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Impact considerations of post-production processes on cell and gene drug products

  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    John Fink
    Correspondence
    Correspondence: John Fink, MBA. PerkinElmer 68 Elm St, Hopkinton, MA 01748, USA.
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    PerkinElmer, Hopkinton, Massachusetts, USA
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  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Michael Scott
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Novo Nordisk, Fremont, California, USA
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  • Sebastian Rieck
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    ViaCyte, Inc, San Diego, California, USA
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  • Robert Jones
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Cryoport Systems, Irvine, California, USA
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  • Jean-Sebastian Parisse
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Aseptic Technologies, Gembloux, Belgium
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  • Heidi Hagen
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Vineti, San Francisco, California, USA
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  • Yonatan Lipsitz
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Sana Biotechnology, Cambridge, Massachusetts, USA
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  • Steve Oh
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Bioprocessing Technology Institute, A*STAR Research Entities, Singapore, Republic of Singapore
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  • Dominic Clarke
    Affiliations
    International Society for Cell & Gene Therapy Process and Product Development Subcommittee, Vancouver, Canada

    Discovery Life Sciences, Huntsville, Alabama, USA
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  • Author Footnotes
    ⁎ These authors contributed equally to this work.

      Abstract

      Cell and gene therapies are demonstrating clinical efficacy, but prohibitive product costs and operational complexity bottlenecks may limit expanded patient access to these innovative and transformative products. An initial survey and subsequent article published through the International Society for Cell & Gene Therapy in 2017 presented a roadmap on how specific steps, from tissue procurement and material acquisition to facility operation and production, contribute to the high cost of cell and gene therapies. Herein the authors expanded the investigation to provide considerations to better understand how post-production procedures can impact a product's accessibility to patients. The administration of a drug product to and follow-up in a patient involve key decisions in several post-production process areas, such as product storage, distribution and handling logistics and compliance, across the value chain through integrated data management solutions. Understanding as well as carefully evaluating these specific components is not widely considered during early process development but is critical in developing a viable product life cycle.

      Introduction

      Despite tremendous clinical success, the high price tag commonly associated with currently approved cell and gene therapies (CGTs) continues to represent a major hurdle for global industrial translation to a widespread patient pool [
      • Elverum K
      • Whitman M.
      Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine.
      ,

      Growth & Resilience in Regenerative Medicine—Annual Report - 2020, accessed 02 May 2021, < https://alliancerm.org/sector-report/2020-annual-report/>.

      ,
      • Stanton D.
      Cost of goods is crucial for the future of regenerative medicine.
      ,
      • Scott C.
      Challenges and opportunities in CAR T-Cell development and manufacturing.
      ]. Optimization of the economic aspects of a CGT product should be a focus from the beginning of product development, as every cost decision in the early stages of the product lifecycle can significantly impact and may limit the ability to make changes to manufacturing scale, consistency and global access [
      • Spink K
      • Steinsapir A.
      The long road to affordability: a cost of goods analysis for an autologous CAR-T process.
      ,
      • Lopes A
      • Noel R
      • Sinclair A.
      Cost analysis of vein-to-vein CAR T-cell therapy: automated manufacturing and supply chain.
      ]. To that end, the International Society for Cell & Gene Therapy (ISCT) Product and Process Development (PPD) Subcommittee previously published a roadmap to help understand CGT product costs—and thus improve patient access—through the evaluation of key process steps: tissue procurement (cost per unit of cells) and manufacturing (cost per unit of cells and cost per dose) [
      • Lipsitz YY
      • Milligan WD
      • Fitzpatrick I
      • et al.
      A roadmap for cost-of-goods planning to guide economic production of cell therapy products.
      ]. In 2018, a follow-up survey was completed across the ISCT membership asking for the identification and characterization of post-production processes that are critical to bringing CGT therapeutics currently under development to patients (see supplementary Document 1). The goal of the survey and present article was not to articulate the specific impacts post-production processes represent to the final cost of treatment and/or product, but rather to establish a set of central themes and key considerations specific to post-production processes that can inform key decisions inherent in each process step.
      The survey focused on steps or processes required to deliver a manufactured product to a patient: (i) product storage and transport, (ii) receiving and patient administration and (iii) post-administration and follow-up. Survey respondents covered a wide range of institutions pursuing multiple product derivations (autologous and allogeneic) and product cell types across a spectrum of clinical development statuses, regulatory compliance regions and commercial manufacturing strategies (see supplementary Document 1). Strikingly, the survey results suggest that a significant number of CGT product developers do not consider post-production steps as major cost drivers or drivers of logistic complexity early in product development (Figure 1). These steps include how the product is stored, handled, delivered and administered at the clinic. The differences in operational complexity between autologous and allogeneic product modalities can affect post-production cost considerations. Although economies of scale benefit allogeneic therapies by offering cost benefits over patient-specific autologous therapies during product production [
      • Lipsitz YY
      • Milligan WD
      • Fitzpatrick I
      • et al.
      A roadmap for cost-of-goods planning to guide economic production of cell therapy products.
      ], the costs and logistics optimization framework can change in post-production phases depending on product modality. Challenges unique to allogeneic therapies, which can be distributed to patients across a wide geographic area, include deciding where to position product storage and distribution supply chains for delivery to a multitude of administration sites (health care providers and insurers) with varying capabilities and constraints [

      Reed C. Recalibrating the Supply Chain For Allogenic Cell Therapies. 2019. Accessed May, 2021. https://www.cellandgene.com/doc/recalibrating-the-supply-chain-for-allogeneic-cell-therapies-0001.

      ,

      O'Donnell D. The Cell Therapy Supply Chain: Logistical Considerations for Autologous Immunotherapies. 2015. Accessed May, 2021. https://bioprocessintl.com/manufacturing/cell-therapies/the-cell-therapy-supply-chain-logistical-considerations-for-autologous-immunotherapies/.

      ,
      • Viswanathan S
      • Puich M.
      CMC obstacles in cell and gene therapy: four solutions to solve six challenges.
      ].
      Fig 1
      Fig. 1Key considerations roadmap for post-production of CGT therapeutics. ISCT survey respondents indicated anticipated cost drivers of each stage of the post-production process, identifying key themes and considerations. Range = minimum and maximum values of responses. Admin, administration. (Color version of figure is available online.)
      In this article, the authors aim build upon the 2018 ISCT survey to inform therapeutic sponsors in early-stage development of the key considerations of post-production steps required to deliver CGT therapies to the patient. The article together with the ISCT survey results addresses the challenges encountered with each post-production step. Moreover, other considerations are addressed such as the capabilities and product ownership of the storage, distribution and administration/follow-up sites or partners that are needed to comply with measures ensuring the safety and integrity of the CGT product (Figure 1).

      Product ownership and liability considerations

      Overall, over 50% of ISCT survey participants did not consider multiple post-production steps (thawing, dilution, media exchange/wash, on-site formulation) as part of their manufacturing process. In addition, approximately two thirds of respondents placed product compliance responsibility on the point of delivery and/or administration site.
      An important issue affecting post-production steps is the ownership of the product at each point in the supply chain of custody (COC) and the party responsible for the drug substance, drug product (DP) or intermediates throughout the potentially complex operational processing steps. The implementation of additional critical process steps performed by clinical staff to minimize production costs can create a trade-off that increases costs, operational complexity and liability at the clinical site. Conversely, clinical sites may require manufacturers to pay for on-site product storage and preparation costs and may expect the manufacturer to provide specialized equipment, devices, training and consumables. Does the manufacturer's responsibility end at the hospital loading dock if the clinical facility is responsible for performing quality-critical dose preparation activities? If a clinical site improperly handles a dose, is it the responsibility of the clinical site or the manufacturer to pay for it? If a patient experiences an infection after administration, how will the source of contamination be identified and who will be responsible? Few hospitals will be willing to accept this level of accountability or ambiguity outside of the confines of a limited clinical trial, and this may limit patient access to CGT products.
      Some academic hospitals on the leading edge of cell therapy development and clinical investigations have the facilities and know-how to prepare products for administration. Many of these are even willing to accept some of the cost, responsibility and liability for preparation and formulation. However, will they still be willing and able to support this burden when the product transfers into a high-volume commercial model? What about the many more hospitals that do not have a Good Manufacturing Practice (GMP)-compliant cleanroom facility and staff trained in aseptic cell handling? It is critical to consider product format, supply chain logistics and resulting impact on clinical site requirements early in development to maximize the commercial potential of a product. Thoughtful design of how, when and where the customer will interface with the cell therapy product, from pre-clinical product development through clinical trials, will pay significant dividends by ultimately controlling costs, improving patient safety and maximizing the potential for a successful clinical and commercial outcome.

      Product compliance through data management throughout post-production value chain

      One of the key areas wherein a therapy developer can set up their product for operational and regulatory success is strategic and incorporates early adoption of data management. Indeed, the majority of respondents indicated multi-faceted requirements for the administration site to document data regarding product handling, characterization and/or patient records.
      Data management and data handling are important in all therapeutic, GMP-compliant research developments. The personalized nature of advanced therapies, such as CGTs, profoundly changes the paradigm of data management and drives the need for modern data management practices. It is essential to establish a compliant method to track the product from manufacturing to patient and start this tracking early in the clinical trial stage. When to implement an electronic data management system relies primarily on three elements: complexity of the product and process, volume of patients per trial and number of collection and treatment sites [

      U.S. Department of Health and Human Services. Food and Drug Administration. Center for Biologics Evaluation and Research. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). 2020. Accessed May 2021. https://www.fda.gov/media/113760/download.

      ,

      European Commission. Guidelines of 22.11.2017 Good Manufacturing Practice for Advanced Therapy Medicinal Products. 2017. Accessed May 2021. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf.

      ]. There are three main areas for consideration, and these will be discussed in the following sections.

      Chain of identity and COC management from order to administration

      Chain of identity (COI) and COC are essential data sets for each advanced therapy order. COI is the fundamental method for ensuring patient safety and provides an overarching method for linking key identifiers and data to a particular patient or donor from order to treatment. It is critically important to trace patient cells from start to finish, as both the Food and Drug Administration and European Medicines Agency require robust traceability systems for any advanced therapy [

      U.S. Department of Health and Human Services. Food and Drug Administration. Center for Biologics Evaluation and Research. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). 2020. Accessed May 2021. https://www.fda.gov/media/113760/download.

      ,

      European Commission. Guidelines of 22.11.2017 Good Manufacturing Practice for Advanced Therapy Medicinal Products. 2017. Accessed May 2021. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf.

      ].

      GMP data collected across the supply chain from all participants in the ecosystem

      Multiple sources of data across the supply chain—both GMP and non-GMP—drive high variability in data quality and create accessibility issues. This is amplified as the ecosystem is scaled and patient or product volume increases. High quality data are the starting point for timely, accurate delivery of the product and for product and process understanding. Whether data are being gathered manually or electronically, utilizing industry standards—or best practices where established standards do not exist—is an important first step toward reducing variability. It is also important to consider the stakeholders’ needs and provide forms, processes and systems that are easy to use and set them up for success. Automating data capture is an important consideration given the complexity of CGTs. Focusing on automating one key thread of this, such as COI/COC, and capturing data across the entire value chain, may aid in reducing variability and help to prevent product mix-ups.

      Integration of data and analysis across the value chain

      The value chain (product order to post-administration follow-up) for advanced therapies is characterized by the “many-to-many” nature of interactions among ecosystem participants (partners, functions, process steps and geographical locations). This complex, multi-dimensional network of interactions results in unique data complexities. Integration of data across the value chain provides (i) easy access to and visibility of operational information that can be analyzed to understand opportunities for improvement; (ii) transparency and effective collaboration, which improves service to patients and providers; and (iii) speed and efficiency in regulatory compliance.
      Initially, it may be simple and inexpensive to manage COI/COC with a manual paper-based system, but as patient volume and participants in the ecosystem scale, a manual system can become difficult and present an increased risk of mistakes and cost. The right time to consider a digital traceability platform depends on the complexity of the product and ecosystem and how well a developer understands the operational process, rather than the clinical trial stage. Ultimately, these discussions and decisions should be carried out early in the clinical stages, as this sets the digital framework through commercialization.

      Product configurations and clinical impact

      The type of product configuration has a strategic impact on post-production processes. ISCT survey respondents indicated various formats of product storage pre-administration, of the total 22% had fresh product and 55% required cryogenic storage. In addition, the expected product shelf life ranged from immediate use (approximately 32% of respondents) to greater than 1 year (approximately 39% of respondents).
      Because of difficulties maintaining DP stability for cell therapies, both fresh and cryopreservation formulations may be unsuitable for direct patient administration. In these scenarios, added steps may be required at the manufacturing or clinical site, which can significantly impact supply chain and clinical administration risks and costs. Cell handling or culture at the clinical site and buffer exchange steps, which are more common for cryopreserved products, can introduce unique obstacles. In the following sections, four scenarios are described that present a potential to increase early development costs but decrease the risk to patients and increase clinical study success (Table 1).
      Table 1Ramifications of various DP delivery-to-patient strategies of post-production processes.
      Product use scenarioRelative COGSDevelopment costsClinical site responsibilitiesClinical site requirementsRisksShelf lifeClinical site burden
      Manufacturer ships frozen DP in cryovials or bagsLLStore DS in LN2; thaw, wash and formulate DP dose per cGMP; transfer viable DP to OR; transfer into delivery device; administerGMP cleanroom with qualified cell culture systems and equipment; LN2 storage

      Manufacturer-provided delivery system
      Safety/efficacy: H

      Product loss: M

      Technical risk: L
      HH
      Manufacturer ships fresh DP in cryovials or bagsM-HMStore at controlled temperature; transfer into delivery device; administerCold chain/RT storage

      Manufacturer-provided delivery system
      Safety/efficacy: M

      Product loss: H

      Technical risk: L
      LM
      Manufacturer ships frozen DP, which is prepared in ORL-MHStore in LN2; thaw and prepare dose in closed system; transfer into delivery device; administerLN2 storage; manufacturer-provided dose preparation and delivery systemsSafety/efficacy: L

      Product loss: L

      Technical risk: L-M
      HL-M
      Manufacturer ships frozen DP in ready-to-use doseLHStore in LN2; thaw and transfer into delivery device; administerLN2 storage; manufacturer-provided delivery systemSafety/efficacy: L

      Product loss: L

      Technical risk: M-H
      HL
      cGMP, current GMP; DS, drug substance; H, high; L, low; LN2, liquid nitrogen; M, medium; OR, operating room; RT, room temperature.

      Cryopreserved cell product requiring on-site cell handling and dose preparation

      The easiest and least expensive approach in the short term is for the manufacturer to deliver cryopreserved DP in an off-the-shelf container closure. This represents the simplest configuration for the manufacturer, although they would be required to prove sterility, sterile barrier integrity and other safety elements of the DP as delivered. The burden of dose preparation, which frequently involves risky open operations, would shift to the clinical site, which may need to thaw, rinse, concentrate, formulate, store and transfer the dose prior to administration, possibly performing some operations multiple times. Because the manufacturer effectively loses control over the product once it is received by the hospital pharmacy, clinical results become highly dependent on the clinical site's staff, equipment and quality control system. This may increase product variability, impact efficacy, result in differences in formulated DP between sites and increase patient safety risk as a result of open processing and the inability to perform compendial 14-day sterility testing on the product prior to administration. Regulators may also consider this type of on-site processing as part of the manufacturing process, increasing the burden on the sponsor company.

      Just-in-time manufacturing of fresh cell product

      To avoid point-of-use preparation steps, a manufacturer may ship a ready-to-use dose in the form of a viable cell product at cold chain (e.g., 4–8°C) or controlled room temperature. Although tight temperature control during transport and storage of the product becomes more critical, this may reduce or eliminate the risk presented by open procedures performed by clinical staff. However, the production and shipping logistics of a viable DP are substantial. For many cell therapy applications, the administration procedure is considered elective, which requires pre-scheduling of operating rooms and staff to ensure that production is tightly aligned with demand to avoid wasted overproduction or fulfillment failure. The short shelf life stability, long process durations and variable yields of most current cell therapy productions present significant hurdles for this delivery model. Other items to consider in this scenario include the following: (i) limitations on clinical scheduling flexibility and related border/customs delays; (ii) expired product caused by emergent clinical cases that bump elective procedures; (iii) hospitals unwilling to pay for expired product, as most hospital procurement departments push to maximize product shelf life and frequently will not accept durations of less than 6 months or 12 months, with unused doses possibly charged back to the manufacturer.
      Given these constraints, companies may elect to pursue a just-in-time manufacturing approach to support phase 1/2a trials and then transition to a more scalable product configuration and distribution model for later-stage development. This adds the challenge of demonstrating comparability of the clinical product. This approach does not preclude a cryopreservation step during the manufacturing process. For example, the manufacturing process could produce and cryopreserve the DP and then thaw (reformulating as necessary) and ship a fresh product for direct administration.

      Cryopreserved cell product with on-site dose preparation using a closed system

      In this scenario, an option could be considered that optimizes a cell-based DP for safety and efficacy while limiting technical development risk. Providing a highly stable cryopreserved DP promotes efficacy by maintaining cell health, and when combined with a closed dose preparation and delivery system, this can dramatically reduce risks related to on-site dose preparation. By eliminating open handling operations and the need to perform dose preparation steps in a dedicated cell processing facility, the risk of product contamination is minimized. A properly designed closed system also controls for environmental variables and potential user errors and can be validated through a medical device design control process. However, development of an integrated, closed system with aseptic connections between the DP container closure, formulation system and administration device requires a significant investment in development time and resources to realize these benefits once the product enters clinical studies. This approach also requires co-development of medical devices, which may require the CGT manufacturer to develop in-house device expertise or engage with external design–build partners.

      Cryopreserved ready-to-administer cell product

      In many cases, the ideal DP configuration for both customer ease of use and product quality is a cryopreserved ready-to-use cell dose in a container closure that aseptically connects to a delivery system. This is the ideal product configuration for many applications, as it minimizes logistical complexity and cost, simplifies end user handling and reduces risks caused by user errors. In a best case scenario, all that would be required is control over the thaw process. Although this approach may pay dividends in the longer term, it should be expected that the technical challenges to develop such a cell product formulation may be greater than other delivery models and could lead to higher development costs and longer timelines. The cells would have to tolerate cryopreservation utilizing a dose of cryoprotectant that could be safely co-delivered to the patient. However, the cost of goods sold (COGS) could be kept lower by automating large batch production with long product shelf life stability, eliminating the need to develop sophisticated medical device formulation systems. With minimal clinical site preparation required, no dose preparation costs or facility requirements would be incurred and the risk of product contamination or variability that could impact safety or efficacy would be minimized.
      Other scenarios are certainly possible, but those just described identify some of the product quality and customer satisfaction issues that a cell therapy manufacturer should consider when determining how the product will be delivered, prepared and administered. It is likely that clinical studies will provide important information related to product design and clinical use that may drive significant product changes late in development, which are typically very expensive and may delay commercialization. To mitigate the risk that major future product design iterations will be required, it is important to ensure that planning for clinical and commercial success is incorporated during product development and pre-clinical assessments. Despite frequent pressure on the product development team to move quickly into clinical studies, to avoid the need for additional phase 1 patient cohorts and minimize the costs and delays related to clinical bridging studies, the drug substance/DP configuration utilized in early clinical studies (e.g., using a fresh DP) should be designed so that it may be considered equivalent to the version intended for commercial distribution (e.g., cryopreserved DP).
      Regulators may determine that on-site formulation procedures are actually part of the company's current GMP manufacturing processes, increasing the burden on both the company and clinical sites. To mitigate this, streamlined point-of-use dose preparation should be prioritized. The sterility of the administered dose must be assured at the point of use, and other controls implemented to ensure patient safety and product quality need to meet the requirements of regulators. In contrast to the possibility that shipping and customs delays may consume precious shelf life of fresh cell products, leading to customer refunds, considering logistical and practical customer issues early in development minimizes the risk of late-stage product changes and ensures that hospital purchasing agents will be willing to purchase products with an acceptable shelf life. To help identify potential issues early, a preliminary production and distribution plan should be established that determines the number and regional distribution of manufacturing and logistics facilities to support all targeted regions. As an example, such planning for shipment of fresh cell products will identify the costs of establishing multiple manufacturing facilities and ongoing logistical challenges and related product costs, which should be weighed against the up-front product development cost and related timeline impact to advance a ready-to-use cryopreserved product. It is not possible to fully understand all the issues that will arise during clinical and commercial launch activities, but careful planning early in the process can have a tremendous impact on product candidate success.

      Product storage or packaging for shipment

      ISCT survey respondents illustrated a range of cryopreservation strategies, shipping temperatures and product shelf lives. The majority of respondents indicated their products to be cryopreserved in either bags or cryovials at volumes of ≤50 mL. A total of 72% of respondents included the use of dimethyl sulfoxide (DMSO) in their cryoprotectant.

      Cryopreservation media

      The composition of the formulation medium, sometimes referred to as cryopreservation medium, is one of several critical process factors in DP development. A properly formulated DP medium should maintain the critical quality attributes (CQAs) of the therapy; provide DP stability, enabling the appropriate shelf life; and contain only components that are safe and appropriate for patient administration. These considerations apply to both fresh and cryopreserved DPs. Cryopreservation media must also minimize the impact of cold and freezing on CQAs during formulation, cryopreservation, shelf life and thawing. The development of formulations for cell therapies is especially complex because of the incomplete understanding of the factors that dictate the safety and efficacy of these cells. Hunt et al. [
      • Hunt CJ.
      Technical Considerations in the Freezing Low-Temperature Storage and Thawing of Stem Cells for Cellular Therapies.
      ] documented a comprehensive list of considerations for freezing, storage and thawing cells for therapies, including a review of cryoprotective agents (CPAs), such as DMSO, glycerol, ethylene glycol, propylene glycol, sucrose, polyvinylpyrrolidone and hydroxyethyl starch. Formulation studies should occur during the research and development phase of a DP to develop an understanding of the relevant CQAs and appropriate analytical tools to measure whether the performance of the DP is affected by the CPA and cryogenic processes. Minimally, cell viability and yields on recovery should be measured. Additional assays, such as T-cell killing and immunosuppressive ability, can be measured depending on the DP. Several commercial options may be considered to avoid customized formulation and alleviate raw material risks [
      • Scott M
      • Clarke D
      • Lipsitz Y
      • et al.
      Transitioning from development to commercial: risk-based guidance for critical materials management in cell therapies.
      ].
      The decision of formulation media may have significant cost implications, reaching from manufacturing to patient administration. Changing formulations during a clinical campaign is a significant action that can impact safety and efficacy and jeopardize product equivalence. Developers should plan out a commercialization strategy early on that addresses desired DP considerations and invest in enabling that strategy to avoid making formulation or cryopreservation changes as the product moves through the different stages of clinical trials. Woods et al. [
      • Woods EJ
      • Thirumala S
      • Badhe-Buchanan SS
      • Clarke D
      • Mathew AJ
      Off the shelf cellular therapeutics: Factors to consider during cryopreservation and storage of human cells for clinical use.
      ] reviewed factors to consider in cryopreservation and storage of cells for clinical use. Among the issues raised are mechanisms of damage that can occur during cryopreservation, elements to consider for successful preservation (cell concentration, cold shock injury, slow or rapid cooling injury, storage injury, thawing injury and cytotoxicity and osmotic effects of the CPA), systems and devices used and best practices for GMP applications.

      Product storage and packaging-for-shipment formats

      In selecting containers, the different types of clinical applications as well as volume of product and how it is to be administered to the patient should be considered. For allogeneic applications, the number of patients and potential use of the product for several different indications (which may require different doses) will influence the choice of containers for products made from one large production batch. The type of container determines the manufacturing fill–finish process, level of automation, shipping and storage devices, inventory density and freeze–thaw equipment, among other elements. A cell therapy product cannot be delivered without a container, and although this seems like a relatively simple decision, it also has the potential to materially impact cost. Depending on the dose volume, container options are typically a bag or vial.
      Cell therapy bags have been in use for decades, come in a wide range of sizes, can be aseptically filled and hermetically sealed and have a high sample:container area ratio to improve freeze–thaw performance. However, the filling and processing of these bags are often performed manually, thus requiring specific operator skills, such as bulk massaging for homogenization and air removal to avoid breaking. These requirements can necessitate atypical storage methods and preclude automated handling; therefore, processing is intrinsically hard to scale up or scale out. Bags must also be able to withstand DMSO.
      Cell therapy cryogenic vials are relatively new to the market, and most were initially introduced in small-volume sizes but have since increased to 50 mL. The price of the container itself is typically not significant compared with the total cost of a therapy product, but the processes and equipment the container type requires could impact facility costs and the overall cost of the final product. Woods and Thirumala [
      • Woods EJ
      • Thirumala S.
      Packaging Considerations for Biopreservation.
      ] reviewed packaging considerations for biopreservation of mesenchymal stromal cells and introduced a closed system cryovial called CellSeal(R) (Sexton Biotechnologies, Indianapolis, IN). Although freeze–thaw performance may be affected by its lower sample:container area ratio, its size and shape make CellSeal more amenable to automated handling and storage as well as more resistant to breakage [
      • Woods EJ
      • Thirumala S.
      Packaging Considerations for Biopreservation.
      ]. Aseptic Technologies’ AT-Closed Vial(R) (Raleigh, NC) system, which is a scalable closed filling system, has been widely adopted in the industry. There are now several companies offering sterile bags with automated filling (e.g., Miltenyi, Terumo, Saint-Gobain, OriGen Biomedical, Takara Bio).
      If using vials and stoppers, it is important to understand their behavior during cryopreservation so that container closure integrity can be maintained under the desired storage conditions and temperatures. The glass transition temperatures of the materials in the vial are a vital component of container closure integrity, and the field has started to use polymer materials where appropriate since they reduce the negative effects of the transition temperatures inherent to traditional glass containers while being comparable in terms of cost. Vials that are pre-closed and sterilized with the stopper in place will offer better behavior when frozen, even for larger volumes, as a result of the bonding and entanglement between the vial body and stopper [

      Aseptic Technologies. Container Closure Integrity of the AT-Closed Vial® Stored at Cryogenic Temperatures Proven Using Non-Destructive Headspace Analysis. 2014:2. Accessed May 2021. http://www.aseptictech.com/sites/default/files/publications/at-closed_vial_container_closure_integrity_using_headspace_analysis.pdf.

      ,]. Finally, the materials used in the vials or bags should be biocompatible for maintaining the CQAs of the CGT product.
      No matter which container is selected, automation is needed to scale the manufacturing process economically and enable high output and exacting reproducibility, both of which require machine precision beyond human skill. Additionally, a closed process can prevent contamination from product handling, especially at the point of delivery to the patient, where contamination risk should be minimized or eliminated. In the long run, investment in automation can result in reduction of COGS as a result of fewer failures, opportunity to scale up/out and meeting compliance with quality standards.
      A developer should consider the therapy, dose volume, freeze–thaw conditions, automation requirements, storage, transportation, fill–finish procedures and expected commercialization volume ranges as well as other supply chain logistics to best decide the container type. Understanding the fill–finish needs of the intended therapeutic early in process development will be essential to implementing a scalable solution to support commercial demand.

      Distribution supply chain: putting it all together

      The transport of a CGT product from a production site will be required for the majority of respondents to the ISCT COGS survey, with cold chain distribution being an integral part of the product delivery. The administration facility varied across respondents (hospital with GMP capabilities, hospital with surgical capability, general hospital, private clinic or physician's office).
      The distribution strategy of the CGT product-to-patient is determined by a combination of a product's modality and configuration, operational complexity, ownership/liabilities and compliance requirements. The cost drivers for these focus areas, as highlighted in previous sections, can influence the magnitude and identity of the cost drivers within the distribution supply chain. Implementing the appropriate cost and logistics optimization early in the development cycle of the product can reduce COGS in the long-term (Table 2).
      Table 2Product configurations, modalities or requirements.
      Post-production stepR&D/phase 1Phase 2Phase 3/commercialization
      Storage, packaging and/or shipmentSmall number of fresh doses with short shelf life to be delivered to one siteHundreds of frozen doses with longer shelf life to be delivered to many sitesThousands of frozen doses with longer shelf life in dispenser delivered to multiple sites
      Storage mediaHome brewCommercially formulated cryoprotectantOptimized and commercially formulated cryoprotectant
      Product and/or regulatory complianceEasy transport and administrationComplex thaw, wash, delivery and complex transportation

      Supplier validation and qualification
      Automation of delivery and logistics challenges

      Supplier validation and qualification

      Special handling services

      Reverse logistics and returns or recall
      Paper trailWeb-based inventory, order and fulfillment management

      Data services

      Product compliance support services

      Risk management program

      R&D, research and development.
      Because of the high cost and risk of shipping fresh apheresis materials, autologous therapies may benefit from being manufactured close to patient populations, although cryopreservation techniques at apheresis sites may help by increasing the time the material is viable. However, decentralized manufacturing significantly increases early development costs by requiring multiples of equipment, staff and procedures for each site but reduces overall costs and risk of loss in large-scale manufacturing and distribution when shipping internationally. Decentralized manufacturing also requires consistency of product specification and quality, probably best achieved through automated manufacturing processes and integrated management systems [
      • Harrison R.P.
      • et al.
      Decentralised manufacturing of cell and gene therapy products: Learning from other healthcare sectors.
      ]. Other factors for a decentralized manufacturing strategy should be considered, such as the additional cost and complexities of regulatory approvals at all sites and whether all sites would be suitable for both clinical and commercial manufacturing operations.
      For allogeneic therapies, a single manufacturing site may be sufficient to meet global requirements, but a distribution strategy would have to be developed to supply and resupply local treatment centers from local distribution “hubs” to keep costs manageable. “Hubs” providing current GMP storage and secondary packaging services would be critical for cost-effective, rapid supply of therapies to local clinics. In the future, it may be possible for existing pharmaceutical distribution infrastructure to adapt to provide storage and distribution services for CGT products, although this would mean significant investment in the necessary equipment and systems to manage ultra-cold and cryogenic materials. Overall, this additional network of infrastructure may be able to contribute to a reduction in the cost of management and distribution of CGTs. The availability and cost of such facilities may need to be considered, though commercial logistics companies are available to provide the necessary services. For ultra-rare therapies, direct shipping may be feasible.
      As a case study example of this, a European Union (EU)-based cell therapy developer that had effectively conducted phase 1 and 2 trials in a single hospital (phase 1) and within a single country (phase 2) needed a strategy for a phase 3 study involving distribution to over 1000 patients in multiple EU countries and the USA. The drug for the phase 1 and 2 studies had been stored at cryogenic temperatures at the manufacturing site and shipped to the local clinics on dry ice, as it had been determined that this had no demonstrable negative effect on the product over the short transportation time. However, this method could not be used for journeys longer than 4 h. For the phase 3 study, transportation had to be conducted using liquid nitrogen dry shippers from off-site GMP drug storage locations in the UK and USA. The company concluded that they could not handle the necessary volume of shipments from their own facility and so worked with a third party to provide additional storage and distribution hubs in the EU and USA. This strategy worked well and was significantly more cost-effective than the other option, which was to expand the storage areas at the manufacturing site, employ more staff to handle the shipments and ship to all clinics from a single EU location. A developer must determine insource versus outsource needs when defining the most appropriate distribution strategy.
      As another example, the manufacturing processes and supply chain structure for Dendreon's Provenge proved to be inefficient, initially resulting in manufacturing costs approaching 77% of the selling price. Even after significant process improvements and the introduction of automation, with significant headcount reduction, costs were brought down to only 53%. Compare this with typical biopharma manufacturing costs of 15–25% of the selling price [

      Palmer E. China's Sanpower takes on expensive Provenge manufacturing with Dendreon deal. 2017. Accessed May 2021. https://www.fiercepharma.com/manufacturing/china-s-sanpower-takes-expensive-provenge-manufacturing-dendreon-deal.

      ,
      • Spink K
      • Steinsapir A.
      The long road to affordability: a cost of goods analysis for an autologous CAR-T process.
      ].
      The recent publication of ISO 21973, General Requirements for Transportation of Cells for Therapeutic Use [

      International Organization for Standardization. ISO 21973:2020(E) Biotechnology — General requirements for transportation of cells for therapeutic use. 2020:19

      ], provides valuable guidance to address some of the inconsistencies and issues in the advanced therapy supply chain. The standard seeks to mitigate the risks associated with the movement of fragile materials by considering packaging and transportation as an integrated quality process that must be risk-assessed using validated shipping equipment with known historical data, validated shipping lanes and information technology systems to guarantee that COC and COI are maintained. Therapy developers and supply chain service providers should ensure they are familiar with this standard when planning clinical and commercial distribution strategies.
      An effective supply chain strategy is holistic, not segmented by development phase, and considers DP formulation and stability. Ideally, the strategy should be established before phase 1 studies. The long-term supply chain strategy should form part of regulatory submissions to demonstrate the product will be delivered to patients safely and efficiently. Like many of the variables discussed in this article, changes later in the development process can significantly affect time and cost, so it is beneficial to consider all variables up front along with the manufacturing strategy to ensure that product design and formulation requirements are met.

      Discussion

      The cell therapy modality presents unique DP and clinical administration considerations. Cell therapy development requires important decisions that interrelatedly impact the DP formulation and preservation strategy, supply chain and clinical handling and administration, all of which are important aspects of the overall costs related to the development and commercial distribution of a cell therapy product. The ISCT survey results have illustrated that as the field is maturing and more drug developers are establishing approaches to bring their products forward, a range of solutions are being applied. However, the survey results highlighted earlier do not capture how each of these DP and clinical administration decisions impact one another, and not all options are available to every cell therapy type. The 54 survey respondents represent diverse therapeutic approaches that include different geographies, institutions, cell types, allogeneic and autologous therapies and other aspects of this diverse modality. As a result, it is not yet possible to recommend ideal approaches by correlating DP and clinical handling and administration decisions with specific therapy types. Lessons from more established cell therapies and related therapeutics have informed the discussions herein, but novel therapy types may uncover additional considerations and combinations of approaches that provide insight into the reduction of costs and logistic complexity and minimization of risks related to new cell therapies.

      Funding

      No funding was received.

      Declaration of Competing Interest

      The authors received salary and/or equity from their employers.

      Author Contributions

      Conception and design of the study: JF, MS and DC. Acquisition of data: JF, MS and JP. Analysis and interpretation of data: JF, MS, RJ, JP, HH and SR. Drafting or revising the manuscript: JF, MS, RJ, JP, HH, DC, SR and YL. All authors have approved the final article.

      Acknowledgments

      The authors thank the members of the ISCT Process and Product Development Subcommittee for their thorough review and suggested edits.

      Appendix. Supplementary materials

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