Standardizing Practices for Cellular Therapy Manufacturing

Cellular therapies are positioned to be the next revolution in the healthcare industry. Disciplines such as bio-printing and tissue engineering also require high quality living cells and can be considered a part of the overall cellular therapy industry. Multiple diseases that were traditionally incurable are being addressed by cellular therapies with promising early clinical results. Both large and small companies are developing cellular therapies, and currently, more than a thousand clinical trials are being conducted (1).

Stem cells are unique in their ability to divide and regenerate themselves and in their ability to remain unspecialized or differentiate into specialized cells that can perform critical tasks in the human body. Because of these unique traits, these cells hold a great deal of promise in helping researchers learn about disease and develop treatments. The regenerative properties of stem cells are proving useful in developing treatments for common conditions such as diabetes, heart disease, Parkinson’s disease, spinal cord injuries, and strokes.

There are two primary categories of cellular therapies: autologous and allogeneic. Autologous therapies are patient- or donor-specific; allogeneic therapies generally do not have a specific donor or source requirement. Each therapy presents opportunities for treatments, but also faces unique challenges to overcome before it can get to the clinic. Autologous therapies typically are not scalable; allogeneic therapies are scalable from a manufacturing perspective. The number of product doses that can be manufactured or required for a single patient for an autologous therapy are limited compared to a scenario where multiple patients can be treated using the same off-the-shelf allogeneic therapy.

Manufacturing Unit Operations
Although recent scientific and technological advances in the cellular therapy arena portend great therapeutic promise, the final objective is to accelerate the development path of these therapies to the clinic and make them universally available to all patients. Several steps along the pathway are fraught with challenges that institutions and biopharma will face in the attempt to commercialize these products.

One approach is to segment the various steps of the development process into discrete unit operations. This approach has been successfully implemented in the manufacture of chemicals, automobiles, and food, as well as other pharmaceutical industry sectors. The lessons learned can be applied to the development of cellular therapies. It is here that cell biology meets engineering with the application of sound manufacturing principles. These unit operations range from science and discovery to the successful execution of clinical trials and commercialization of product. This article focuses on the manufacturing operations that include supply chain management of raw materials, manufacturing processes with facility capabilities, quality control, quality assurance release, regulatory requirements, and shipping and distribution.

Each unit operation needs to be scalable to effectively meet clinical demand. The volume and complexity to make product for an early-phase clinical trial is different when compared to what is required at commercial scale-up. There is a need for process development within each unit operation and while the process starts out being flexible, it needs to be locked in by Phase III and before commercial launch. An important component of this overall strategy is to identify each of these requirements early in the process.

Cost drivers increase as the product moves through the different phases of clinical development with the majority of the costs closer to commercialization. While safety and efficacy are primary drivers, the cost of the final therapeutic product is also important for therapies to be universally accessible; there should be no limitations in getting these therapies reimbursed and delivered to patients (2).

Regulatory Affairs
Regulatory requirements for different cell therapies are at different stages of development, and national and international regulatory agencies are discussing guidance documents for the industry to follow. The regulators are willing to provide significant support to drug developers and will work with organizations to determine the correct path forward, resulting in a clear regulatory path to the clinic. Japan’s regulatory agency, for example, has recently retooled its drug authorization framework through legal reform to produce the world’s fastest approval process specifically designed for regenerative medicine therapies (3).

Supply Chain Management
Supply chain management of key materials is the first unit operation within manufacturing. Cellular therapies depend on the acquisition of the right source material that, in most cases, is derived from tissue or blood. A good donor program needs to be established to ensure that reproducible procedures are in place using standard methods to procure material.

While there are several options that work well, there is limited standardization in approaches. Using a standardized accreditation process for blood and tissue sourcing, entities will help establish that the process being followed is uniform and consistent. Donor-to-donor variability will exist, so eliminating the collection process as a variable will improve reliability.

Another issue is a short supply of serum, a critical raw material in the supply chain. Projections indicate that there is insufficient serum to meet the commercial demands for cell therapy (4). Using synthetic biology approaches with computational modeling can identify substitutes to serum that are more abundantly available. A synthetic biology approach also offers better characterization and chemical definition, which will help deliver a consistent product and streamline the regulatory pathway. Many media developers have launched serum-free media, which are also under evaluation to address this bottleneck. Using raw materials and consumables that are well characterized and from qualified suppliers is important. Suppliers should have quality systems in place and open to an audit.

Facility Design
The manufacturing facility needs to be built and equipped with the appropriate infrastructure and environmental controls. Options include building a facility, contract manufacturing, and using modular pods that are prefabricated and can be implemented quickly to meet requirements. Autologous cell- therapy production may be biased towards having a modular facility for each product dose to minimize cross contamination. Allogeneic facilities can be designed in a ballroom arrangement, as each production lot represents multiple doses made at larger scales.

Because terminal sterilization for cellular therapies is limited, it becomes important to minimize open system processing where a contaminant can be introduced into the system and lead to failed product batches. Open-system processing requires a higher degree of personnel training, aseptic process validation, stringent environmental controls, and increased costs. Using methods to ensure maximum closed-system manufacturing with automation will reduce some of the requirements on the facility.

Scale-Up and Manufacturing
Most manufacturing processes start off being manual as they are developed in a laboratory-based environment with only small quantities required for preclinical testing. These processes are seldom scale-up friendly and require significant process development efforts to get them ready for large-scale production. Organizations face this dilemma when they review the process development costs versus moving the process as-is into clinical manufacturing. Technology transfer of the laboratory based process may work in the short term, but creates issues when the only option available is scale-out to achieve required product volumes.

Research and development scientists require insight into what scale-up options exist with protocols and application notes. These protocols will provide early opportunities to identify processes that can be easily translated into large-scale formats with some process development. Process development and technology transfer will always be required but using standard methods will streamline the process. When developers are working with T-flasks, they seldom think about transitioning into multi layers vessels and bioreactors. Producing 10 million cells can be achieved in a laboratory environment but when cells have to be produced at the billion to trillion scale, technology requirements are different. Some of this development can be done via computational modeling or small-scale experiments using well-characterized methods that have been qualified for their scalability potential. Large-scale experiments are expensive to run and while large, well-funded organizations have the resources, smaller organizations will find it cost prohibitive. Cost-of-goods modeling is required as the drug products approach commercial launch. By understanding the drivers of cost early in the development phase, the process can be optimized while there still is some flexibility. Once the process is locked down, much work and expense is required to establish equivalence with the previous process.

Automation options should also be evaluated to determine which steps of the process can be automated. Several automation options can be plugged in without extensive customization and process development. For example, automated and semi-automated filling systems for the final dose of the product are not only a faster and scalable than manual processes, they also minimize the opportunity for contamination. Other options from the pharmaceutical industry and other ancillary industries can be leveraged. Several academic and industrial consortia are being created to generate standardized platforms and methods to be used across a wide spectrum of requirements.

Quality Control/Assurance
Intermediates used in the manufacturing process and the final product must go through quality-control testing prior to release. Multiple assays and methods are available to address sterility, safety, and efficacy. Many assays may seem relevant but have no consequence on the drug product. The development of the acceptance criteria should be relevant. Doing more assays does not necessarily impact outcome but doing the correct assays with the relevant acceptance criteria is important.

Shipping and distribution
The drug product must reach clinical sites without compromising its sterility, safety, and potency; therefore, bio-preservation and cold chain management need to be addressed. Standard off-the-shelf bio-preservation options have been successfully used with supporting regulatory documentation (5). Evaluating existing options from the industry is recommended before designing custom options and will help in the regulatory submission.

Most cellular therapies are shipped and distributed under liquid nitrogen at -80°C or -20°C conditions. Many vendors and service providers meet national and international requirements. In addition, new technologies stabilize these cells at higher temperatures without compromising viability, shelf life, and efficacy. Final shipping and distribution costs can constitute more than 25% of the product cost, a factor that should not be underestimated during the budgeting process.

The Path Forward
Challenges will always exist when launching new therapies and technologies. Established expertise from other fields can be leveraged and applied to cellular therapies. Options and tools are available to address each of these challenges. Execution of a commercialization strategy can be done in multiple stages over time and, most importantly, when required. In some cases, the investment needs to be made early enough to be ready for the next stage.

Accelerating a cellular therapy to clinic can be executed by identifying the relevant unit operations; identifying the major components within the unit operation and those that need the most attention; leveraging existing expertise or standards; implementing the right solution; and validating the implementation.

It is only a matter of time before treatments become available for diseases that were considered difficult to cure. The industry is focused on the promise of delivering effective cellular therapies worldwide.

References
1. Alliance for Rengerative Medicine,

(January 2014), accessed Oct. 15, 2014.
2. R. Shaw, B. Hampson, C. Betz, Bioprocessing Journal, 13 (2), 26-31 (2014).
3. D. Cyranoski, Nature Medicine. 11 (9), 510-513 (2013).
4. S. Jung, K.M. Panchalingam, R.D. Wuerth, L. Rosenberg, L.A. Behie, Biotechnol Appl Biochem. 59 (2), 106-120 (2012).
5. AJ Mathew, Cryobiology.  67 (3), 412 (2013).

About the Authors
Uplaksh Kumar, PhD, MBA, cGMP expert, AABB Consulting Services team
Naynesh R. Kamani, MD, division director for the Center for Cellular Therapies and Research, AABB Center for Cellular Therapies