Living cells are foundational technologies in the biopharmaceutical industry. They serve as hosts for production of therapeutic proteins, models by which to test clinical candidate efficacy and potency, tools for developing and validating bioanalytical methods, and even as medicines. To enrich our understanding of the past 20 years of bioprocessing, BPI distributed questions to supplier companies, including those that have spurred on innovation in the manufacture of critical starting materials. Below, representatives from ATCC reflect on advances in developing, banking, and authenticating cell lines and cellular by-products that are used in biopharmaceutical research, development, and manufacturing.
The Business of Biotechnology
Shalmica Jackson: The global biopharmaceutical market is growing at an unprecedented rate and is predicted to reach a value of >US$400 billion by 2025, with a healthy compound annual growth rate (CAGR) of 8.1% (1). Most of that growth can be attributed to the rising prevalence of chronic and acute diseases and to the rising global geriatric population. However, market growth has been spurred on by the need for a more extensive drug-development pipeline. Companies also are pursuing biosimilars aggressively, searching for ways to increase the efficiency of manufacturing technologies and reduce production costs.
In the 40 years since US Food and Drug Administration (FDA) approval of the first biotechnology-derived product, a recombinant human insulin produced by Eli Lilly, the most notable business development has been the emergence of collaborations between biotechnology and pharmaceutical companies. The creation of a distinct biopharmaceutical entity speaks volumes about the willingness of â€” and urgency for â€” such companies to enter partnerships that would advance science and create medical breakthroughs.
Many large pharmaceutical companies were slow to enter the biopharmaceuticals industry but now are moving forward in it through joint ventures, licensing agreements, and acquisitions. Steadily, a pattern of increasing interdependence between the pharmaceutical and biotechnology industries has manifested as both sectors sought to share risk and decrease costs for research. Now, the affinity between biotechnology and pharmaceuticals is accepted and well established. These strategic partnerships also have resulted in discovery of novel drug targets and technological innovations that have increased the productivity of existing unit operations. Together, the biotechnology and pharmaceutical industries are making science and bioproduction faster and more reliable than ever before.
Changing Needs for Starting Materials
James Fantuzzo, Shalmica Jackson, and Fang Tian: For nearly a century, ATCC has been a trusted global partner for high-quality cell production, banking, and authentication. We have provided cells that were used to discover and develop some of the most notable advancements in the life-sciences industry. Over the past 20 years, our work has changed, but our commitment to providing and protecting critical starting materials for pharmaceuticals and biologics remains the same.
With the shift from synthetically derived small-molecule drugs to an emphasis on complex, large-molecule therapeutics produced using cell lines, including cell and gene therapies (CGTs), the pharmaceutical industry has transformed. Moreover, end-user expectations for starting-material quality have increased.
From a technological standpoint, our work has evolved from simply characterizing morphological criteria with advanced tags, probes, and microscopes to making highly sensitive assessments of cellular functionality with better readouts, high-content imaging, screening of metabolic reactions, and electrophysiological measurements. Genomic and molecular analyses, including gene sequencing and genome editing, have accelerated biomedical advances. Workflows also have begun incorporating more automation than ever to increase throughput.
We have observed improvements to both user-interface graphics and equipment operation and diagnostics. The movement of data to cloud-based software suites is enhancing system oversight and reliability, helping to ensure that all computer systems are operational and compliant. Centralized monitoring is improving traceability and data storage capacity. As a global biological resource leader with extensive process, production, and engineering controls, ATCCâ€™s aseptic operations are designed to ensure compliance with current regulatory standards.
Critical Regulatory Developments
Patrick Laverty and Toni Pipes: For ATCC, the most significant regulatory development has been the advent and rapid growth of CGT applications. Cells and their by-products continue to have ground-breaking success as therapeutics and diagnostics, paving the way for new businesses and technologies in the biotechnology industry. Needs for innovative production methodologies, reproducible aseptic procedures, improved microbiological and molecular testing, and thorough authentication have created an ecosystem of businesses supporting the research, development, and production of biologics. Breakthrough CGT technologies and applications also are driving new regulations, guidance, and best practices from the FDA and other regulatory agencies to ensure that biologics are safe and effective for the public.
As a leader in biological standards and resources, with experts in cell processing and authentication and almost a century of success in preserving and storing biological materials, ATCC is primed to be a reliable partner in the advancement of public health. We recognize the stringent compliance requirements of the industry and therefore are adapting our offerings to support not only research, but also the regulated development, production, and testing of biologics. ATCC is committed to providing current good manufacturing practice (CGMP) cell banking and supportive services to ensure that biologics are safe, effective, and of the highest quality, and we continue to augment our capabilities in support of regulatory requirements and customer needs.
Cells in the Age of Advanced Therapies
Catherine Fox and Brian Shapiro: We hope to find increased development of personalized medicines. Currently, circulating tumor cells can be analyzed at the genomic level without harming a patient. We also hope for continuing innovation in cell culture techniques. There is much promise for autologous therapies, for which patient cells are cultured and expanded outside of the body and then reintroduced. That approach has been used effectively to address many needs, from treating dermatological conditions to repairing damaged bone marrow. Advances also have been made in developing chimeric antigen receptor (CAR) T-cell therapies, in which patient T cells are modified genetically to destroy tumors.
To expand the accessibility of personalized medicine, the biopharmaceutical industry must consider limiting factors and invest in technologies that will help it to develop associated diagnostics and regimens. One such consideration is the need for CGMP bioproduction and storage of physical materials, including cells and their derivatives. Biorepositories such as ATCC that bank and process cells under CGMP standards are already critical for advancing the development of cell-based therapies, vaccines, and other biological products. Such organizations will grow in importance over the coming decades.
Another consideration is the need for tools that will quicken the pace of bioproduction. For example, vaccines are essential for disease prevention; however, their manufacture often is limited by low-yielding upstream processes. To address such concerns, developers need improved versions of the legacy cell lines that were used during therapeutic development.
ATCC is fulfilling such needs by using clustered, regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) gene-editing technologies to develop knock-out cell lines that can produce viral stocks at much high titers than the parental lines. Knock-out signal transducer and activator of transcription protein 1 (STAT1-KO) cell lines are not only good candidates for enhancing virus titers during vaccine development, but also useful tools for packaging viral vectors that are used to deliver DNA sequences into target cells for applications such as gene therapy and cancer immunotherapy.
1 Global Medicine Spending and Usage Trends: Outlook to 2025. IQVIA Institute for Human Data Science: 28 April 2021; https://www.iqvia.com/insights/the-iqvia-institute/reports/global-medicine-spending-and-usage-trends-outlook-to-2025.
James Fantuzzo is director of bioproduction; Catherine Fox is segment marketing specialist; Shalmica Jackson, PhD, is marketing segment manager; Patrick Laverty, PhD, is vice president of quality, safety, and product compliance; Toni Pipes is senior manager of quality assurance; Fang Tian, PhD, is director of biological content; and corresponding author Brian Shapiro, PhD, is scientific content specialist, all at ATCC, 10801 University Boulevard, Manassas, VA 20110; email@example.com; 1-703-365-2700; https://www.atcc.org.