By Mark F. Witcher, Ph.D.
Cellular and gene therapies, sometimes called advanced therapy medicinal products (ATMPs), represent a very rapidly emerging field of biotechnology with tremendous promise for future therapeutic applications. A reasonable question is: Are the methods used for developing the current generation of biopharmaceuticals, monoclonal antibodies, hormone replacements, etc., applicable to the next generation of biotech ATMPs? Or more importantly, can the similarities and the differences between the two generations of products be used to build methods that improve the development and commercialization of all types and future generations of biopharmaceutical products? In my opinion, while there are significant differences, the basic principles for developing both are nearly identical, requiring a clear understanding of the primary development and manufacturing goals for all biopharmaceutical products.
The two generations have significant differences in their business and reimbursement models, life cycle durations, patient selection, methods of administration, supply chain issues, etc. However, some very significant similarities can be identified. Both involve extremely complex products manufactured through very complicated processes. Both have a significant number of critical quality attributes (CQAs) that determine a product’s safety and efficacy. But, very importantly, both have unknown and unmeasurable product attributes that can be classified as unknown-CQAs (U-CQAs) that very likely also have a significant impact on the product’s safety and efficacy.1 Control of U-CQAs can likely only be achieved by careful control of the manufacturing processes over the pre-clinical, clinical, and commercial manufacturing life cycle to assure control of the processes’ behavior and performance as both the CQAs and U-CQAs are produced. The level of U-CQAs is likely even higher in cellular and gene therapies because of the complex nature of the cellular products and the more intricate and semi-random incorporation of the gene therapy products into the patients’ genetic structures.
Thus, all biopharmaceutical products have the same manufacturing problems that can best be solved using the same approaches and methods during their development and manufacturing life cycles, including a product’s path through the regulatory approval processes. Although different therapies will likely reach different kinds of product attributes, the methods used to follow the paths can be essentially the same. The industry as a whole will be far more effective if it uses the same methods for all types of biopharmaceutical products. Methods based on sound science and basic engineering principles will be far more effective in solving very complex problems and providing effective communication platforms with regulatory agencies.
For an industry that is unfortunately largely currently focused on compliance2 as a design criterion, the new generation of ATMPs can present a wide variety of problems because many compliance standards have not yet been identified or established. Further, compliance standards beyond vague good manufacturing practices (GMPs) may never be desirable because of the complex, ever-changing definition of these products. In addition, these products may separate out into large multifaceted families of therapies based on genetic and epigenetic differences between groups of patients and various diseases.
If the industry can focus on prospectively building appropriate methods for achieving excellence rather than seeking compliance with poorly defined guidelines to address the fundamental life cycle challenges, the industry can more effectively achieve high product quality. If common methods based on sound principles are identified and widely used, the biopharmaceutical industry may also greatly reduce the development time for new products.
The industry basically needs two types of methods for developing complex manufacturing processes. The first is a method for managing the manufacturing process’ life cycle. This approach was initiated using ICH Q8 and the FDA’s 2011 Process Validation Guidance3,4 and further expanded by using lifecycle process development and validation (LPDV) concepts.5,6 LPDV is built around four basic questions: What, How, Will it work, and Did it work? These four questions are basic requirements for all processes and provide a universal framework that can be used to develop fundamentally sound methods required for manufacturing complex products using complicated processes.
When supported by a well-structured design space (ws-DS) and quality by design (wQbD), LPDV provides an effective tool for managing all types of process life cycles, especially the difficult problem of controlling U-CQA.6 LPDV focuses on building control strategies within the ws-DS for controlling both the CQAs of the final product and the process’ behavior over the development life cycle to assure successful commercialization of the product conceived and initially tested in early clinical trials.1
The second method uses quality risk management (QRM) tools initially described by ICH Q9.7 However, the methods recommended in Q9, such as FMEA (failure modes and effects analysis), etc. have proven to be ineffective.8 These methods do not properly address the risk’s uncertainty of knowledge levels and probability of occurrence. 9,10 If the risks are viewed as being caused by input threats passing through a process to produce a risk consequence, a more structured approach is accessible for quickly assessing risks as part of a system risk structure (SRS).9 The uncertainty of the structured risks can then be assessed using prospective causal risk models (PCRMs) to estimate the knowledge level and likelihood of the risk consequence’s occurrence.10 While SRS and PCRM might provide better approaches for managing risks, the biopharmaceutical industry and regulatory agencies must work diligently on better QRM methods to quickly and efficiently assess, manage, accept, and communicate the wide variety of risks necessary to make both proteins, ATMPs, and future generations of biopharmaceuticals.11
- Witcher, M. F., “Phase III Clinical Trials – Ever Wonder Why Some Products Unexpectedly Fail?” Pharmaceutical Engineering iSpeak Blog, Aug. 7, 2019. https://ispe.org/pharmaceutical-engineering/ispeak/phase-iii-clinical-trials-ever-wonder-why-some-products-unexpectedly-fail
- Shanley, A., “Moving From Compliance to Quality." BioPharm International 32 (8) 26–28 (2019). http://www.biopharminternational.com/moving-compliance-quality
- FDA (CDER/CBER/CVM) – Guidance for industry: Process validation: general principles and practices. Jan. 2011, Rev 1.
- FDA (CDER/CBER) – Guidance for industry: Q8(R2) pharmaceutical development. Nov. 2009. ICH, Rev 2.
- Witcher, M.F. “Expanding the process validation paradigm and applying it to the biopharmaceutical product lifecycle from development through commercial manufacturing.” Pharmaceutical Engineering, Jan. 2013; 33(1): 1–8.
- Witcher, M.F., “Integrating Development Tools into the Process Validation lifecycle to achieve six sigma pharmaceutical quality.” BioProcessing Journal, 17 (Apr. 2018). https://doi.org/10.12665/J17OA.Witcher.0416
- FDA (CDER/CBER) – ICH Q9 – Quality Risk Management.
- Giannelos, K., et al. “RIP Spreadsheets and Fishbones: Their Time Has Come and Gone.” Pharmaceutical Engineering iSpeak Blog. https://ispe.org/pharmaceutical-engineering/ispeak/rip-spreadsheets-and-fishbones-their-time-has-come-and-gone#
- Witcher, M.F. “Analyzing and managing biopharmaceutical risks by building a system risk structure (SRS) for modeling the flow of threats through a network of manufacturing processes.” BioProcessing Journal, 16 (Sept. 2017). https://doi.org/10.12665/J16OA.Witcher
- Witcher, M. F., “Understanding and Analyzing the Uncertainty of Pharmaceutical Development and Manufacturing Execution Risks using a Prospective Causal Risk Model (PCRM).” Accepted by BioProcessing Journal on Jul. 9, 2019.
- Witcher, M. F., “Stop Talking about Risk, Get Serious about Developing Effective Risk Management Tools,” ISPE Pharmaceutical Engineering iSpeak Blog, June 19, 2019. https://ispe.org/pharmaceutical-engineering/ispeak/get-serious-about-developing-effective-risk-management-tools
About the Author:
Mark F. Witcher, Ph.D., has over 35 years of experience in biopharmaceuticals. He is currently a senior consultant with Brevitas Consulting. Previously, he worked for several engineering companies on feasibility and conceptual design studies for advanced biopharmaceutical manufacturing facilities. Witcher was an independent consultant in the biopharmaceutical industry for 15 years on operational issues related to: product and process development, strategic business development, clinical and commercial manufacturing, tech transfer, and facility design. He also taught courses on process validation for ISPE. He was previously the SVP of manufacturing operations for Covance Biotechnology Services, where he was responsible for the design, construction, start-up, and operation of their $50-million contract manufacturing facility. Prior to joining Covance, Witcher was VP of manufacturing at Amgen. You can reach him at firstname.lastname@example.org