A cell therapy is defined as the administration of intact living cells to patients for the treatment of disease. The first successful cell therapy was performed in 1956 by Dr. E. Donnall Thomas, who treated leukemia by transplanting bone marrow between identical twin siblings, for which he was awarded the Nobel Prize in Physiology or Medicine in 1990. Cell therapy has since progressed from basic bone marrow transplantation to the use of genetically modified and ex vivo manufactured chimeric antigen receptor (CAR) T-cell therapies for the treatment of advanced blood cancers (Locke et al., 2017). Next generation cell therapies under development expand upon the successes of CAR T-cell products to move from liquid to solid tumors (Brown et al., 2016) and demonstrate the potential to regenerate diseased organs such as the heart (Liu et al., 2018) and brain (Wakeman et al., 2017). Unfortunately, the widespread clinical adoption of cell therapies is limited by high development and manufacturing costs, as well as the need for a complex logistical distribution network that can maintain cell health during transit. Current efforts are underway to develop new technologies and processes that can standardize cell therapy commercialization and enable the efficient and economical delivery of living cells to patients at a global scale.
Realizing the complexities of employing cells as ‘living drugs’ and to help transition promising preclinical inventions into the clinic, the US Food and Drug Administration (FDA) in 2016 signed the 21st Century Cures Act (Cures Act) into law. With respect to cell therapies, the Cures Act defines Regenerative Medicine Advanced Therapy (RMAT) products and outlines an expedited pathway for approval (United States Congress, 2016). To qualify for RMAT designation, the drug must be: 1) A regenerative medicine therapy defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or combinations of these products; 2) Intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and 3) Preliminary clinical evidence demonstrating the potential to address an unmet medical need. The first two cell therapies that received approval under the RMAT designation were the CAR T-cell therapies Kymriah™ and Yescarta™ in 2017. Since then, the pace of cell therapy products granted RMAT designation has accelerated, with 33 products currently at various stages of clinical trial (US Food and Drug Administration, 2019). Despite an increased interest in the RMAT approval pathway, it is important to note that designation only expedites the clinical trial process but does not lessen the regulatory scrutiny necessary for FDA approval. Indeed, the traditional FDA phased development process generally applies to the RMAT-designated therapies, and consists sequentially of proof-of-concept work (both in vitro and in vivo), preclinical studies (pharmacology/toxicology), Investigational New Drug (IND) Filing/Approval, Phase I, Phase II, Phase III, Biological Licensing Approval (BLA), and Commercial/Phase IV and Post-Marketing Surveillance. To navigate the phased development required by the FDA under the condensed timeframe of RMAT designation, a deep understanding of the development and manufacturing workflow of a cell therapy product is crucial in order to avoid the bottlenecks and common pitfalls that can derail accelerated clinical development.
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Maintaining Cell Health Throughout Manufacturing and Patient Delivery
One common pitfall in cell manufacturing is that ‘living drugs’ intended for clinical use require constant environmental control to ensure viability and proper functionality. In reality, cells begin to lose function as soon as they are removed from either the body or from controlled culture conditions. This is true for all cell therapies, whether they are derived from the patients themselves (autologous product) or from a single donor source (allogeneic product). As such, a vital and often overlooked component of cell manufacturing centers is the ability to maintain cell function during storage, at critical developmental steps, and during transport to and from the clinic. Biopreservation refers to the processes required to maintain the health and function of RMATs while outside the body or culture conditions (Hawkins, Abazari, & Mathew, 2017). Successful biopreservation enables cells to rapidly return to functionality and be reinserted into the product workflow during manufacturing or into patients at the bedside. Conversely, inadequate biopreservation controls can result in excessive cell loss and improper function, rendering a clinical product ineffective and unable to re-enter the manufacturing or clinical process. Early in product development, a single clinical site may be used for all phases of a workflow, from cell collection to patient delivery. As such, detailed biopreservation controls may not be required for clinical efficacy. However, as clinical trials advance to a larger and more diverse patient population at multiple sites, biopreservation practices need to be optimized to ensure consistency in cell function and viability. Identifying the critical points where biopreservation is required and applying adequate process controls is therefore essential for the progression of a cell therapy through the traditional FDA staged development process or under an expedited RMAT pathway.
Biopreservation in a GMP Environment
The transition from a promising preclinical invention to a commercialized cell therapy via the RMAT designation requires the timely adoption of Good Manufacturing Practices (GMP) to ensure a consistent product with minimal lot-to-lot variability. And while transition to a GMP workflow can occur at any time during development, early adoption can translate to significant financial savings as realized by cost of goods (COGs) analysis (Mizukami et al., 2018). This is especially true with regards to biopreservation, which during early product development may be largely based upon historical protocols and investigator preferences. Such nonoptimized protocols may result in highly variable post-preservation cell viability and function that can complicate product development during a condensed RMAT timeline. For autologous products, biopreservation is typically needed for both the source material and final product and should be as close to the final process and ‘locked’ prior to Phase I trials. Conversely, for allogeneic products that follow a more traditional biopharmaceutical manufacturing development process, biopreservation is required at multiple developmental stages which include source material, master cell bank, working cell bank, and final product configuration. The master cell bank in particular is intended to serve as the primary source material throughout all phases of clinical trial and production for the entire product lifespan. As such, biopreservation of a master cell bank should be optimized as one of the first steps in cell therapy product development. Optimizing biopreservation during the generation of both master and working cell banks is especially advantageous, as it would permit the establishment of regulatory-compliant, genetically and phenotypically characterized, and pathogen-free seedstock that serve as a uniform platform for both research and development and GMP production of the final clinical product (Abbasalizadeh, Pakzad, Cabral, & Baharvand, 2017). Generation of a GMP-compliant master cell bank (MCB) from a biological source requires numerous steps that include, but are not limited to; a documented chain of custody from an eligible source, cell expansion in defined and qualified media devoid of potentially xenopathic animal products, utilization of approved production records and standard operating procedures (SOPs), final product testing to ensure identity and viability, and finally, cryopreservation and storage with appropriate environmental monitoring (Baghbaderani et al., 2015). Consequently, the cost of generating a GMP-compliant MCB can be prohibitive during early preclinical development, and many groups generate research grade banks as an alternative approach. Unfortunately, clinical products developed from research grade MCB (especially those employing animal-derived components) that are nearing market approval would have to be ‘re-derived’ under GMP conditions and subject to repeat cell expansion, validation, and release testing at significant financial cost (Devito et al., 2014).
The unique characteristics of a given cell therapy, disease target, and commercialization model (e.g. centralized vs. local manufacturing) likely do not translate to a generalized and uniform pathway to MCB GMP compliance. Indeed, the biopreservation process alone contains multiple critical process parameters than can greatly influence postthaw cellular health, including the selection of an appropriate media (and cryoprotectant for frozen products), the rate of media addition, the biopreservation temperature, ice nucleation for frozen products, cooling rate, storage temperature, rewarm/thaw rate, and finally, finish formulation for patient administration (Hawkins, Abazari, & Mathew, 2017). For instance, non-optimized biopreservation protocols that employ historical processes containing animal-derived components may not be amenable to GMP and regulatory scrutiny. And because cellular function is entirely dependent upon the manufacturing process, removal of animal components from a biopreservation protocol may alter product efficacy. For cell therapies designated for the RMAT pathway, ‘re-derivation’ of banks could effectively derail accelerated development and may even halt a promising therapy from reaching the clinic. Biopreservation of an MCB should therefore be a major push early in allogeneic product development to avoid costly delays that are not amenable to a condensed RMAT timeline.
Summary
Cell and gene therapies are ‘living drugs’ that have proven highly effective in the clinic, particularly as a means to treat formerly untreatable diseases such as cancer. However, as ‘living drugs’, cell and gene therapies require complex chemistry and manufacturing controls (CMC) to enable efficient commercialization and maintain therapeutic consistency and potency. To speed the development of these revolutionary therapies, the FDA has implemented the RMAT accelerated approval process to speed the development of these therapies from the bench to the bedside. However, this accelerated regulatory oversight means that complex CMC development must progress and evolve rapidly and in parallel with clinical development activities at each clinical phase. Biopreservation is a critical component of cell and gene therapy product development and to ensure cell viability and function during both storage and transport, and must be detailed as part of the CMC for FDA review. However, biopreservation is often overlooked early in development, which can result in the redesign of product CMC and lead to lengthy and costly delays that may slow or even halt product review through RMAT designation. Biopreservation should therefore be optimized early in cell and gene therapy product development to speed the translation of promising therapies from the bench to the bedside.
References
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