By Maria-Teresa Gutierrez-Lugo, Ph.D., Office of Biotechnology Products, OPQ/CDER/FDA
The end of the COVID-19 public health emergency (PHE) in the United States appears to be on the horizon and although the emergence of SARS-CoV-2 variants is still a challenge, tremendous progress on bringing possible therapies to the public was achieved in very short time. The first SARS-CoV-2 neutralizing monoclonal antibody (mAb) for the treatment of patients with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization was authorized (EUA 90, Nov. 9, 2020) approximately eight months after the PHE declaration by the Secretary of the Department of Human and Health Services (March 27, 2020) justifying authorizing the emergency use of certain drugs and biological products during the COVID-19 pandemic. By February 2022, five more SARS-CoV-2 neutralizing mAb products were authorized for emergency use (EUA 91, EUA 94, EUA 100, EUA 104, and EUA 111)1.
As we transition into 2023, we are now reflecting on what we learned from this experience and whether any of the chemistry, manufacturing, and control (CMC) regulatory strategies applied to the development of SARS-CoV-2 neutralizing mAbs can inform or can be used for the development of other mAbs.2, 3, 4
The need for therapies to address the SARS-CoV-2 PHE – i.e., COVID-19 pandemic – required industry and regulators to use existing and new CMC strategies to expedite the development of SARS-CoV-2 neutralizing mAbs.2, 3, 4 From the CMC regulatory perspective, the acceptability of these strategies considered, among other factors, benefit/risk, the scientific knowledge available at the time, and regulatory expectations for supporting initiation of clinical studies and eventually issuing an emergency use authorization (EUA).
The benefits of faster drug development are evident, especially for products addressing unmet medical needs. While it is important to initiate clinical studies of promising lead drug candidates as soon as possible and align the CMC development program with an accelerated clinical development timeline, a robust CMC program should be designed and implemented to ensure drug quality. Compressing, abbreviating, or postponing CMC activities until later in development can be of high risk and in some cases can potentially delay approval of a product if the CMC program is deficient.
In this article, I’ll briefly analyze how some of the CMC strategies applied to the development of SARS-CoV-2 neutralizing mAb products helped expedite their development and explore their potential applicability to the development of mAbs for other indications.2, 3, 4
Challenges And Examples Of CMC Strategies
The development of SARS-CoV-2 neutralizing mAbs for emergency use posed multiple challenges from the identification of lead candidates through having limited time to generate product-specific knowledge and data to develop optimized manufacturing processes and control strategies. The rapidly changing knowledge of SARS-CoV-2 and disease pathology remain significant challenges. For example, little is known about long COVID.5 The emergence of SARS-CoV-2 variants has outpaced product development timelines. Manufacturing capacity was impacted by supply chain constraints, shortages of materials, and in some cases, inspections of manufacturing facilities were delayed by travel restrictions due to the COVID-19 pandemic.
Compressing, abbreviating, or postponing CMC activities until later in development can be of high risk and in some cases can potentially delay approval of a product.
FDA’s existing guidance and newly published guidance documents were utilized for the development of products addressing the COVID-19 PHE.6 From the CMC regulatory perspective, two key FDA guidances provided important considerations for their development. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use provided considerations for developing products for feasibility clinical trials in serious or immediately life-threatening conditions7 and Development of Monoclonal Antibody Products Targeting SARS-CoV-2, Including Addressing the Impact of Emerging Variants, During the COVID 19 Public Health Emergency8 provided examples of CMC strategies for expediting development of these products. The CMC strategies described in these guidances can be organized into the three general categories described below.
Strategies That Are Appropriate For Limited Early Phase Development To Enable First In Human Studies
The first category is strategies that enabled the rapid introduction of a product into clinical trials by deferring some of the early development activities (e.g., production of a clonally derived cell line) for later in the development program. The agency also provided flexibility in the timing (e.g., full study reports for cell bank safety testing at a prespecified time when sufficient interim results were provided) and amount of data (limited initial stability data) submitted to the original IND. These strategies carry different levels of risk. The agency assessed the adequacy of each strategy on a case-by-case basis and considered, among other factors, the benefit/risk and proposed mitigation strategies to ensure safety and phase-appropriate product quality. For example, in some cases, enhanced control strategies (e.g., additional testing) were implemented to mitigate risks associated with using a stable bulk culture (SBC) instead of a clonally derived cell line. In other cases, when full study reports were not available at the time of IND submission for some key safety testing, an agreement was implemented not to dose patients until the results of the full study reports were provided for review and until the agency provided concurrence.
Some strategies (e.g., the use of SBC) may be considered more broadly, but other strategies, such as delayed safety testing, may only be reasonable in another pandemic, epidemic, or other public health emergencies. Regardless, one should consider the risks associated with these approaches in the context of the overall development program, including the nature of the molecule under development. For example, the use of an SBC for producing clinical materials could allow clinical studies to be initiated sooner. However, there could be risks associated with potential product quality drift and comparability when a heterogeneous cell substrate is used to produce clinical materials. The lack of comparability between clinical materials after manufacturing changes would question the relevance of the data generated with the pre-change product, which can potentially jeopardize the entire development program and result in delays in the development program.
Strategies That Leverage Experience From Licensed mAbs And Those In Development
The strategies in the second category are those related to prior knowledge and platform technologies. This category is probably the one that has the most potential for applicability to other mAbs. Platform approaches are frequently applied to different areas of drug development, such as, for example, in screening platforms for identification of potential leads, in product formulation development, manufacturing processes,9 and control strategies,10, 11 etc. The term “platform” can have a variety of meanings, and here I do not try to define it for a specific regulatory purpose. Rather, I use it broadly to include leveraging in-house data for like molecules. Critically, the ability to use “platform” information has long been open to the biopharmaceutical industry, and the limitations for it have largely been scientific rather than regulatory in nature, namely linking the leveraged knowledge to the applicability of the case for which companies sought to leverage it. The pandemic did not create the idea of leveraging platform knowledge but, rather, reinforced its potential value.
It is important to note that in some cases manufacturers skipped process optimization for these products because their goal early in the pandemic was to address the emergency, not, for example, to optimize yields or increase robustness.
The biopharmaceutical industry applied its own in‐house technologies, platforms, and knowledge in different areas of mAb development to expedite the availability of SARS-CoV-2 neutralizing mAbs for emergency use. Frequently, it created a starting point from which to begin product development. In some cases, platform manufacturing processes started from an in-house cell line to platform unit operations and platform manufacturing processes were used with little additional optimization. It is important to note that in some cases manufacturers skipped process optimization for these products because their goal early in the pandemic was to address the emergency, not, for example, to optimize yields or increase robustness.
Some in the biopharmaceutical industry have noted that very few new technologies were created and applied to address the COVID-19 pandemic because there was no time to perform critical development activities. While this is perhaps unsurprising in a public health emergency, the need for innovation is crucial to overcome current challenges and to develop new technologies that would address unmet needs. This is a profound reminder of the need to support innovation long before the technology may be needed. Nevertheless, it is reasonable to consider and use prior knowledge, including platform knowledge to support and advance product development.
There are many opportunities for leveraging industry knowledge, data, and experience in platform technologies. In fact, platform approaches were possible and worked for SARS-CoV-2 neutralizing mAbs because industry and regulators have been applying them already. But the applicability of platform and prior knowledge is limited by the data and information submitted in an application. For the agency to assess the adequacy of a proposed platform to support the development of a mAb, industry is expected to provide the scientific rationale for the applicability of such knowledge to the proposed product. To be more specific, it is not sufficient to just state, e.g., it is based on “platform knowledge.” Platform and prior knowledge have been and can continue to be applied; however, industry needs to be willing to do the work up front and willing to share not just the information and data but also the argument for its relevance for the agency to assess its adequacy.
Strategic Timing For Interaction With Regulators At Critical Elements Of The Development Program
The third category of strategies involves timing interactions with regulators at critical elements of the development program. It includes, for example, discussions with the agency regarding prospective comparability plans for major manufacturing changes (e.g., scale up, site transfers, transition to a clonally derived cell bank) or critical data supporting manufacturing process consistency and control strategies for supporting an EUA. This interaction allows for discussion of key development aspects to reduce regulatory risks and encourage careful planning of manufacturing changes to minimize comparability risks.
Early and frequent communications with the agency along with abbreviated review timelines and rapid FDA guidance development helped expedite development of mAb products to fight SARS-CoV-2. These approaches allowed open scientific discussions, clarified regulatory expectations in a timely manner, and facilitated the initiation of FIH studies and the use of these products under EUA, including addressing emerging variants.
Mechanisms for discussions with the agency at critical points of a development program are already in place through meeting requests,12 including those related to expedited programs.13 During the COVID-19 pandemic, meetings and reviews for investigational products were expedited and more frequent. In a PHE situation, the need for such rapid interactions is obvious; however, this dynamic is resource-consuming and should be used judiciously.
COVID-19 Taught Industry And Regulators To Collaborate Better
Many of the strategies discussed above were used to support IND submissions and EUA requests for SARS-CoV-2 neutralizing mAbs. While we acknowledge that an EUA and a marketing application (e.g., a biologics license application or BLA) are different regulatory mechanisms for very different purposes14 and that regulatory flexibility was used for EUAs to address the COVID-19 PHE, analyzing and reflecting on how the CMC regulatory strategies applied to SARS-CoV-2 neutralizing mAbs helped expedite their development can help to inform when it would be appropriate to consider these regulatory strategies for other mAb development programs. This decision considers the context of the need, such as, for example, whether there is a public health emergency, a life-threatening condition, or an unmet medical need. Other considerations may include the benefit/risk, the intended purpose of the product (treatment vs. prophylaxis), the uncertainties present and the mitigation strategies, and available knowledge of the disease and the technology applied.
It is important to highlight that industry embarked on the development of these products, not without high business risks. In addition to the various CMC strategies referenced above, some manufacturers conducted parallel development with at-risk up-front investments to increase the likelihood of a successful development program. For example, parallel processes (e.g., using different cell substrates) and parallel scale-up and site transfers were conducted as alternatives in case there were problems with one of the options.
The need for potential therapies to address the COVID-19 PHE prompted us to leverage prior knowledge and platform technologies and to test new approaches. This experience also allowed us to identify new opportunities where additional development and knowledge is needed. We were also challenged to adapt quickly to evolving knowledge and a changing environment. The progress in developing products to address the pandemic was possible through industry, regulators, and partnership with other stakeholders and, hopefully, this experience can help to better prepare us for future challenges.
- https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs, retrieved February 11, 2023.
- Kelley, B. Developing therapeutic mAbs at pandemic pace. Nat Biotechnol 38, 540–545 (2020). https://doi.org/10.1038/s41587-020-0512-5.
- Higgins MF, Abu-Absi N, Gontarz E, Gorr IH, Kaiser K, Patel P, Ritacco F, Sheehy P, Thangaraj B, Gill T. Accelerated CMC workflows to enable speed to clinic in the COVID-19 era: A multi-company view from the biopharmaceutical industry. Biotechnol Prog. 2022 Dec 22:e3321. doi: 10.1002/btpr.3321. Epub ahead of print. PMID: 36546782; PMCID: PMC9880703.
- McGovern ĀT, Salisbury CM, Nyberg GB. The pandemic and resilience for the future: AccBio 2021. Biotechnol Prog. 2022 Jan;38(1):e3207. doi: 10.1002/btpr.3207. Epub 2021 Sep 24. PMID: 34463436; PMCID: PMC8646774.
- https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html, retrieved February 11, 2023.
- https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-related-guidance-documents-industry-fda-staff-and-other-stakeholders, retrieved February 11, 2023.
- FDA guidance: Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, February 1997. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/points-consider-manufacture-and-testing-monoclonal-antibody-products-human-use, retrieved February 11, 2023.
- Development of MAb Products Targeting SARS-CoV-2, Including Addressing the Impact of Emerging Variants, During the COVID-19 Public Health Emergency, February 2021.
- ICHQ11, Development and manufacture of Drug Substances (Chemical entities and Biotechnological/Biological Entities.
- ICHQ2R2, Draft guideline Validation of Analytical Procedures.
- Krause SO. Using Analytical Platform Technologies to Support Accelerated Product Development—Concept Review and Case Study. PDA Journal of Pharmaceutical Science and Technology. Vol 76 (3), 2022.
- Formal meetings between the FDA and sponsors or applicants of PDUFA products draft guidance for Industry, September 2017. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products-guidance-industry, retrieved March 7, 2023.
- Expedited Programs for Serious Conditions- Drugs and Biologics, May 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics, retrieved March 7, 2023.
- https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization, retrieved February 11, 2023.
About the Author:
Maria-Teresa Gutierrez-Lugo, Ph.D., is a product quality review chief in the Office of Biotechnology Products, OPQ, CDER, FDA, where she oversees the review of monoclonal antibodies and other biotechnology products, including biosimilars from development, license applications, and post-approval as well as Emergency Use Authorization of COVID-19 neutralizing antibodies. Gutierrez-Lugo conducted postdoctoral research at the NIH and at the University of Arizona. She holds a Ph.D. in chemical sciences from the National Autonomous University of Mexico.
This publication reflects the views of the author and should not be construed to represent FDA’s views or policies.
The author thanks Marjorie Shapiro, Ph.D., Joel Welch, Ph.D., and Steven Kozlowski, Ph.D., of the Office Pharmaceutical Quality, Office of Biotechnology Products, CDER, FDA, for comments and discussions on this manuscript.