January 20, 2020 PAP-Q3-19-CL-009
The cell and gene therapy segment of the pharmaceutical market is evolving at lightning speed. Only a few years ago, these treatments comprised the smallest fraction of products in the clinical pipeline. At the end of the second half of 2019, the Alliance for Regenerative Medicine (ARM) counted more than 930 companies — from emerging biotechs to major international biopharma firms — that were pursuing cell and gene therapies, with more than 1,000 clinical trials underway around the world.1
Meanwhile, the U.S. Food and Drug Administration (FDA) expects 200 cell and gene therapy IND applications each year by 2020 and 30–60 approvals by 2030.2 Not surprisingly, the cell and gene therapy market is predicted to expand at a CAGR of greater than 36%, rising from approximately $1 billion in 2018 to nearly $12 billion by 2025.3
With so many candidates reaching late-stage clinical development and nearing commercialization, demand for cell and gene therapy manufacturing capacity is rapidly increasing. Despite heavy investment by contract manufacturers to expand their capabilities, they cannot possibly meet the growing needs of the sector; many cell and gene therapy developers are, therefore, establishing in-house facilities.
Designing new facilities for cell therapy manufacturing is a challenging task. Commercialization remains in the nascent stage, with only a few facilities constructed to date. Production experience thus far has largely been limited to the laboratory scale, and, particularly for cell therapies, most processes involve highly manual operations. The current equipment, technologies and techniques require significant modification for practical scale-out (for autologous therapies) or scale-up (for allogeneic therapies).
In addition, the potential demand for any given new therapy is typically not well understood at the earliest stages of commercialization. Lead times for key raw materials are also often unknown. The significant complexity of the supply chain — most notably for patient-specific cell and gene-modified cell therapies — further complicates the situation.
As a result, facility designers and engineers are challenged to develop robust solutions while facing uncertainties including plant footprint, the types and quantities of equipment, the required staff, and the flow of people and materials.
All cell therapies cannot be terminally sterilized. Therefore, very rigorous quality control is essential in their production, regardless of the batch size — whether it is a patient-specific autologous therapy or a large-volume batch of an allogenic, off-the-shelf product. The entire production process must be performed aseptically, including extensive in-process and final product quality control testing, in a manner that ensures sterility and efficacy with a high degree of certainty.
The traditional approach has been to perform processes in biosafety cabinets within cleanrooms. However, these processes are not closed but are open to the environment. As such, the cleanroom must be Grade A or B, and with a Grade A biosafety cabinet in an environment that is very tightly controlled. Product purity is heavily reliant on operator procedures, and the risks of contamination can be high, the training and qualification is costly, and the process is highly unforgiving for a human "having a bad day."
Isolators, when used as primary containment, provide a closed environment in which the process is performed, allowing the use of a lower HVAC classification cleanroom. This typically leads to reduced facility capital expenditure and lower operating costs due to the reduced need for gowning and airlocks. The facility footprint is often smaller as well.
Perhaps most importantly, using an isolator protects both operators and the product, because the process environment is aseptic, contained and closed. The product is separated from the operators who are manipulating the process, which significantly reduces the potential for contamination.
The use of isolators presents its own set of challenges, however. Isolators have traditionally been designed for aseptic fill-finish and non-aseptic potent compound manufacturing operations, not for small-volume, manual cell and gene therapy production. Typically, aseptic isolators have been associated with automated equipment, such as a vial or syringe fill line. For cell and gene therapy production, several different pieces of equipment must be contained within the isolator.
Isolators for cell and gene therapy production are very complex. Considerations must be made for ergonomics to ensure that operators can easily perform necessary manipulations and material can be moved smoothly from one unit operation to another. Transfer in and out — as with the removal of waste and the collection of samples — are generally more complicated. Other issues that must be addressed in the isolator design include the heat load it will need to support and the electronic connections necessary to automate the equipment and for data transfer.
Decontamination of the isolator also requires a special approach. Much of the processing equipment used in cell and gene therapy manufacturing cannot be sterilized using vapor phase hydrogen peroxide (VPHP), the most common agent used to decontaminate traditional isolators. It is often necessary to wipe down the individual pieces of equipment and then protect them so the isolator chamber can be treated with VPHP. Development of a robust decontamination cycle and validation of an aseptic environment within the isolator is, in fact, a key component of the overall process development activities for cell and gene therapies produced in isolators. The components associated with the isolator design can have a significant impact on these efforts. The isolator is more than just the metal and glass box that surrounds the process. The elements used to transfer materials in and out of the isolator, as well as the monitoring of the strict microbial and particulate control of the isolator, are a large part of designing an isolator for a higher ease of operation and higher quality of product.
Complicating the situation further is the fact that much of the equipment used in the cell and gene therapy field to date has been designed for research applications, and not all options on the market are sufficiently robust for use in cGMP manufacturing with respect to CFR Part 11 compliance and other regulations. In addition, no two cell and gene therapy production processes are alike, which adds to the difficulty. Processes can vary dramatically from company to company and even from product to product.
Isolator modules must be customized to fit the particular pieces of equipment and the operation steps used for each process. In addition, because most of the equipment was originally designed for use in a research or clinical environment, it is often not sized appropriately for conventional isolators, leading to even greater need for customized solutions.
The infrastructure for GMP cell and gene therapy manufacturing continues to evolve, with vendors of tubing, bags, bioreactors, etc. working hard to catch up to the demands of developers of these next-generation medicines.
Given the nascent nature of cell and gene therapies, regulatory agencies have only begun to focus on the specific requirements for these products with respect to development and manufacturing. The majority of efforts have been directed toward development aspects, notably the data required to prepare INDs for clinical studies and rules and guidance for conducting clinical trials.4
The FDA, European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and other regulatory bodies, have issued several draft guidances regarding cell and gene therapies, including a limited number recommending manufacturing practices. Early in 2019, the FDA announced that it was working on several additional guidance documents covering clinical development through manufacturing, with the intention of fostering innovation and advances in manufacturing and enforcement to promote efficiencies and address the complexities of cell and gene therapy manufacturing.5
The FDA, along with other government agencies, has also encouraged the formation of new public/private consortiums such as the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and the Advanced Regenerative Medicine Institute (ARMI), which are supported by the National Institute of Health and the US Department of Defense, respectively. The Standards Coordinating Body, an independent non-profit 501(c)(3) organization spun out of an initiative of the ARM’s Science & Technology Committee is working to promote coordination of standards activities, including those for manufacturing.
There remains significant debate regarding whether the guidelines proposed to date are sufficiently strict for the manufacture of ATMPs.
While there is much that can be done to standardize equipment use for cell and gene therapy within an isolator environment, which would then allow for more standardization of isolator designs, the use of isolators is not the ultimate goal for ATMP production.
The ideal objective is closed processes — manufacturing equipment and systems for cell culture, harvest, viral vector production, downstream purification and all other unit operations involved in cell and gene therapy production that preclude the need for an isolator environment. The development of such systems is occurring in parallel with advances in isolators and their attendant technology.
CRB has been providing consulting services services in aseptic processing, in biological therapeutic production, and in regenerative medicine for over 30 years. CRB has even been instrumental in facilities in the cell and gene therapy manufacturing space for over a decade. We have been involved in the forefront of manufacturing systems and facility development, largely with academic and research institutions with candidates advancing through clinical development.
CRB has been involved in more than 215 different cell and gene therapy projects ranging from feasibility studies to the design and construction of entire manufacturing facilities. Our engineers and designers listen closely to our clients and work to truly understand their needs. With this understanding, they are able to guide clients from the research scale to processes that are commercially robust and performed in facilities that are designed to garner acceptance by regulatory agencies around the world.
We are also actively engaged with vendors of cell and gene therapy manufacturing equipment and isolators to identify areas for improvement and advances that will enable more efficient design and installation of isolators — and ultimately closed processing systems. We are committed to staying abreast of developments in the field in order to be able to anticipate how cell and gene therapy processing may evolve over time.
References
Allan Bream has more than 30 years of engineering and manufacturing experience, including 25 years in the biotechnology industry. His expertise includes Advanced Therapy Medicinal Products (ATMPs), large-scale bacterial fermentation, mammalian cell culture, vaccines, downstream processing, protein purification and immobilization and Current Good Manufacturing Practice facility design, operations and assessment. Bream’s facilities experience includes all phases of process design, including master planning, conceptual and detailed design, construction services and equipment procurement across the United States, Puerto Rico, Europe and Asia. His experience also includes biosafety level 2 and biosafety level 3 facility design projects. He has also worked in corporate engineering, process development and biomanufacturing positions for Chiron Corp. and Baxter Healthcare. Bream has a Master of Science in biochemical engineering and a Bachelor of Science in chemical engineering from the University of Iowa.
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