Regenerative medicine, as defined by the National Institutes of Health, is the “process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects” (NIH, 2013). The multidisciplinary field of regenerative medicine encompasses many areas of study, such as tissue engineering, gene and cell therapies, the development of cell-free materials designed to aid in tissue regeneration in vivo, and three-dimensional scaffolding. In addition to relying on scientific experts in the drug and biotech industry, those involved in the research and development of regenerative medicine therapies are increasingly drawing on the unique expertise of regulatory scientists, engineers, physicians, and patients to inform an integrated and efficient development process.
Although regenerative medicine has great potential for producing both health and economic benefits, this relatively new field faces unique regulatory and manufacturing challenges. The reliance of regenerative medicine products on living cells and tissues, which are inherently dynamic, adds a fundamental complexity to the manufacturing and scale-up process that is not present in the manufacture of most non-biologic therapies. Since the variety of cells and tissues used in regenerative medicine is vast and
1 The planning committee’s role was limited to planning the workshop, and this Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.
the characteristics of cells can differ between in vitro and in vivo environments, defining and assessing the quality of products is challenging. In addition, it can be difficult to accurately measure or test for critical quality attributes (CQAs) (i.e., physical, chemical, biological, or microbiological characteristics that should be within an appropriate limit, range, or distribution in order to ensure the desired product quality2) of cells because these attributes can change over time as they are affected by the cell maturation process and exposure to environmental stimuli.
In October 2016 the Forum on Regenerative Medicine hosted a public workshop,3 State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies. Discussions at the workshop focused on challenges along the path to bringing promising new therapeutics to market (NASEM, 2017). Several critical challenges to commercialization were described, including the need for reliable methods to scale up the production of cell-based therapies in a safe and cost-effective manner that fits within regulatory parameters (Haddock et al., 2017). Identifying and measuring markers of quality in regenerative medicine products is one possible way to support the consistent development of higher-quality products that are both safe and potent. Forum members were interested in examining issues related to CQAs for cell-based therapies and also how deep characterization of cells could potentially lead to a more streamlined manufacturing process.
Therefore, on June 26, 2017, the Forum on Regenerative Medicine hosted a public workshop in Washington, DC, titled Navigating the Manufacturing Process and Ensuring the Quality of Regenerative Medicine Therapies in order to examine and discuss the challenges, opportunities, and best practices associated with defining and measuring the quality of cell and tissue products and raw materials in the research and manufacturing of regenerative medicine therapies.4 The goal of the workshop was to learn from existing examples of the manufacturing of early-generation regenerative medicine products and to address how progress could be made in identifying and measuring CQAs. While there are increasingly more regenerative medicine products in the clinical pipeline and on the market,
2 FDA defines the term “critical quality attributes” in the Guidance for Industry, Q8(R2) Pharmaceutical Development document, which is available at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf (accessed August 28, 2017).
3 The Forum on Regenerative Medicine held a previous workshop titled State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies in October 2016. Workshop materials including presentations, videos, and the Proceedings of the Workshop can be found at http://www.nationalacademies.org/hmd/Activities/Research/RegenerativeMedicine/2016-OCT-13.aspx (accessed August 22, 2017).
there is not yet consistency in the approaches to cell sourcing, product characterization, manufacturing processes, or logistics and delivery models. This may be due in part to the rapid evolution of the field and the wide variation in regenerative medicine products. Thus, it was hoped that by bringing the regenerative medicine community together to discuss the development of common approaches and standards for crosscutting tools, measurements, functional assays, and manufacturing platforms, the community could identify common challenges and share innovative new practices that might help advance the field and support valuable collaboration. The workshop also addressed the challenges of designing and adhering to standards as a way of helping those who are working to scale up processes and techniques from a research laboratory to the manufacturing environment. Stakeholders, including research scientists, clinicians, regulators, and representatives from patient groups and pharmaceutical and biotech companies, presented their perspectives and participated in discussions throughout the day. The specific workshop objectives are listed in Box 1-1.5
Producing regenerative medicine therapies relies on using advanced manufacturing technologies. The workshop explored the different steps along the research and clinical development pathway from the point when
5 While the workshop objectives focused on exploring the importance of cell populations for defining quality and purity, the concepts discussed during the workshop include other raw materials that are important to manufacturing and developing standards for regenerative medicine therapies.
a promising discovery is made in the laboratory to when it has become a therapeutic product available on the market. Speakers highlighted lessons from their current experiences and addressed issues regarding scaling and commercialization, identifying and measuring the CQAs of regenerative medicine products and their source cells and raw materials, developing new production technologies for regenerative medicine, and understanding regulatory challenges and opportunities. In each of the five sessions, experts discussed the main challenges to and opportunities for progress as well as the research and regulatory efforts aimed at addressing those challenges.
Inherent Challenges to Preparing and Regulating Biologics
Many of the approaches and practices that the day’s presentations and discussions would highlight are rooted deeply in the history of biologics development, said Jay Siegel, a forum co-chair and the chief biotechnology officer and head of scientific strategy and policy at Johnson & Johnson. Vaccine production is centuries old, he noted, with the use of antisera products to treat infections going back to the 1890s. Monoclonal antibodies and cell and gene therapies are examples of more recent biologic products used to treat disease. Although each of these biologics has its unique manufacturing obstacles, he said, they share common challenges, such as difficulty in characterizing the final product and the variations that inherently occur when living cells and tissues from several different sources are used. Unlike the case with non-biologic drugs, there is no method to sterilize a cell-based biologic in its final packaging, Siegel said, and the cell-based biologics can be reactive, immunogenic, and relatively unstable.
Today’s regulatory requirements for any human or animal therapeutic are based on regulations created in the early 1900s, Siegel said. After a batch of horse antisera used to treat diphtheria resulted in the death of 13 children in 1901, it was discovered that one of the horses used to produce that antisera had contracted tetanus, but without a means of tracing the source of the contaminated serum, regulators were unable to identify the underlying problem efficiently. The incident gave rise to the Biologics Control Act of 1902, which mandated that vaccine producers be licensed annually, undergo regular inspections, and implement new labeling protocols for their products.6 This regulation was followed by the Federal Food and Drugs Act of 1906, which outlawed the production of any foods or drugs that were produced using inferior or impure ingredients or that
6 More information about the Biologics Control Act of 1902 can be found here: https://history.nih.gov/exhibits/history/docs/page_03.html (accessed August 22, 2017).
made misleading claims about their health effects or benefits.7 Years later, Congress passed the Food, Drug, and Cosmetic Act of 1938 that authorized the U.S. Food and Drug Administration (FDA) to oversee drug safety and to address issues of quality and consistency. This law formally classified biologics as drugs, relying on the stipulations of 1902 Biologics Control Act to regulate them. Today, biologics are regulated under the Food, Drug, and Cosmetic Act of 1938 and the Public Health Service Act of 1944, which gave the U.S. Public Health Service control over biologic products (FDA, 2012).
The challenge with producing biologics, Siegel said, is how to assess quality and consistency when, unlike a defined drug molecule, it is impossible to characterize every detail of the final product. This can only be addressed by controlling the manufacturing process, controlling raw materials, testing donors, and developing standardization processes and reliable assays to characterize the unique markers of consistency, efficiency, and potency for a product, said Siegel.
Additional unique factors are spurring the rapid evolution of the regenerative medicine industry, said Claudia Zylberberg, workshop co-chair and the president and chief executive officer of Akron Biotech. Regenerative medicine is entering an era of automation, she said, which will require shifting from a model of product development based on vertical integration to one based on horizontal integration that relies on manufacturers, customers, suppliers, and researchers working together to create manufacturing solutions for new therapies. Open and frequent communication, in addition to the implementation of effective methods for data sharing, will be vital in implementing this approach, she added. Zylberberg called on the workshop participants to embrace collaboration in order to address the shared challenges of developing and implementing manufacturing standards, identifying CQAs, creating new technologies to enable product consistency and analytics, and improving comparability between regenerative medicine products. “Serving patients worldwide and helping them not only live longer, but better, is our community’s responsibility,” she said.
Workshop speakers were asked by Stephen Oh, workshop co-chair and the acting deputy director of the Division of Cellular and Gene Therapies in the Office of Tissues and Advanced Therapies at FDA, to emphasize how important it is to develop a clear scientific understanding of what is involved in characterizing the cell populations of a regenerative medicine product and in testing them for quality and purity. Oh also asked the speakers to discuss the challenges and successes associated with identifying
7 More information about the Federal Food and Drugs Act of 1906 can be found here: https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/ucm148690.htm (accessed August 22, 2017).
and measuring CQAs as well as possible approaches for developing effective regulatory and manufacturing standards. Finally, he asked that the speakers explore specific mechanisms and technologies that might improve the field’s ability to ensure that regenerative medicine products are safe and effective and that they can be manufactured efficiently.
Following this introductory chapter, Chapters 2 through 6 explore issues in the manufacturing of regenerative medicine therapies, discuss the obstacles that hinder progress, and identify opportunities to address these obstacles. Chapter 2 provides background and context about the manufacture of regenerative medicine therapies by discussing the challenges and opportunities associated with translating discoveries from the laboratory to production and navigating the process of scaling manufacturing of new therapies. This chapter also presents examples of the methods and capabilities for manufacturing and collecting quality control data to inform the transition from research and development to the implementation of good manufacturing practices (GMPs).
Chapter 3 addresses issues related to identifying and measuring CQAs of regenerative medicine products and source cells. This chapter discusses methods and processes used to identify and measure CQAs for raw materials and regenerative medicine products.
Chapter 4 describes various technologies that facilitate the efficient and cost-effective development of products that meet manufacturing and regulatory standards, and it explores opportunities for new technologies and manufacturing models to increase efficiency and quality. The chapter also discusses novel and more precise in-process and final-release testing technologies and reviews the existing manufacturing infrastructure available in academic centers and the commercial sector.
Chapter 5 considers the regulatory landscape for regenerative medicine, including developing standards, enforcing regulations, and meeting the needs of patients. Chapter 6 summarizes the lessons learned throughout the day and discusses ways to support the development, manufacture, and regulation of safe and effective regenerative medicines.