Transitioning from development to commercial: risk-based guidance for critical materials management in cell therapies

A key hurdle to ensuring patient access to cell and gene therapies (CGTs) and continued growth of the industry is the management of raw materials. The combination of rapid growth, individual product and process complexity and limited industry-specific guidance or awareness presents non-obvious risk mitigation challenges for transitioning from development to clinical application. Understanding, assessing and mitigating the varied raw material risks for CGT products during product and clinical development are critical for ensuring smooth transitions into commercialization and for preventing interruption of product supply to patients. This article presents a risk-based approach driven by concerns for patient safety that can help focus and coordinate efforts to address the most critical risk factors. Highlighted are some of the highest risk materials common to the manufacture of many CGTs, including the primary starting material, culture media, reagents and single-use components. Using a hypothetical gene-edited cell therapy as an example, we describe the general manufacturing process and subsequently incorporate the described methodology to perform a sample risk assessment. The practical approach described herein is intended to assist CGT manufacturers and suppliers in actively assessing materials early in development to provide a basic starting point for mitigating risks experienced when translating CGT products for clinical and long-term commercial application.     

Decentralised manufacturing of cell and gene therapy products: Learning from other healthcare sectors

Decentralised or ‘redistributed’ manufacturing represents an attractive choice for production of some cell and gene therapies (CGTs), in particular personalised therapies. Decentralised manufacturing splits production into various locations or regions and in doing so, imposes organisational changes on the structure of a company. This confers a significant advantage by democratising supply, creating jobs without geographical restriction to the central hub and allowing a more flexible response to external pressures and demands. This comes with challenges that need to be addressed including, a reduction in oversight, decision making and control by central management which can be critical in maintaining quality in healthcare product manufacturing. The unwitting adoption of poor business strategies at an early stage in development has the potential to undermine the market success of otherwise promising products. To maximise the probability of realising the benefits that decentralised manufacturing of CGTs has to offer, it is important to examine alternative operational paradigms to learn from their successes and to avoid their failures. Whilst no other situation is quite the same as CGTs, some illustrative examples of established manufacturing paradigms are described. Each of these shares a unique attribute with CGTs which aids understanding of how decentralised manufacturing might be implemented for CGTs in a similar manner. In this paper we present a collection of paradigms that can be drawn on in formulating a roadmap to success for decentralised production of CGTs.     

Cell,tissue and gene products with marketing authorization in 2018 worldwide

Cell and gene therapies (CGTs) are progressively entering into clinical practice in different parts of the world. The International Society for Cell & Gene Therapy (ISCT), a global scientific society, has been committed since 1992 to supporting and developing knowledge on clinical applications of CGTs. Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions. This article reflects the dynamic momentum around authorized CGTs coinciding with the parallel increase of unproven approaches where cells are delivered without appropriate and rigorous scientific and regulatory assessment and authorization. This is intended to be a living document with a yearly update linked to a dedicated section of the ISCT website for faster adjustments. The aim is to ultimately inform, by periodic snapshots, the scientific community, healthcare stakeholders and patient associations on authorized CGT products as a way to increase communication around the approved therapeutic approaches charged with heightened expectations.     

Current state of U.S. Food and Drug Administration regulation for cellular and gene therapy products: potential cures on the horizon

Cellular & Gene Therapies (CGTs) are complex products, which have been key foci of the International Society for Cell & Gene Therapy (ISCT). For this ISCT North American Legal & Regulatory Affairs Committee review publication, CGTs include but are not limited to somatic cell-based therapies, pluripotent cell-derived cell-based therapies, gene- or non-gene-modified or gene edited versions of these cell-based therapies, in vivo gene therapies, organ/tissue engineered products, and relevant combination products. These products are regulated by the Food and Drug Administration (FDA) in the United States. This publication reviews selected laws, regulations, guidance, definitions, processes, types of meetings and submissions, and other key factors that the FDA follows and implements to regulate and support development of these types of products. These factors may be considered in order to help current and potential product developers/sponsors/applicants navigate through FDA regulatory pathways. We also review expedited programs including types of Designations available at the FDA, and their specific eligibility criteria. We include FDA and other stakeholder resources to consider regarding CGT regulation, to help prepare for CGT development and subsequent FDA approval.     

Cell and gene therapy: a snapshot of investor perspectives

In a collaborative effort between the Commercialization Committee of the International Society for Cell & Gene Therapy (ISCT) and Bloomberg Intelligence, a broad survey of the investment community was executed in order to understand investor perceptions of companies that develop cell and gene therapies (CGTs) and gauge the trajectory of future investment. A broad spectrum of investors responded to the survey, including both health care specialists and generalist investors across a wide range of fund sizes and geographies. A majority of survey respondents have limited exposure to CGTs in their health care portfolios today, which highlights the opportunity to increase awareness of this burgeoning field in the investment community. The survey established that clinically significant data are the most important consideration when making an investment in this area, whereas safety concerns were highlighted as the most prominent barrier to making an investment. Challenges with manufacturing and scale-up were also ranked as a significant concern. The majority of investors hold the belief that both autologous and allogeneic cell therapies can co-exist. The detailed findings of this survey will help to provide a foundation for educational content that the ISCT Commercialization Committee can bring forth to further the investment in CGTs through the newly created Investigators to Investors program.     

An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies

Background aimsThe novelty of cell and gene therapies (CGTs) has introduced unique supply chain challenges and considerations not seen by chemically synthesized (small-molecule) drugs. These complexities increase during the clinical phases, where drug safety and efficacy milestones are still underdeveloped. For example, for autologous therapies such as chimeric antigen receptor T-cell therapies, in which the treatment is developed from the patient's own cells, supply chain management plays an integral role in chemistry, manufacturing and control processes. Supply chain management requires proactive planning because of the strict cold chain requirements and time sensitivity of CGTs. This research examines strategies and responses to challenges experienced by industry stakeholders (e.g., sponsors and manufacturers) during the implementation phases of clinical supply chain management. This research further evaluates the adequacy of the current regulatory framework for distribution and supply chain management of CGTs in the US.MethodsA survey methodology was used to query subject matter experts from the biopharmaceutical industry who were familiar with the clinical supply management of CGTs in the US. The survey instrument was developed using an implementation framework and disseminated electronically to mid- and senior-level subject matter experts who had experience with clinical trials, supply chain management and CGTs.ResultsA total of 128 respondents accessed the survey, and 105 respondents answered at least one question. Seventy-five respondents completed the survey. Results showed that a lack of harmonization in regulations across the supply chain, limited resources, challenges with vendor management, high costs and complexities in the supply chain due to product specificity and customization proved to be impediments for the industry. In addition, the coronavirus disease 2019 pandemic had a significant impact on supply chain implementation. The results revealed that less than half of the respondents had business continuity plans in place. These challenges increased for smaller and mid-size organizations. Thirty percent of small and mid-size organizations were less prepared to scale up than larger companies.ConclusionsSuggestions from industry stakeholders were to adopt and enforce Good Distribution Practices in the US (81%), pre-plan distribution strategies with internal and external stakeholders along the supply chain and develop agile systems and robust processes end to end. Hurdles in scaling up and scaling out from the clinical to commercial phases for time- and temperature-sensitive CGT products make it difficult to predict the supply chain's long-term feasibility. Although there are initiatives to improve these impediments, such as improving industry partnerships and creating global CGT transportation standards, there are still regulatory knowledge gaps present for CGTs. Therefore, it is essential to establish a baseline and foundation for CGT supply chains extending beyond the loading dock.     

Compliance and cost control for cryopreservation of cellular starting materials: An industry perspective

Over the last decade, cancer immunotherapy has progressed from an academically interesting field to one of the most promising forms of new treatments in which not the cancer but the immune system is treated. In particular, genetic modification for purposeful redirection of autologous T cells is providing hope to many treatment-resistant patients. This personalized form of medicine is radically different from more traditional oncologic drugs. With these evolving medical advancements and more cellular therapies becoming available, some regulatory agencies have created new regulatory requirements to manage the production of these types of products. The regulations are specifically suited for the manufacture of gene and cell therapy products, as they use a risk-based approach towards product development and manufacturing, when there is limited characterization available. The correct interpretation of how and when requirements apply is crucial, since theoretical approaches to implementing GMP can easily lead to disproportionate and unwarranted restrictions that may not address the specific risks that regulators were intending to control. This is especially relevant for cell collection and biopreservation preceding the manufacturing process for products manufactured from autologous T cells. Both the fresh and cryopreserved apheresis materials can be filed as minimally manipulated starting materials to the authorities. The preservation of such cellular material can then routinely be managed using the available regulations for tissues and cells, allowing for a more fit-for-purpose approach to the control measures implemented.     

Cell and gene therapy manufacturing capabilities in Australia and New Zealand

Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region.     

Role of the blood service in cellular therapy

Cellular therapy is a novel form of medical or surgical treatment using cells in place of or in addition to traditional chemical drugs. The preparation of cellular products - called advanced therapy medicinal products - ATMP in Europe, requires compliance with good manufacturing practices (GMP). Based on long-term experience in blood component manufacturing, product traceability and hemovigilance, selected blood services may represent ideal settings for the development and experimental use of ATMP. International harmonization of the protocols and procedures for the preparation of ATMP is of paramount importance to facilitate the development of multicenter clinical trials with adequate sample size, which are urgently needed to determine the clinical efficacy of ATMP. This article describes European regulations on cellular therapy and summarizes the activities of the 'Franco Calori' Cell Factory, a GMP unit belonging to the department of regenerative medicine of a large public university hospital, which acquired a certification for the GMP production of ATMP in 2007 and developed nine experimental clinical protocols during 2003-2011.     

Quality risk management of the chimeric antigen receptor T cell pharmaceutical circuit in one of the first qualified European centers

Background aimsAccording to European Directive 2001/83/EC, chimeric antigen receptor T (CAR T) cells belong to a new class of medicines referred to as advanced therapy medicinal products (ATMPs). The specific features and complexity of these products require a total reorganization of the hospital circuit, from cell collection from the patient to administration of the final medicinal product. In France, at the cell stage, products are under the responsibility of a cell therapy unit (CTU) that controls, manipulates (if necessary) and ships cells to the manufacturing site. However, the final product is a medicinal product, and as with any other medicine, ATMPs have to be received, stored and further reconstituted for final distribution under the responsibility of the hospital pharmacy. The aim of our work was to perform a risk analysis of this circuit according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q9 guidelines on quality risk management.MethodsWe evaluated the activities carried out by the Saint-Louis Hospital CTU and pharmacy. Process mapping was established to trace all the steps of the circuit and to identify potential risks or failures. The risk analysis was performed according to failure mode, effects and criticality analysis. The criticality of each risk (minor [Mi], moderate [Mo], significant [S] or major [Ma]) was scored, and corrective actions or preventive actions (CAPAs) for Mo, S and Ma risks were proposed.ResultsWe identified five Mo, six S and no Ma risks for the CTU part of the process. The most frequent risk was traceability failure. To reduce its frequency, we developed and validated software dedicated to ATMP activities. Another S risk was non-compliance of CAR T cell-specific steps due to the significant variability between companies. Our CAPA process was to implement procedures and design information sheets specific to each CAR T-cell program. In addition, critical steps were added to the ATMP software. Our CAPA process allowed us to reduce the criticality of identified risks to one Mi, seven Mo and three S. For the pharmacy part of the process, five Mo, two S and one Ma risk were identified. The most critical risk was compromised integrity of the CAR T-cell bag at the time of thawing. In case of unavailability of a backup bag, we designed and validated a degraded mode of operation allowing product recovery. In this exceptional circumstance, an agreement has to be signed between the physician, pharmacy, CTU and sponsor or marketing authorization holder. The implemented CAPA process allowed us to reduce the criticality of risks to three Mi and five Mo.ConclusionsOur risk analysis identified several Mo and S risks but only one Ma risk. The implementation of the CAPA process allowed for controlling some risks by decreasing their frequency and/or criticality or by increasing their detectability. The close collaboration between the CTU and pharmacy allows complete traceability of the CAR T-cell circuit, which is essential to guarantee safe use.     

Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies

Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing.     

Shipping of therapeutic somatic cell products

Background aimsShipment of therapeutic somatic cells between a current good manufacturing practice (cGMP) facility and a clinic or between different cGMP facilities requires validated standard operating procedures (SOP). Under National Heart Lung & Blood Institute (NHLBI) sponsorship, the Production Assistance for Cellular Therapies (PACT) group conducted a validation study for the shipping SOP it has created, including shipments of cryopreserved somatic cells, fresh peripheral blood specimens and apheresis products.MethodsComparisons of pre- and post-shipped cells and cell products at the three participating facilities included measurements of viability, phenotypic profiles and cellular functions. The data were analyzed at the University of Pittsburgh Biostatistics Facility.ResultsNo consistent shipping effects on cell viability, phenotype or functions were detected for cryopreserved and shipped peripheral blood mononuclear cells (PBMC), monocytes, immature dendritic cells (iDC), NK-92 or cytotoxic T cells (CTL). Cryopreserved mesenchymal stromal cells (MSC) had a significantly decreased viability after shipment, but this effect was in part because of inter-laboratory variability in the viable cell counts. Shipments of fresh peripheral blood and apheresis products for the generation of CTL and dendritic cells (DC), respectively, had no significant effects on cell product quality. MSC were successfully generated from fresh bone marrow samples shipped overnight.ConclusionsThis validation study provides a useful set of data for guiding shipments of therapeutic somatic cells in multi-institutional clinical trials.     

Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience

>himeric antigen receptor (CAR) T-cell therapy is a novel approved cancer treatment that has shown remarkable efficacy in the treatment of patients with relapsed leukemia and lymphoma. Implementation of CAR T-cell therapy in a hospital setting requires careful and detailed planning because of the complexities in delivering this specialist service. A multi-disciplinary approach with dedicated funding is required to meet clinical, scientific, logistic and regulatory requirements. Tisagenlecleucel was the first approved CAR T-cell therapy in Australia. The treatment has been made available to Australian patients in specialist public hospitals through federal and state funding. Royal Prince Alfred Hospital (RPAH) is one of Australia's oldest tertiary referral public health care institutions and was approved for the provision of CAR T-cell therapy service in 2019. A multi-disciplinary clinical program has been established for the collection and cryopreservation of donor cells shipped for manufacturing as well as for the receipt, storage and administration of CAR T-cell therapy and patient management. The program encompasses a Therapeutic Goods Administration-accredited apheresis unit and a state-of-the-art facility for cell processing, cryopreservation and storage. The program's clinical expertise extends to hematology, oncology, intensive care, pharmacy, neurology and radiology services with direct experience in managing patients receiving CAR T-cell therapies. The introduction of CAR T-cell therapies at RPAH was a complex undertaking facilitated by the existing infrastructure and clinical expertise.     

Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers’ requirements that currently poses a challenge when managing multiple different protocols.     

The implementation of tissue banking experiences for setting up a cGMP cell manufacturing facility

Cell manufacturing for clinical applications is a unique form of biologics manufacturing that relies on maintenance of stringent work practices designed to ensure product consistency and prevent contamination by microorganisms or by another patient's cells. More extensive, prolonged laboratory processes involve greater risk of complications and possibly adverse events for the recipient, and so the need for control is correspondingly greater. To minimize the associate risks of cell manufacturing adhering to international quality standards is critical. Current good tissue practice (cGTP) and current good manufacturing practice (cGMP) are examples of general standards that draw a baseline for cell manufacturing facilities. In recent years, stem cell researches have found great public interest in Iran and different cell therapy projects have been started in country. In this review we described the role of our tissue banking experiences in establishing a new cGMP cell manufacturing facility. The authors concluded that, tissue banks and tissue banking experts can broaden their roles from preparing tissue grafts to manufacturing cell and tissue engineered products for translational researches and phase I clinical trials. Also they can collaborate with cell processing laboratories to develop SOPs, implement quality management system, and design cGMP facilities.     

Proceedings of the first academic symposium on developing,qualifying and operating a cell and gene therapy manufacturing facility

A significant portion of the more than 1000 candidate cell and gene therapy products currently under clinical investigation (clinicaltrials.gov) are born out of academic research centers affiliated with universities, hospitals and non-profit research institutions. Supporting these efforts are myriad academic clinical materials production facilities with more than 40 such facilities currently operational in the United States alone. In March 2018, Stanford University's Laboratory for Cell and Gene Therapy held a symposium with the leaders and staff of more than 25 similar facilities to discuss the collective experience in developing, qualifying and operating cell and gene therapy manufacturing facilities according to current Good Manufacturing Practices. Topics included facility design, construction, staffing and operations and compliance. Leaders from several institutions gave overviews of the history of development of the facilities and discussed challenges and opportunities they had experienced over the past 10–20 years of operations. Working sessions were also held to discuss specific aspects of Process Development, Manufacturing, Quality Systems, Regulatory Affairs and Business Development with all participants contributing to the discussions. We summarize here the findings of this inaugural meeting with an emphasis on best practices and suggested guidelines for operations.     

Management of externally manufactured cell therapy products: the Mayo Clinic approach

BackgroundThe rise of investigative and commercially available cell therapy products adds a new dynamic to academic medical centers; that is, the management of patient-specific cell products. The scope of cell therapy has rapidly expanded beyond in-house collection and infusion of cell products such as bone marrow and peripheral blood transplant. The complexities and volumes of cell therapies are likely to continue to become more demanding. As patient-specific “living drugs,” cell therapy products typically require material collection, product provenance, transportation and maintenance of critical quality attributes, including temperature and expiration dates. These requirements are complicated by variations in product-specific attributes, reporting requirements and interactions with industry not required of typical pharmaceuticals.MethodsTo manage these requirements, the authors set out to establish a framework within the Immune, Progenitor and Cell Therapeutics Lab, the Current Good Manufacturing Practice facility responsible for cell manufacturing at Mayo Clinic Rochester housed within the Division of Transfusion Medicine. The authors created a work unit (biopharmaceutical unit) dedicated to addressing the specialized procedures required to properly handle these living drugs from collection to delivery and housing the necessary processes to more easily integrate externally manufactured cell therapies into clinical practice.ResultsThe result is a clear set of expectations defined for each step of the process, with logical documentation of critical steps that are concise and easy to follow.ConclusionsThe authors believe this system is scalable for addressing the promised growth of cell therapy products well into the future. Here the authors describe this system and provide a framework that could be used by other centers to manage these important new therapies.     

Long-term follow-up of cancer patients treated with gene therapy medicinal products

European Union requirements are discussed for the long-term follow-up of advanced therapy medicinal products, as well as how they can be applied to cancer patients treated with gene therapy medicinal products in the context of clinical trials, as described in a specific guideline issued by Gene Therapy Working Party at the European Medicine Agency.     

Variations in novel cellular therapy products manufacturing

Background aimsAt the frontier of transfusion medicine and transplantation, the field of cellular therapy is emerging. Most novel cellular therapy products are produced under investigational protocols with no clear standardization across cell processing centers. Thus, the purpose of this study was to uncover any variations in manufacturing practices for similar cellular therapy products across different cell processing laboratories worldwide.MethodsAn exploratory survey that was designed to identify variations in manufacturing practices in novel cellular therapy products was sent to cell processing laboratory directors worldwide. The questionnaire focused on the manufacturing life cycle of different cell therapies (i.e., collection, purification, in vitro expansion, freezing and storage, and thawing and washing), as well as the level of regulations followed to process each product type.ResultsThe majority of the centers processed hematopoietic progenitor cells (HPCs) from peripheral blood (n = 18), bone marrow (n = 16) or cord blood (n = 19), making HPCs the most commonly processed cells. The next most commonly produced cellular therapies were lymphocytes (n = 19) followed by mesenchymal stromal cells (n = 14), dendritic cells (n = 9) and natural killer (NK) cells (n = 9). A minority of centers (<5) processed pancreatic islet cells (n = 4), neural cells (n = 3) and induced-pluripotent stem cells (n = 3). Thirty-two laboratories processed products under an investigational status, for either phase I/II (n = 27) or phase III (n = 17) clinical trials. If purification methods were used, these varied for the type of product processed and by institution. Environmental monitoring methods also varied by product type and institution.ConclusionThis exploratory survey shows a wide variation in cellular therapy manufacturing practices across different cell processing laboratories. A better understanding of the effect of these variations on the quality of these cell-based therapies will be important to assess for further process evaluation and development.     

Automated Good Manufacturing Practice–compliant generation of human monocyte-derived dendritic cells from a complete apheresis product using a hollow-fiber bioreactor system overcomes a major hurdle in the manufacture of dendritic cells for cancer vaccines

BackgroundAlthough dendritic cell (DC)–based cancer vaccines represent a promising treatment strategy, its exploration in the clinic is hampered due to the need for Good Manufacturing Practice (GMP) facilities and associated trained staff for the generation of large numbers of DCs. The Quantum bioreactor system offered by Terumo BCT represents a hollow-fiber platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. In the respective established protocols, the hollow fibers are coated with fibronectin and trypsin is used to harvest the final cell product, which in the case of DCs allows processing of only one tenth of an apheresis product.Materials and ResultsWe successfully developed a new protocol that circumvents the need for fibronectin coating and trypsin digestion, and makes the Quantum bioreactor system now suitable for generating large numbers of mature human monocyte-derived DCs (Mo-DCs) by processing a complete apheresis product at once. To achieve that, it needed a step-by-step optimization of DC-differentiation, e.g., the varying of media exchange rates and cytokine concentration until the total yield (% of input CD14⁺ monocytes), as well as the phenotype and functionality of mature Mo-DCs, became equivalent to those generated by our established standard production of Mo-DCs in cell culture bags.ConclusionsBy using this new protocol for the Food and Drug Administration–approved Quantum system, it is now possible for the first time to process one complete apheresis to automatically generate large numbers of human Mo-DCs, making it much more feasible to exploit the potential of individualized DC-based immunotherapy.