A recent survey of experts from 145 cell and gene therapy (CGT) companies revealed the ability to appropriately optimize the manufacturing process as their top concern. Red flags have been raised for quite some time that much of what is pouring out of R&D and research institutes with seemingly great promise is not readily reproducible1. The challenges that come with cell and gene therapy products are steeper than with traditional medicine. Due to the personalized nature of cell and gene therapies, we are dealing with starting materials that possess the complexities and unknowns of human cells, difficult to grasp processes, and, almost always, much smaller hypothesis test sample sizes. As a result, the current process optimization paradigm for small-molecule therapies is likely to fall flat for CGT.
The lifecycle-stage appropriate process optimization standards that are defined in guidances ICHQ8 – ICHQ12, including the disciplines of Pharmaceutical Development / Quality by Design, Quality Risk Management, Knowledge Management, and Product Lifecycle Management, respectively, are not required by the regulators to be implemented in order to obtain agreement that a CGT product may move from the lab, to the clinic, and beyond. Until this becomes a level playing field of regulatory requirements, it is up to the Sponsor to understand that embracing these principles is in their longer-term scientific, financial, and ethical interests. Without doing so, programs will be delayed, opportunities for life changing therapies lost, product supplies interrupted, and costs will soar for therapies that simply check all the regulatory boxes.
Partnering cell and gene therapy subject matter experts (SMEs) with process optimization SMEs very early in, and throughout the product lifecycle is a critical component in the evolution of process optimization. By doing this, it would create awareness and recognition that process optimization is a unique, scientific discipline2 that creates tremendous value when positioned synergistically with cell and gene therapy development expertise. When applied to cell and gene therapies, process optimization is deployed as a product-specific, risk-based, lifecycle-stage appropriate roadmap that is fully integrated and executed within the overall product-program’s quality, time, and cost requirements.
Process optimization experts create an objective environment boundary in which the cell and gene therapy expert’s knowledge is translated to maximum effect for process optimization, and simultaneously for cell and gene therapy discovery and innovation. Recently, a clients’ cell and gene innovations suffered significant setbacks because the teams charged with their development could not step away from pre-defined solutions long enough to realize that the actual solution was right in front of them. After working closely with optimization experts and confronted with their own data inside a process optimization framework, these same teams were able to change their paradigm, establish a deeper understanding, and provide next-level therapies.
Because each cell and gene therapy product is unique, the expertise provided by the CGT expert is an indispensable source of knowledge for the discovery and innovation required to bring safe, life-changing cell and gene therapies to patients. What should also be indispensable and common to every cell and gene therapy effort is a process optimization framework, within which, discovery and innovation take place. For example, the principle of reproducibility, which is foundational to process optimization science, is also a critical component of the process optimization framework and should be established by the process optimization expert. The resultant commitment to the principle of reproducibility focusses the team’s efforts on high-value activities, such as the quantification of critical cause-and-effect relationships, establishment of capable measurement systems, and control of experimental error. All these activities are undertaken within the context of another critical component of the process optimization framework (i.e., risk management3.) Although it is not possible to eliminate all risk, time must be allotted for risk identification, evaluation and control, and the explicit acceptance of residual risk.
Consider some of the benefits that may be realized by working within the process optimization framework, when transferring a cell and gene therapy product from an academic research environment to one required for manufacture of pre-clinical study material. Specifically, consider that current practice often yields quantitative information that is insufficiently reliable to support the production of pre-clinical supplies at an acceptable risk level, with respect to the cause-and-effect relationship between raw material attributes and cell and gene therapy product attributes (e.g., potency.) The discipline imposed under the process optimization framework should focus the team’s expertise on the establishment of quantitative, causal relationships for the targets of highest value with respect to program success, both in the research lab AND in pre-clinical manufacturing. High-value targets might include analytical methods that are demonstrably capable of characterizing material attributes, design and execution of experiments that efficiently and reproducibly test hypothesized, causal relationships under controlled conditions, and quantification of raw material variation, such as that seen from lot to lot. Taken together, these efforts are very likely to reduce the number of “surprises” that occur in pre-clinical supply manufacturing, which are inevitably more expensive and time consuming to correct than to prevent.
Are you in the process of developing a cell and gene therapy? Ensuring you have efficient and effective process optimization in place is critical to your product’s eventual success. Our Cell and Gene Therapy Center of Excellence has the breadth and depth of expertise you need to reach the next regulatory and developmental milestone. Regardless of where you are in development, we can work with you to establish optimized processes for your cell and gene therapy product. Contact us today to learn more about the capabilities, qualifications, and experience of our team of cell and gene therapy experts and how we can help with all of your cell and gene-related needs.
1 Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions (Basic Books, 2017), Richard Harris
2 Process optimization is a methodology that combines key scientific, engineering, and economic principles to postulate that any process at any point in its lifecycle may be configured to produce output that satisfies all customer requirements. It assumes that critical cause and effect relationships are identifiable and knowable through the rigorous and judicious application of the scientific method.
3 Risk management (ICHQ9), deployed within the process optimization framework may be viewed as the platform for on-going, construction and testing of well-informed hypothesis, such that the current risk controls listed therein, define the optimized process at any point in the CGT product lifecycle.
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