prior reviewer experience with or exposure to new technologies offers important advantages during the review cycle, but mechanisms for that opportunity are highly constrained.

External Perception of Risks and Benefits Associated with Implementing Innovative Technologies

It is evident to the committee that industry decisions to implement innovative technologies do not depend solely on the maturity and readiness of a specific technology itself. Key considerations in implementing innovations are the risk of disrupting timelines to market, the possibility of extensive and expensive efforts to gain regulatory approval, and the potential for substantial post-approval commitments. Although the industry’s perception of risk is influenced by many factors, it appears that the uncertainties associated with regulatory review timelines and overall resource burdens are substantial disincentives to innovate. The agency’s visible posture toward innovation therefore highly influences industry decisions to go to market or to implement innovative manufacturing technology. Although CDER uses guidance documents to represent its posture toward innovation, the timeline and

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⁵ See http://phrma-docs.phrma.org/files/dmfile/TEConomy-PhRMA-STEM-Report-Final.pdf, pp. 16-17.

⁶ See https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program.

⁷ See https://www.fda.gov/industry/prescription-drug-user-fee-amendments/pdufa-vi-fiscal-years-2018-2022.

process for developing and formalizing guidance hamper the effectiveness of this mechanism to signal readiness on a timescale that would support innovative companies.

Industry’s concerns about the readiness of CDER suggest that the following perceived risks are critical factors in business decisions related to innovation in manufacturing processes.

• Protracted or unsuccessful reviews. The approval process for regulatory filings requires the product sponsor to anticipate the data that reviewers might require to demonstrate the identity, safety, purity, and potency of a drug through a consistent manufacturing process. That approach poses a dilemma for sponsors who are introducing novel technologies because either an excess or an insufficiency of data to support the application could place the sponsor (and the agency) at risk of a protracted regulatory review process that could undermine the ability to achieve timely approval. Novel applications that incorporate new types of data or data integration might demand a greater level of communication and comprehension than is manageable by either the sponsor or the reviewer.
• Clarity and consistency in the evaluation of residual risk to product quality. Innovation in process or analytic technology might introduce new uncertainties for product quality that cannot be fully eliminated, especially in the case of complex drug products. It is unclear to stakeholders how the regulators will weigh risk and benefit for innovations that greatly enable flexibility and agility (for example, highly intensified, small-footprint modular systems) and thus address public-health needs but that might present a theoretical quality concern with no clear and cost-effective path to resolution. Industry’s perception is that inconsistencies in this risk–benefit calculus for residual risk will propagate through all stages of review and inspection of the product life cycle.
• Global regulatory environment. As discussed above, the resource-intensive effort to satisfy regulators in multiple geographic areas is a disincentive to implement innovation because it is uncertain whether the benefit outweighs the burden. Industry’s perception that CDER is committed to leading the development of international guidance would heavily influence the balance of this risk–benefit evaluation in favor of innovation.

COMMITTEE RECOMMENDATIONS

CDER’s capabilities and capacity to evaluate innovative technology should be perceived by industry as more certain if the pace of deployment is to increase. This report has identified technologies that are likely to come before CDER in the next 5–10 years. In general, innovations that enable new products to market (for example, patient-centric dosage formulations) have greater business incentives to balance industry concerns with the uncertainties in the regulatory review processes. Decisions to deploy manufacturing innovation to improve supply-chain agility will be more sensitive to the perceived readiness of regulators because access to new markets is not a business driver for this type of innovation. On the basis of that distinction, industry will likely deploy innovations that bring new products to market more quickly than ones that improve manufacturing and supply-chain agility, assuming equivalent technical maturity and no change in external drivers. The status quo is unlikely to support CDER’s objective of reducing drug shortages associated with manufacturing failures related to existing products, including generic drugs. It should be noted that the committee thoughtfully considered the specific challenges that face the generic-drug manufacturers with respect to innovation. The challenges are substantially different from those facing the original product developer because the cost–benefit analysis rarely justifies changing established manufacturing processes for generic drugs except if the original product was manufactured by using an innovative process that must be adopted to produce the equivalent generic product. The committee concludes that the incentives needed to change the calculus for generic-drug manufacturers belong primarily in the policy sphere, not the regulatory sphere. Although FDA should continue to be an influential voice advising policy-makers who are considering ways to lessen the cost pressures and increase the business drivers in favor of innovation to improve quality and increase our domestic supply of generic medicines, the committee does not feel that new recommendations to the agency directed specifically to innovation for generics manufacturing are warranted.

As noted above, CDER’s public-health mission to ensure patient access to safe and efficacious therapies drives the strategic need to facilitate innovation in manufacturing pharmaceuticals. The committee commends CDER for its willingness to examine mechanisms to strengthen the important role that the center plays in changing the status quo, which is too often a paralyzing stasis because of industry’s perception of risk. The overall observation of the committee is that the center’s resources, culture, and practices are tilted so heavily toward its oversight role that it is challenging to support innovation. For CDER to be more effective in supporting innovation, it should address four areas in concert:

• Expertise and capacity of regulators at all stages of product life cycles so that they can apply risk-based evaluation to innovative technologies.
• Mechanisms to decouple consideration of innovative technologies from applications for specific products under review.
• Stakeholder perception of readiness so that stakeholders are assured that innovative technologies will not result in unpredictable resource demands and long review timelines.
• Engagement of CDER staff as regulatory scientists so that precompetitive shared knowledge and principles of practice can be established and inform implementation of innovative technologies.

It should be noted that the first item above refers to internal CDER capabilities, whereas the others refer to positioning the center for more active roles in fostering innovation both internally and externally. Unless CDER acts to strengthen its stance in all four areas, industry will continue its risk avoidance with respect to innovation unless innovation is necessary to bring a new product to market. The recommendations that follow support the development of expertise, expanded capacity, and opportunities to strengthen FDA’s role in incentivizing the use of the innovative technologies to improve the quality and consistency of pharmaceutical manufacturing.

Strengthen Expertise in Innovative Technology Throughout CDER

The committee concludes that expertise in novel manufacturing technology needs to be cultivated not only within the ETT but throughout the center to ensure consistency in review and inspection. The committee recommends that CDER examine internal practices to increase technical fluency among its scientists through such actions as the following:

• Evaluate priorities in hiring and retention practices to determine whether there is appropriate emphasis on acquiring, retaining, and rewarding future-leaning expertise and whether additional flexibility in compensation structures might be necessary to compete for talent and to motivate and support people who demonstrate thoughtful and effective leadership in fostering innovation.
• Ensure that staff-development plans support continuous education in innovative technologies through such mechanisms as dedicated time in performance plans for targeted training and attendance at technical conferences on innovative technologies, periodic rotation of reviewers and inspectors through assignments in the ETT, and mentorships that pair innovation-oriented staff with field inspectors.

Advance Innovative Mechanisms for Evaluating Technology Outside Product Approvals

A consistent theme expressed to the committee is that CDER’s ability to foster innovation is fundamentally constrained by the center’s formal evaluation of technology only as it applies to specific products. It is clear to the committee that any substantial acceleration in implementation of innovative technology requires the center to engage earlier and more broadly in considering the suitability of the novel enabling technologies. Therefore, the committee recommends that CDER create new mechanisms and evaluate, expand, and consolidate existing pilot programs that allow consideration of innovative technology outside individual product submissions to accelerate implementation, lessen risk, and increase regulatory familiarity in ways that are transparent to the pharmaceutical ecosystem. To manage demand, CDER could set priorities for suggestions to consider innovative technologies from industry consortia over those from individual organizations. Consideration of evaluation also could depend on the broad applicability of a technology and the willingness of sponsors to share lessons and outcomes. Although the committee is aware of limitations on the center’s authority for formally reviewing technology outside the context of individual products, the importance of finding a path forward for other types of evaluation is a critical strategic need that should be addressed by the agency. For example, the center should consider more fluid and targeted guidance and participation in other publication mechanisms, such as case studies and white papers. It would be highly valuable to disseminate more timely and smaller units of information on the center’s perspective regarding the maturity and challenges of enabling technologies and likely applications and to allow public comment in an interactive and collaborative environment. Those approaches could be particularly valuable for emerging technologies for which few opportunities for product review have been presented to the agency and for which it might be premature to contemplate meaningful guidance. CDER’s role in stimulating and supporting the International Symposia on Continuous Manufacturing of Pharmaceuticals and associated whitepapers is a good example to build on and might be extended to many of the emerging technologies discussed in this report.

Expand the Scope and Capacity of the Emerging Technology Program

During this study, stakeholders expressed appreciation for the Emerging Technology Program as an effective pilot-scale effort that is recognized as a valuable bidirectional mechanism by which FDA and industry can explore the issues related to innovative manufacturing technology and how they might affect technical development, manufacturing, control, and regulatory expectations. However, there was a consensus that the program would have greater impact if capacity and scope constraints were lessened. The committee recommends expanding the influence of the ETT through the following actions:

• Dedicate independent funding of the ETT to decrease dependence on other CDER organizations and PDUFA-associated constraints and to enable greater external engagement and balance between CDER’s internal priorities and external priorities for implementation of innovations.
• Increase the number of dedicated full-time employees in the ETT to ensure relevant expertise and capacity to evaluate innovative technologies for small-molecule and complex biotechnology product submissions and to ensure effective and consistent dissemination of expertise from the ETT to reviewers and inspectors.
• Broaden the criteria for entry into the Emerging Technology Program to include innovation that is neutral to product quality but enables agility, flexibility, and efficiency in the manufacturing process, the supply chain, or control strategy to encourage deployment of innovations in both new products and post-approval modifications.
• Increase transparency of the capacity of the ETT and program outcomes to inform expectations of program utility, highlight common themes, and inform case studies for implementing innovative technologies in regulatory submissions.

Increase External Engagement to Facilitate Innovation and Increase Awareness of Readiness of CDER to Evaluate Novel Technologies

The committee concludes that increased external engagement speeds shared learning between regulatory and industry scientists and lessens uncertainty in the assessment of risk from the perspective of both parties. The committee recommends that CDER strengthen its external engagement through the following efforts:

• Increase engagement of regulatory scientists with public–private partnerships, nonprofits, and academic institutions in technical activities, such as workshops, case-study and road-mapping exercises, and industrywide initiatives that help to develop a shared sense of purpose, lexicon, and activities to drive innovation and alleviate the risks associated with introducing innovation in manufacturing technologies.
• Increase visible leadership in organizing, planning, and conducting open technical meetings and less structured “listen-and-learn” sessions—hosted by CDER or in partnership with outside organizations—to facilitate a consensus on principles of practice for implementing innovative manufacturing technologies and to encourage sharing of applications by industry groups to the Emerging Technology Program.
• Leverage agency investment, extramural-research funding mechanisms, and partnerships with nonprofit consortia and academia to define research and development priorities, create affordable workforce-development training courses, and facilitate short-term sabbaticals for reviewers and inspectors. Industry consortia—such as the International Consortium for Innovation and Quality in Pharmaceutical Development, the National Institute for Innovation in Manufacturing Biopharmaceuticals (which is sponsored by the Department of Commerce) and the Advanced Mammalian Biomanufacturing Industrial Consortia (which are sponsored by the National Science Foundation)—can serve as mechanisms to share knowledge. Greater leverage of academic partnerships through the FDA-sponsored Centers of Excellence in Regulatory Science or encouragement of the formation of consortia modeled on the Advanced Simulation and Computing Predictive Science Academic Alliance Program, which is sponsored by the Department of Energy, could offer additional opportunities to engage directly in precompetitive research to advance CDER’s research and personnel-development priorities.

Expand Leadership Role in Global Regulatory Harmonization

The heterogeneity of regulatory requirements in various regions is a critical factor in guiding industry’s willingness to implement innovative technologies and in CDER’s strategic objective to foster innovation. As mentioned above, the committee concludes that guidelines, such as ICH Q12, in development are highly effective in reducing real and perceived barriers to post-approval modifications but require sustained leadership by the United States to align global practices. Furthermore, substantial effort is needed to ensure that ICH guidelines are interpreted consistently within CDER. Therefore, the

committee recommends that CDER increase dedicated resources and incentives to support greater emphasis on consistency in implementation of existing ICH guidelines and to enable leadership in ICH working groups to accelerate harmonization. To complement ICH-focused efforts, CDER should consider and pursue more direct interaction with key regulatory agencies through information exchange, training, and mechanisms to support mutual recognition programs for inspections. Where possible, FDA should emphasize advancement of innovative manufacturing technology as an explicit purpose and benefit of harmonization activities.

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