Summary

Ensuring patient access to safe and efficacious drugs is a primary public-health mission of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). To accomplish its mission, CDER has a critical role in fostering manufacturing innovations that can improve product quality and prevent drug shortages that have become all too frequent. The coronavirus pandemic has also highlighted the need to modernize pharmaceutical manufacturing so that drugs can be produced swiftly and reliably. The current status compromises the ability to harness the power of science and technology fully and make vital products as available and accessible as possible. Many innovative technologies have been developed in recent years to advance pharmaceutical manufacturing, but much remains to achieve an agile, flexible pharmaceutical manufacturing sector that can produce high-quality drugs reliably without extensive regulatory oversight—a goal that FDA leadership has promoted. To assist its efforts to realize that goal, CDER asked the National Academies of Sciences, Engineering, and Medicine (the National Academies) to identify emerging technologies—such as product technologies, manufacturing processes, control and testing strategies, and platform technologies—that have the potential to advance pharmaceutical quality and modernize pharmaceutical manufacturing in the next 5–10 years for products regulated by CDER.¹ The agency also asked that technical and regulatory challenges be identified and suggestions provided to overcome the regulatory challenges.² It is important to note that the committee was not asked to recommend what innovations should be pursued but rather was asked to identify innovations that FDA is likely to see in the next 5–10 years. As a result of the request, the National Academies convened the Committee to Identify Technologies to Advance Pharmaceutical Manufacturing, which prepared this report. Here, the committee highlights some key innovations, identifies underlying regulatory constraints and potential impediments at FDA to foster manufacturing innovations, and provides some overarching recommendations and concluding statements.

KEY MANUFACTURING INNOVATIONS ON THE HORIZON

In this report, the committee has described many innovations to modernize the manufacture of drug substances and drug products,³ to advance new control approaches, and to develop integrated, flexible, and distributed manufacturing networks. The technologies highlighted here perhaps represent the most probable and extensive opportunities to advance pharmaceutical manufacturing within 5–10 years. The committee has represented many of these innovations as classes rather than individual technologies; it is likely that diverse innovative technologies within a class will be implemented on similar timelines. Details of these and other innovations are provided in the report’s chapters with a discussion of technical and regulatory challenges that they would face.

• New routes to drug substances. Innovations in manufacturing technology to synthesize active pharmaceutical ingredients (APIs) or drug substances include photochemical and electrochemical approaches, biocatalysis, cell-free protein synthesis, and cell-based biosynthesis that uses alternative hosts. All those technologies are gaining traction and are motivated by product innovations and by opportunities to improve process efficiency, speed, cost, throughput, safety, and environmental sustainability. They also have the potential to improve the assurance of

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¹ The committee notes that products regulated by CDER do not include vaccines, blood products, and cell and gene therapy products.

² The full task statement is provided in Chapter 1 of this report.

³ A drug substance (or active pharmaceutical ingredient) is any substance or mixture of substances that is intended to be used in the manufacture of a drug product. A drug product is the physical form in which drug substances are delivered to patients; common types are tablets, capsules, injections, and infusions.

• product quality by reducing the risk of byproduct formation or other undesired variants.
• Co-processed APIs. An innovation in the manufacture of APIs is the addition of a nonactive excipient or carrier to improve yields or to manipulate attributes of a process stream to achieve a desired outcome. For example, co-processed APIs might be advantageous in particle formation, crystallization, or drying operations to improve the stability of a desired solid state or to tailor physical properties of the drug substance.
• Process intensification. Technologic innovations that create more efficient, higher-yielding processes and enable smaller manufacturing footprints and reduced capital and operating costs are characterized as process intensification. Anticipated innovations include the integration or reduction of multiple traditional unit operations, the replacement of batch processes with continuous formats, and the incorporation of recirculation and recycle approaches. Such innovations afford improvements that are also foundational to the development of modular systems and flexible, distributed manufacturing networks. They will also help to overcome some of the most difficult impediments in supply-chain investment and decision-making and make it more feasible for redundant and surge capacity to be created and thus improve overall capability and security of the pharmaceutical supply.
• Additive manufacturing. Product formation by three-dimensional printing (additive manufacturing) is a radical alternative for manufacture of drug products in comparison with conventional tablet production. There are various approaches, but all use precise layering of materials in a successive, specific pattern to arrive at the final dosage form. The technologies can tailor the desired characteristics of a drug product—for example, its geometry, porosity, and API composition—and customize them for a specific indication or an individual patient requirement. Additive manufacturing also enables monitoring and acceptance or rejection of a product at the individual-dose level and can be scaled down to a compact size and thus potentially support highly distributed manufacturing.
• Advanced process control and automation. 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 capabilities of various 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 automated operation and management of manufacturing.
• Modular systems. Modular systems are composed of interconnected unit-operation “modules” that can be arranged and adapted to enable a single facility to manufacture a large array of drug products. They present an opportunity to reshape the very nature of manufacturing facilities and the global supply chain and offer the possibility of creating integrated, flexible, and distributed manufacturing networks. These modular systems can be easily replicated and deployed quickly in an existing facility or to other locations and thus provide the ability to respond rapidly to patient and health-care system needs that range from personalized therapies to varying patient needs across geographic and demographic boundaries. It is important to note that integrated, flexible, and distributed manufacturing networks 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 innovations described here represent exciting opportunities to modernize pharmaceutical manufacturing, but many challenges must be overcome for them to achieve widespread adoption. The following sections highlight some of the overarching issues that challenge adoption of innovative technology.

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 only in the context of an individual product. That is, technology is evaluated for its suitability to deliver a high-quality product consistently and is not approved outright on its own. That regulatory approach places a large burden on any manufacturer that wants to use an innovative technology in support of product approval for the first time. Even if regulators have had exposure to and are generally supportive of 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 might need to approve the product, and introducing an innovative technology might result in unanticipated activities, costs, and time that could affect the financial viability of the product. Unless there is sufficient incentive for a manufacturer to bear that burden 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. Even when a first such approval is achieved, it will take much time and effort—through the review and approval of other products—before a particular manufacturing technology is broadly and successfully adopted.

THE NEED FOR ALIGNMENT OF INCENTIVES TO ADVANCE TECHNOLOGY INNOVATION

Strong and consistent views have been expressed regarding the effect of incentives and disincentives on innovation. The committee concludes that although technical and regulatory challenges described in this report pose hurdles, none likely presents a greater barrier than insufficient, conflicting, or countervailing incentives. In some cases, there is a strong incentive for a manufacturing innovation, as when a pharmaceutical product depends on the technology for its production. However, many cases are not so clear-cut, for example, when a manufacturing innovation is a central feature of a potentially disruptive business model, such as small-scale, automated, integrated, and portable drug-manufacturing systems. In that situation, the business incentive is the potential to create and participate financially in a new drug-supply paradigm, but the disincentives begin to surface when one considers how to get the technology reviewed, approved, and accepted. In the current regulatory framework, the technology has to be part of a drug-approval process. If it is attached to an innovative product, there is a risk that the product could be delayed because of a slower, more complex, expensive, and riskier development program. If it is attached to established products, the effort and cost of gaining approvals for products manufactured with the innovative technology might negate a positive return on investment. Other scenarios can provide similar examples of competing incentives and disincentives. Ultimately, there is always a question of whether the incentives for the industry to invest in innovative technologies are sufficient.

This discussion assumes that the responsibility for proposing and justifying innovative technologies rests entirely with manufacturers. The committee finds that incentives need to be sufficiently aligned among all stakeholders and concludes that the work of aligning incentives should be broadly shared and not wait for industry-centric incentives alone to evolve and prevail. A more active, strategic, and system-focused effort will be required if the desired agility and flexibility of the manufacturing sector are to be achieved.

THE NEED FOR GLOBAL CONVERGENCE AND HARMONIZATION

Differences in regulatory expectations and requirements of international health authorities pose considerable challenges. Given that pharmaceutical companies often aspire to register and commercialize their products in multiple geographic regions, often globally, the cost, effort, and complexity of this endeavor can be daunting. International guidelines have been developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 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. The industry experience is that queries, interests, and concerns of individual reviewers and institutional health authorities remain highly 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. Thus, 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 reduce disincentives for global implementation of innovative manufacturing technology.

POST-APPROVAL CHANGES: ESSENTIAL FOR ACCELERATING INNOVATION

The regulatory requirements concerning changes in the manufacturing process after a product has been approved or licensed are an impediment to advancing innovative technologies. To create wide-scale change, com-

mercial pharmaceutical products—many of which were developed and registered years or even decades ago—need legitimate, viable access to post-licensure manufacturing improvements after the product is approved. Otherwise, the 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 investments will be constrained by the risks and potentially long timelines associated with research and development.

ICH has developed guidance (Q12) that is directed explicitly to the commercial phase of the product life cycle and constitutes 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 ultimate success of the guidance will hinge not only on the specific merits and comprehensiveness of the guidance itself but on 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 ICH guidance has a chance to make a lasting difference.

CHALLENGES IN THE FOOD AND DRUG ADMINISTRATION

FDA leadership has acknowledged and emphasized its role in supporting manufacturing innovation in presentations and various reports, and CDER has taken important steps to foster innovation by creating the Emerging Technology Program and the associated Emerging Technology Team (ETT) in 2014. However, the views expressed in the workshops that were held by the committee to gather information indicate that the role of CDER in enabling innovation is underdeveloped, and this underdevelopment jeopardizes its ability to ensure access to safe and efficacious drugs reliably. The committee identified two areas in which the agency can play a prominent role in addressing impediments: (1) the expertise, capacity and culture of CDER and (2) the external perception of risks and benefits associated with implementing innovative technologies. The committee emphasizes that it is fully aware that CDER cannot advance innovation without efforts by other stakeholders in the pharmaceutical manufacturing ecosystem; success will depend 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.

The ability of CDER to evaluate the risks to patient safety that are associated with innovative manufacturing technology is related directly to its technical expertise, capacity, and culture in supporting manufacturing innovation. The agency faces several challenges. First, the breadth of innovation in products, manufacturing processes, analytic technology, and control approaches present staffing and training challenges for CDER to ensure that it has the necessary expertise to evaluate new technologies. Second, there appear to be capacity constraints that affect consistency in evaluating innovative technologies. Views expressed in the committee’s workshops suggest that the Emerging Technology Program lacks sufficient capacity to sustain external engagement with industry, cultivate internal expertise necessary to inform that interaction, and support the transfer of the expertise to reviewers and inspectors. 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 a product. Third, there appears to be dissonance between the oversight and facilitation roles. Although FDA leadership has encouraged the use of novel technologies to strengthen the robustness of pharmaceutical-manufacturing processes, 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 Prescription Drug User Fee Act (PDUFA) provides the agency with substantial funding through user fees paid by industry and requires reviewers to conform to aggressive review timelines to meet performance benchmarks. 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 the industry and regulators. Prior reviewer experience with or exposure to new technologies offers important advantages during the review cycle, but such learning opportunities appear to be rare.

Industry decisions to implement innovative technologies clearly do not depend solely on the maturity and readiness of a specific technology itself. Rather, a key consideration is the risk that implementing an innovation might disrupt product timelines to market, and the uncertainties associated with the regulatory-review timelines and resource burdens appear to pose a substantial disincentive to innovate. The committee identified three specific concerns that appear to be critical factors in business

decisions to innovate. First, there is the question of what data will be needed for regulatory filings to demonstrate the identity, safety, purity, and potency of a drug that is manufactured with innovative technology. Second, there is no clarity or consistency in the evaluation of residual risk to product quality. An innovation might introduce new uncertainties regarding product quality that cannot be fully eliminated, especially for complex drug products, and it is unclear how regulators will weigh risks and benefits associated with innovations that greatly enable flexibility and agility and thus address public-health needs but might present a theoretical quality concern with no clear and cost-effective path to resolution. Third is the issue of the global regulatory environment. As discussed, the resource-intensive effort to satisfy regulators in multiple geographic areas is a disincentive to implement innovation, and the committee perceives that a commitment from CDER to lead the development of international guidance would heavily influence the industry’s risk–benefit evaluation in favor of innovation.

OVERARCHING COMMITTEE RECOMMENDATIONS

As noted, CDER’s public-health mission to ensure patient access to safe and efficacious drugs drives the strategic need to facilitate innovation in manufacturing pharmaceuticals. The committee commends CDER for its willingness to examine mechanisms to strengthen its important role in changing the status quo, which often appears immutable given the industry’s perception of risk. However, the committee’s overall observation is that the center’s resources, culture, and practices are tilted so heavily toward its oversight role that it is challenging to support innovation. Unless CDER addresses the challenges raised in the previous section, industry will continue its risk avoidance with respect to innovation unless innovation is necessary to bring a new product to market. Thus, the committee offers five overarching recommendations to strengthen FDA’s role in fostering the use of innovative technologies to improve the quality and consistency of pharmaceutical manufacturing. The committee 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 also undertake actions in support of shared goals. Details associated with these recommendations are provided in Chapter 6.

• Strengthen expertise in innovative technology throughout CDER. The committee concludes that expertise in innovative manufacturing technology should be cultivated not only within the ETT but throughout CDER to ensure consistency in review and inspection. It recommends that CDER examine internal practices to increase technical fluency among its scientists through such actions as evaluating priorities in hiring and retention practices and ensuring that staff-development plans support continuous education on innovative technologies.
• Advance innovative mechanisms for evaluating technology outside product approvals. It is clear to the committee that any substantial acceleration in the pace of implementation of innovative technology requires CDER to engage earlier and more broadly in considering the suitability of 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. Although the committee is aware of limitations of the center’s authority for formally reviewing technology outside the context of individual products, finding a path forward for other types of evaluation is a critical strategic action that should be undertaken by the agency.
• Expand the scope and capacity of the Emerging Technology Program and the Emerging Technology Team. In the committee’s workshops, stakeholders expressed appreciation for the Emerging Technology Program as an effective pilot-scale effort and agreed that it would have a greater impact if capacity and scope constraints were lessened. The committee recommends expanding the influence of the ETT through the following actions: (1) dedicate independent funding to the ETT; (2) expand the number of dedicated full-time employees in the ETT; (3) broaden the criteria for entry into the program to include innovations that are neutral to product quality but enable agility, flexibility, and efficiency in the manufacturing process, control strategy, or supply chain; and (4) increase transparency of the capacity of the ETT and program outcomes.
• Increase external engagement to facilitate innovation and increase awareness of readiness of CDER to evaluate innovative technology. The committee concludes that increased external engagement speeds the exchange of knowledge between regulatory and industry scientists and lessens both parties’ uncertainty in the assessment of risk. 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 insti

• tutions in technical activities; increase visible leadership in organizing, planning, and conducting open technical meetings and less structured “listen-and-learn” sessions; and leverage agency investments, 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.
• Expand the leadership role in global regulatory harmonization efforts. The heterogeneity of regulatory requirements in various regions is a disincentive to the industry to implement innovative technology and impedes CDER’s strategic objective to foster innovation. As noted, the committee concludes that guidelines, such as those being developed by ICH, 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. 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.

CONCLUDING STATEMENT

A common concern expressed throughout this study was that the agility, robustness, and overall maturity of the pharmaceutical-manufacturing sector need attention and investment to overcome the many potential vulnerabilities that could threaten access to products essential to public health. There is a strong consensus that advanced manufacturing technologies can and must play a central role in creating this future agile, flexible industry that can produce high-quality drugs reliably. However, what became evident to the committee in conducting its analysis is that many stakeholders have a role to play and can influence the adoption of innovative technology. Reflecting on the various parties and the overall system responsible for delivering high-quality medicines, the committee concludes that no single organization or entity—however well-financed, large, powerful, or influential—has either the capability or the mandate to lead the broader community to this desired future state on its own.

The historical pace of improvement arguably has suffered at the whole-system level because of the fundamental structural barriers and 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—not the technologies deployed to manufacture them. That reality has important implications both for industrial developers and manufacturers of products and for regulatory authorities that review and oversee them. Thus, neither manufacturers nor regulators 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 mandate, no concerted driving force or “invisible hand” is guiding the system toward an overall desirable end point. A dramatic change in the relationship and collective leadership among entities most able to affect the outcome will be required. The committee concludes that FDA, as a critical participant and node of influence, can and should play a direct leadership role and emphasizes that FDA needs to support the ability and willingness of manufacturers to lead and drive innovative change.