16 Apr 2024 | Renee Boerner, Dave Malliaros, Norris Pyle
One of the many challenges around developing cell and gene therapy products is establishing representative potency methods. In 2011, the FDA released the Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products, which supported a phase appropriate approach to method development. However, as some cell and gene therapy products have orphan indications, and first-in-human clinical trials may be used for supportive safety and efficacy claims in marketing applications. As such, product potency needs to be established using a representative and validated method at this early stage.
To help navigate establishment of potency at all stages, FDA has released a new draft guidance document, Guidance for Industry: Potency Assurance for Cellular and Gene Therapy Products (Dec 2023). Potency assurance focuses on more than just the potency method and refers to a risk-based strategy to assure that cell and gene therapy products are safe, efficacious, and capable of achieving the desired therapeutic effects in patients. This draft guidance outlines a risk-based, multi-faceted, progressive approach applicable to all stages of a product’s life-cycle called potency assurance. Development of a potency assurance strategy includes:
Other reasons to conduct clinical trials in Australia include:
- Understanding the products mechanism of action (MOA), which may involve multiple steps;
- Evaluation of the product MOA using nonclinical studies supported by analytical development for conducting MOA-related product characterization studies;
- Process development studies to identify the critical process parameters (CPP) which affect potency-related critical quality attributes (CQA) and development of an appropriate process control strategy;
- A GMP manufacturing process and associated control strategy including materials management and in-process analysis, to ensure the production of batches of consistent potency;
- Analytical development and Quality control implementation of validated methods, including potency methods, for lot release and stability testing for assurance that the product consistently meets defined specifications;
- An effective pharmaceutical quality system (ICH Q10, Pharmaceutical Quality System) which includes quality risk management.
This multi-disciplinary holistic potency assurance strategy includes risk management and life-cycle management from a global perspective. Risk management is more effective when a defined Quality Target Product Profile is available (ICH Q8). The QTPP is defined as “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product” and it takes into consideration the product’s MOA, clinical indication, and route of administration. Using formal risk assessment tools, evaluations should be conducted to understand what factors may affect the potency of the product from the time of manufacturing initiation through the time of drug administration to the patient.
Regardless of the phase of development, the potency assurance strategy should be included in Module 3 of the IND. If potency assay(s) are not available for early phase development, the control strategy should focus on how the other aspects (previously mentioned above) provide adequate potency assurance. However, for clinical studies which involve significant risk or are intended to support efficacy claims, the potency assurance strategy should include at least one assay (physicochemical or bioassay). Typically, multiple release assays, each of which quantitates a potency-related CQA, are leveraged, with appropriate acceptance criteria established for the product which allow for rejection of sub-potent lots. The inability to provide adequate assurance of potency may render a Phase 2 or Phase 3 study deficient to provide substantial evidence of effectiveness and lead to a clinical hold. Additionally, the absence of an appropriate potency assurance approach may render comparability assessments between early and late-stage manufacturing processes inadequate, which could prevent early clinical data from being leveraged in the marketing application. Therefore, consultation with the FDA and other global Health Authorities on your potency assurance strategy is recommended across all stages of development.
Regardless of where you are with developing a potency assurance strategy, Syner-G Biopharma Group can help. Our Technical team can assist with cell and gene therapy process development, analytical development, and manufacturing strategies; our Quality team can provide quality risk management expertise; and our Regulatory Sciences and Services team, including Regulatory CMC, can guide strategic interactions with global Health Authorities, and prepare IND/BLA/MAA documentation and submissions.
David Malliaros, Ph.D.
Director, CMC Development & Project Management
Dave has over 30 years of experience in the pharmaceutical, biotechnology and immunodiagnostic industries. He has expertise with several different types of molecules, platforms and programs that include monoclonal antibodies, fusion proteins, AAV gene therapy vectors for rare diseases, peptides, vaccines, and small molecules.
Before joining Syner-G, Dave was employed as an independent consultant. He also assumed positions of increasing responsibilities throughout his career and successfully led small groups and larger departments at companies ranging from start-ups to large organizations.
Dave’s areas of expertise focus on analytical technologies and quality control. He has also worked extensively with CDMOs for over a decade. He understands the complexities and logistical challenges working in the virtual world and is insightful and a problem solver.
He has contributed to various regulatory filings including INDs, BLAs and NDAs focusing on Module 3 of the Common Technical Document.
Dave has published in various journals during his academic and industrial career and has presented at various conferences. He has also taught undergraduate and graduate level courses, most recently at Northeastern University in Boston where he taught a course, Quality Control & Security Validation Issues.
He earned his Ph.D. in Chemistry (Biochemistry concentration) at the University of Lowell. (Now the University of Massachusetts, Lowell) in Lowell, Massachusetts and was a postdoctoral fellow at Harvard University of Public Health/Harvard Medical School in Boston. He received his BS degree from the University of Massachusetts, Amherst.
Norris Pyle
Director CMC, Regulatory Affairs
Norris has over 25 years of experience in the pharmaceutical and biotechnology industries. He is a highly regarded Regulatory Affairs, CMC professional with proven success in investigational and marketing regulatory applications for companies across multiple therapeutic areas, including oncology, and infectious diseases.
Norris has served as a regulatory lead or significant contributor for the approval, launch and maintenance of eight US commercial products, and collaborating within regulatory for commercial approvals in Europe and Australia.
At Syner-G, Norris is responsible for supporting CMC aspects of small molecule and biologic products across all stages of development (IND, CTA/IMPD, BLA, NDA, MAA). His experience includes vaccines, cellular-derived products, antibody-drug conjugates and mRNA products.
Before joining Syner-G, He utilized his regulatory expertise at GSK where he was the US Regulatory Lead for Shingrix. Prior to GSK, he initiated his regulatory experience at Wyeth Pharmaceuticals. His past experience also includes parenteral formulations and manufacturing, as well as heading up the clinical supply department.
Norris earned his BS in Pharmacy from the Philadelphia College of Pharmacy and Science.
Renee J. Boerner, PhD
VP, Regulatory Affairs
Renee has over 25 years of experience in the pharmaceutical and biotechnology industries. She is a highly regarded Regulatory Affairs, CMC, and Quality professional with proven success in investigational and marketing regulatory applications for small and mid-sized companies across multiple therapeutic areas, including oncology, CNS, and infectious diseases.
Renee has served as a regulatory lead or significant contributor for the approval of four US commercial products, including the primary FDA contact for 1 NDA and 1 BLA and collaborating with commercial partners for approvals in Europe, Taiwan, and South Korea.
At Syner-G, Renee is responsible for establishing standards and strategies for worldwide regulatory submissions supporting multiple therapeutic areas across all stages of development (IND, CTA/IMPD, BLA, NDA, MAA). She also provides strategic regulatory support, specializing in biologics and advanced therapies (vaccines, cellular-derived products including extracellular vesicles, and gene therapies).
Before joining Syner-G, she utilized her regulatory expertise at several organizations, including Bavarian Nordic, Argos Therapeutics, and BioDelivery Sciences International, where her responsibilities included establishing and leading regulatory teams, creating and implementing regulatory strategies, and contributing to Modules 1-5. Prior to Regulatory Affairs, Renee was responsible for the Analytical and Formulation development group supporting the clinical development of numerous biopharmaceuticals at Diosynth Biotechnology.
Renee earned her PhD in Biochemistry from the University of Minnesota, Twin Cities, MN, and a BS in Biochemistry from the University of Wisconsin, Madison, WI.