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Introduction

In 2002, the U.S. Food and Drug Administration (FDA) launched the Pharmaceutical Quality for the 21st Century Initiative to encourage adoption of innovative technologies that would lead to an agile, flexible pharmaceutical manufacturing sector.¹ The goal was to encourage a transition to manufacturing processes and approaches that could produce high-quality drugs reliably without extensive regulatory oversight (NASEM 2020a). Much progress has been made toward that goal as the industry has developed and advanced new technologies, but more progress is required as recent natural disasters and the coronavirus pandemic have revealed vulnerabilities in supply chains and highlighted the need to modernize pharmaceutical manufacturing further. To facilitate that modernization, the FDA Center for Drug Evaluation and Research (CDER) strives to foster adoption of innovative technologies by the pharmaceutical industry. To assist those efforts, 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 for products regulated by CDER. In response to that request, the National Academies convened the Committee to Identify Innovative Technologies to Advance Pharmaceutical Manufacturing, which prepared this report.

THE PHARMACEUTICAL INDUSTRY TODAY AND INNOVATION

The pharmaceutical industry is a heterogeneous ecosystem that consists of five broad categories of organizations:

1. Large multinational, research-intensive companies represented by trade associations, such as the Pharmaceutical Research and Manufacturers of America and the Biotechnology Innovation Organization, which traditionally have developed and brought to market patented drug products.
2. Generic-drug companies, represented by the Association for Accessible Medicines, that supply the huge number of medicines whose patents have expired, for which a market is established, and which account for nearly 90% of the prescriptions written in the United States (IQVIA 2019).
3. A broad spectrum of start-up and medium-size companies that innovate in the discovery of novel therapies, especially biologics, and innovative drug-delivery technologies.
4. A variety of contract organizations that offer pharmaceutical-product development and manufacturing services to the first three categories of organizations.
5. Established and start-up technology vendors that provide the process equipment, sensors, analytic tools, and information technology; associated services; and next-generation technology in this space.

Although FDA and regulatory agencies in the European Union and Japan have encouraged manufacturing innovations throughout the entire industry, the innovations in pharmaceutical manufacturing that are the focus of this study are generated largely by categories 1 and 3. The generic companies (category 2) have not generally been the source of manufacturing innovations because they need to replicate the product performance achieved by the originators of patented products and to do so at as low a cost as possible. Those constraints limit the time and resources allotted for the development of innovative manufacturing processes. The contract organizations (category 4) generally do not lead with innovations; rather, they offer such technologies in response to customer demands or, in a

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¹ See https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/pharmaceutical-quality-21st-century-risk-based-approach-progress-report#intro.

few cases, in partnership with innovators in category 1. Although technology vendors (category 5) also typically operate in response to market pull, the rising interest in manufacturing innovations has led to a growing technology push by technology providers, especially those of sensing and process equipment.

Collaborative efforts to foster innovation have resulted in industry consortia, such as BioPhorum,² and in university–industry–government consortia, such as the National Institute for Innovation in Manufacturing Biopharmaceuticals³ and LyoHub.⁴ Those consortia have produced technology roadmaps that have identified manufacturing technology gaps—for example, for the biopharmaceutical industry⁵ and for such specific technologies as lyophilization⁶—and offer promising solutions. Technology gaps have also been identified and research funded by philanthropic organizations, such as the Bill & Melinda Gates Foundation, typically to address needs of health care in underdeveloped countries.⁷

The innovations identified by the roadmaps, other scientific literature, and the committee’s expertise typically fall into four categories:

• Specific operations in drug-substance manufacturing, including integration of steps through intensification, use of microfluidic formats, replacement of traditional separation and purification processes with membrane technologies, new synthesis routes involving electrochemistry or photochemistry, and co-processing of active and excipient components.
• Specific technologies in drug-product manufacturing, such as additive manufacturing modes, continuous lyophilization, highly automated and robotics-enabled aseptic filling, microwave-based drying, microparticle formation, and nanoparticle-based delivery systems.
• Process sensing and control, modeling, and data-analytics technologies, including multiattribute sensing, sensors that exploit a wide range of wavelengths, model-predictive and plantwide control strategies, integrated use of digital twins in manufacturing operations, and condition-based monitoring and management of processes.
• Organization of manufacturing processes, including integration of all the processing steps from synthesis of an active pharmaceutical ingredient to final drug product (end-to-end), use of continuous manufacturing, modularization of manufacturing operations, and downsizing of manufacturing scale to personalized production at point of sales or administration.

Those and other innovations are discussed further in the chapters that follow.

THE FOOD AND DRUG ADMINISTRATION AND INNOVATION

CDER approves drug-product applications, and the technologies and processes used to manufacture the products are evaluated solely as part of the application process for the specific products. CDER does not regulate or approve technologies outside the scope of product submission. Thus, the pharmaceutical industry has traditionally been hesitant to pursue innovations, given the perception that introducing new technologies could delay, impede, or complicate the approval process. To address that tension, CDER created the Emerging Technology Program and Team (ETT), which works with pharmaceutical companies that are considering innovations at the early stages to try to reduce barriers to adoption of innovative technologies.⁸ Also as part of its efforts, CDER tries to stay abreast of technologies that it might see within the timeframe of 5–10 years and asked the National Academies to assist it in that effort.

STATEMENT OF TASK

The committee that was convened as a result of the CDER request included experts in innovative pharmaceutical manufacturing, process engineering, formulations and drug delivery, data science and machine learning, and regulatory compliance. (Appendixes A and B provide biographic and disclosure information, respectively, on the committee.) The committee was asked to identify emerging technologies and challenges that might prevent their adoption and to recommend ways of overcoming any regulatory challenges. 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. The verbatim statement of task is provided in Box 1-1.

THE COMMITTEE’S APPROACH TO ITS TASK

To accomplish its task, the committee held two large public workshops to inform the study process and drew

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² See https://www.biophorum.com/.

³ See https://niimbl.force.com/s/.

⁴ See https://pharmahub.org/groups/lyo/about.

⁵ See https://niimbl.force.com/s/niimbl-roadmaps and https://www.biophorum.com/download/executive-summary/.

⁶ See https://pharmahub.org/groups/lyo/lyohub_roadmapping.

⁷ See https://www.gatesfoundation.org/What-We-Do/Global-Health/Innovative-Technology-Solutions.

⁸ See https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program.

speakers from categories 1, 3, and 4 noted above and academic contributors who represent research groups that work in partnership with the various industrial organizations. Workshop agendas are provided in Appendix C, and the proceedings are freely available on the National Academies Press website (NASEM 2020a,b) and are provided in Appendixes D and E. The committee also held two webinars to get further input from FDA staff and from the generics-manufacturing sector. It considered technology roadmaps and other scientific literature and held six committee meetings to deliberate on its findings and recommendations and prepare its report.

The committee recognizes that various terms in the pharmaceutical industry have often been used inconsistently. To ensure clarity, the committee has defined, in Box 1-2, several terms that are used throughout this report. Also, the terms pharmaceutical industry and biopharmaceutical industry are often used to distinguish between small-molecule manufacturers and biologics manufacturers. For simplicity in this report, the committee generally uses the term pharmaceutical industry as an all-encompassing term; distinctions are made where needed.

ORGANIZATION OF THIS REPORT

This report is organized into six chapters and five appendixes. Chapters 2 and 3 describe innovations in manufacturing of drug substances and drug products, respectively. Chapter 4 discusses innovations in control approaches. Chapter 5 describes innovations in organizing manufacturing networks. Each chapter briefly describes various technologies and possible technical and regulatory challenges specific to each and provides suggestions for overcoming the regulatory challenges. Chapter 6 provides some general observations, describes some overarching challenges, and concludes with some recommendations for overcoming the challenges. Appendixes A and B provide biographic and disclosure information, respectively, on the committee, Appendix C provides workshop and webinar agendas, Appendix D provides the proceedings of the innovations workshop, and Appendix E provides the proceedings of the workshop on technical and regulatory barriers to innovation.

REFERENCES

NASEM (National Academies of Sciences, Engineering, and Medicine). 2020a. Innovations in Pharmaceutical Manufacturing: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/25814/innovations-in-pharmaceutical-manufacturing-proceedings-of-a-workshop-in-brief (accessed August 27, 2020).

NASEM. 2020b. Barriers to Innovations in Pharmaceutical Manufacturing: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/25907/barriers-to-innovations-in-pharmaceutical-manufacturing-proceedings-of-a-workshop (accessed August 27, 2020).