An assessment of the hospital exemption landscape across European Member States: regulatory frameworks,use and impact

The hospital exemption (HE) (Article 28(2) of Regulation (EC) No 1394/2007; the “ATMP Regulation”) rule allows the invaluable opportunity to provide patients with access to innovative, potentially life-saving treatments in situations of unmet clinical need. Unlicensed, developmental advanced therapy medicinal products (ATMPs) - cell-, gene- or tissue-based therapies - can be used to treat patients under certain conditions. Such products should be produced on a non-routine basis, custom-made for an individual patient under the responsibility of the requesting physician, for use in a hospital setting within the same Member State in which they are manufactured. The HE rule, and the specific requirements permitting its use, is further regulated at the Member State level, which has led to divergence in the implementation of HE across the European Union (EU). As a result, HE use varies significantly across Member States depending on their respective national legal implementation, policy makers’ interpretation of HE, clarity of guidance at the national level, reimbursement opportunities and level of ATMP research and development activities carried out by academic and commercial organizations. With important variations in how quality, safety and efficacy standards are implemented and controlled across EU Member States for ATMPs provided via the HE rule and a lack of transparency around its use, the HE rule draws concern around its potential impact on public health. In this article, the authors report results of a legal analysis of the implementation of HE across the UK, France, Germany, Italy, Spain, Poland and the Netherlands and research findings on its current utilization, highlighting divergences across countries as well as gaps in legislation and control in these countries. The significance of these divergences and the differing levels of enforcement are discussed as well as their associated impact on patients, industry and health care professionals.     

Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products

Hospital exemption (HE) is a regulated pathway that allows the use of advanced therapy medicinal products (ATMPs) within the European Union (EU) under restrictive conditions overseen by national medicine agencies. In some EU countries, HE is granted for ATMPs with no demonstrated safety and efficacy; therefore, they are equivalent to investigational drugs. In other countries, HE is granted for ATMPs with demonstrated quality, safety and efficacy and for which centralized marketing authorization has not been requested. The Committee on the Ethics of Cell and Gene Therapy of the International Society for Cell & Gene Therapy reflects here on the ethical issues concerning HE application from the perspective of the patient, including risk–benefit balance, accessibility and transparency, while providing evidence that HE must not be regarded as a conduit for unproven and unethical ATMP-based interventions. Indeed, HE represents a legal instrument under which a patient's need for access to novel ATMPs is reconciled with ethics. Moreover, for some unmet medical needs, HE is the only pathway for accessing innovative ATMPs. Nonetheless, HE harmonization across EU Member States and limitations of ATMP use under the HE rule when similar products have already been granted centralized marketing authorization to avoid a parallel regulatory pathway are controversial issues whose political and economic consequences are beyond the scope of this review. Finally, the institution of an EU registry of HE applications and outcomes represents a priority to improve transparency, reduce patient risks, increase efficiency of health systems, facilitate company awareness of business opportunities and boost progressive entry of ATMPs into the therapeutic repertoire of health systems.     

Regulation of advanced therapy medicinal products in Europe and the role of academia

Background aimsAdvanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients. Academic good manufacturing practice (GMP) centers are major contributors in the development of ATMPs and this study assessed the impact of regulations on them.MethodsEuropean academic and non-industrial facilities (n = 747) were contacted, and a representative sample of 50 replied to a detailed questionnaire. Experienced centres were further selected in every Member State (MS) for semi-structured interviews. Indicators of ATMP production and development success were statistically assessed, and opinions about directive implementation were documented.ResultsFacilities experienced in manufacturing cell therapy transplant products are the most successful in developing ATMPs. New centres lacking this background struggle to enter the field, and there remains a shortage of facilities in academia participating in translational research. This is compounded by heterogeneous implementation of the regulations across MS.ConclusionsGMP facilities successfully developing ATMPs are present in all MS. However, the implementation of regulations is heterogeneous between MS, with substantial differences in the definition of ATMPs and in the approved manufacturing environment. The cost of GMP compliance is underestimated by research funding bodies. This is detrimental to development of new ATMPs and commercialization of any that are successful in early clinical trials. Academic GMP practitioners should strengthen their political visibility and contribute to the development of functional and effective European Union legislation in this field.     

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Background aimMesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation.MethodsThe authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5⁺ MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers.ResultsAs of now, 12 wounds in nine patients have been treated with 5 × 10⁵ autologous ABCB5⁺ MSCs per cm² wound area, eliciting a median wound size reduction of 63% (range, 32–100%) at 12 weeks and early relief of pain.ConclusionsThe authors describe here their GMP- and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5⁺ MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds.     

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States

Background aimsRegulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions.MethodsA retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions.ResultsIn the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU.ConclusionsThe current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.     

Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a novel tailored model for optimizing performance and estimating costs

Background aimsAdvanced therapy medicinal products (ATMP) have gained considerable attention in academia due to their therapeutic potential. Good Manufacturing Practice (GMP) principles ensure the quality and sterility of manufacturing these products. We developed a model for estimating the manufacturing costs of cell therapy products and optimizing the performance of academic GMP-facilities.MethodsThe “Clean-Room Technology Assessment Technique” (CTAT) was tested prospectively in the GMP facility of BCRT, Berlin, Germany, then retrospectively in the GMP facility of the University of California-Davis, California, USA. CTAT is a two-level model: level one identifies operational (core) processes and measures their fixed costs; level two identifies production (supporting) processes and measures their variable costs. The model comprises several tools to measure and optimize performance of these processes. Manufacturing costs were itemized using adjusted micro-costing system.ResultsCTAT identified GMP activities with strong correlation to the manufacturing process of cell-based products. Building best practice standards allowed for performance improvement and elimination of human errors. The model also demonstrated the unidirectional dependencies that may exist among the core GMP activities. When compared to traditional business models, the CTAT assessment resulted in a more accurate allocation of annual expenses. The estimated expenses were used to set a fee structure for both GMP facilities. A mathematical equation was also developed to provide the final product cost.ConclusionsCTAT can be a useful tool in estimating accurate costs for the ATMPs manufactured in an optimized GMP process. These estimates are useful when analyzing the cost-effectiveness of these novel interventions.     

A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies

Background aimsAdvanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area.MethodsWe have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy “Plagencell network” for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years.ResultsThe cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <–150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years.ConclusionsOur data indicate that new guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.     

What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings

Background aimsRecent technical and clinical advances with cell-based therapies (CBTs) hold great promise in the treatment of patients with rare diseases and those with high unmet medical need. Currently the majority of CBTs are developed and manufactured in specialized academic facilities. Due to small scale, unique characteristics and specific supply chain, CBT manufacturing is considered costly compared to more conventional medicinal products. As a result, biomedical researchers and clinicians are increasingly faced with cost considerations in CBT development. The objective of this research was to develop a costing framework and methodology for academic and other small-scale facilities that manufacture cell-based therapies.MethodsWe conducted an international multi-center costing study in four facilities in Europe using eight CBTs as case studies. This study includes costs from cell or tissue procurement to release of final product for clinical use. First, via interviews with research scientists, clinicians, biomedical scientists, pharmacists and technicians, we designed a high-level costing framework. Next, we developed a more detailed uniform methodology to allocate cost items. Costs were divided into steps (tissue procurement, manufacturing and fill-finish). The steps were each subdivided into cost categories (materials, equipment, personnel and facility), and each category was broken down into facility running (fixed) costs and operational (variable) costs. The methodology was tested via the case studies and validated in developer interviews. Costs are expressed in 2018 euros (€).ResultsThe framework and methodology were applicable across facilities and proved sensitive to differences in product and facility characteristics. Case study cost estimates ranged between €23 033 and €190 799 Euros per batch, with batch yield varying between 1 and 88 doses. The cost estimations revealed hidden costs to developers and provided insights into cost drivers to help design manufacturing best practices.ConclusionsThis framework and methodology provide step-by-step guidance to estimate manufacturing costs specifically for cell-based therapies manufactured in academic and other small-scale enterprises. The framework and methodology can be used to inform and plan cost-conscious strategies for CBTs.     

Business oriented EU human cell and tissue product legislation will adversely impact Member States’ health care systems

The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime—i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States’ health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe’s risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States’ health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on “placing on the market of ATMPs,” which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.     

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.     

Comparison of new Brazilian legislation for the approval of advanced therapy medicinal products with existing systems in the USA,European Union and Japan

Background aimsAdvanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on genes, cells and tissues. The first ATMP received marketing authorization in Europe in 2009, whereas Brazil granted the first authorization in 2020. The objective of this study was to compare the regulatory models adopted by Brazil, the USA, Japan and the European Union, which comprise the member countries of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, with regard to the marketing authorization of ATMPs.MethodsThe authors performed a review of the scientific literature and official documents of the regulatory agencies in the aforementioned countries.ResultsThe legislation and regulatory guidelines adopted by the regulatory agencies exhibit similarities and differences. It was not possible to assess whether these differences can be translated into divergent final recommendations by regulatory authorities upon a request for marketing authorization.ConclusionsIn the future, it will be appropriate to start a progressive process of harmonization between these agencies in terms of terminology, legal recommendations and characterization requirements. This is particularly important for emerging countries such as Brazil. In this sense, some measures can be taken to achieve alignment between regulators.     

Utility of routine evaluation of sterility of cellular therapy products with or without extensive manipulation: Best practices and clinical significance

Background

We analyzed the results of routine sterility testing performed in our center over the last 10 years, in the context both hematopoietic stem cell transplantation (HSCT) and Advanced Therapeutic Medicinal Products (ATMPs).

我国二级及以上医疗机构开展公共卫生工作现况分析

目的 对二级以上医疗机构疾病预防控制等公共卫生工作现况进行评估。方法 对全国10个省163家医院进行二级以上医疗机构公共卫生工作开展基本情况调查和人员基本情况调查的问卷调查;对全国34个省、自治区、直辖市和新疆生产建设兵团进行函调以及对浙江、河南、辽宁和甘肃4个省进行实地调研。结果（1）医疗机构应承担的公共卫生职能与落实情况相差甚远。（2）医疗机构从事公共卫生工作积极性不高。（3）医疗机构在公共卫生工作中接受多个部门管理,但在工作中缺乏协调。结论（1）弥合临床医疗服务体系与公共卫生体系的割裂状态。（2）增强医疗机构从事公共卫生工作积极性。（3）加强督察考核,促进公共卫生工作的落实。     

Decisional tool for cost of goods analysis of bioartificial liver devices for routine clinical use

Background aimsBioartificial liver devices (BALs) are categorized as advanced therapy medicinal products (ATMPs) with the potential to provide temporary liver support for liver failure patients. However, to meet commercial demands, next-generation BAL manufacturing processes need to be designed that are scalable and financially feasible. The authors describe the development and application of a process economics decisional tool to determine the cost of goods (COG) of alternative BAL process flowsheets across a range of industrial scales.MethodsThe decisional tool comprised an information database linked to a process economics engine, with equipment sizing, resource consumption, capital investment and COG calculations for the whole bioprocess, from cell expansion and encapsulation to fluidized bed bioreactor (FBB) culture to cryopreservation and cryorecovery. Four different flowsheet configurations were evaluated across demands, with cell factories or microcarriers in suspension culture for the cell expansion step and single-use or stainless steel technology for the FBB culture step.ResultsThe tool outputs demonstrated that the lowest COG was achieved with microcarriers and stainless steel technology independent of the annual demand (1500–30 000 BALs/year). The analysis identified the key cost drivers were parameters impacting the medium volume and cost.ConclusionsThe tool outputs can be used to identify cost-effective and scalable bioprocesses early in the development process and minimize the risk of failing to meet commercial demands due to technology choices. The tool predictions serve as a useful benchmark for manufacturing ATMPs.     

Multicenter cell processing for cardiovascular regenerative medicine applications: the Cardiovascular Cell Therapy Research Network (CCTRN) experience

Background aimsMulticenter cellular therapy clinical trials require the establishment and implementation of standardized cell-processing protocols and associated quality control (QC) mechanisms. The aims here were to develop such an infrastructure in support of the Cardiovascular Cell Therapy Research Network (CCTRN) and to report on the results of processing for the first 60 patients.MethodsStandardized cell preparations, consisting of autologous bone marrow (BM) mononuclear cells, prepared using a Sepax device, were manufactured at each of the five processing facilities that supported the clinical treatment centers. Processing staff underwent centralized training that included proficiency evaluation. Quality was subsequently monitored by a central QC program that included product evaluation by the CCTRN biorepositories.ResultsData from the first 60 procedures demonstrated that uniform products, that met all release criteria, could be manufactured at all five sites within 7 h of receipt of BM. Uniformity was facilitated by use of automated systems (the Sepax for processing and the Endosafe device for endotoxin testing), standardized procedures and centralized QC.ConclusionsComplex multicenter cell therapy and regenerative medicine protocols can, where necessary, successfully utilize local processing facilities once an effective infrastructure is in place to provide training and QC.     

Manufacturing mesenchymal stromal cells for clinical applications: A survey of Good Manufacturing Practices at U.S. academic centers

Background aimsMesenchymal stromal cells (MSC) have gained prominence in the field of regenerative medicine due to their excellent safety profile in human patients and recently demonstrated efficacy in late-stage clinical studies. A prerequisite to achieving successful MSC-based therapies is the development of large-scale manufacturing processes that preserve the biological potency of the founder cell population. Because no standardized manufacturing process exists for MSCs, understanding differences in these processes among U.S. academic facilities would allow for better comparison of results obtained in the clinical setting.MethodsWe collected information through a questionnaire sent to U.S. academic centers that produce MSCs under Good Manufacturing Practice conditions.ResultsThe survey provided information on the number and geographic location of academic facilities in the United States and major trends in their manufacturing practices. For example, most facilities employed MSCs enriched from bone marrow by plastic adherence and expanded in media supplemented with pooled human platelet lysate. Sterility testing and product identification via cell surface phenotype analysis were commonly reported practices, whereas initial and working cell plating densities, culture duration, product formulation and the intended use of the MSC product were highly variable among facilities. The survey also revealed that although most facilities assessed product potency, the methods used were limited in scope compared with the broad array of intended clinical applications of the product.ConclusionsSurvey responses reported herein offer insight into the current best practices used to manufacture MSC-based products in the United States and how these practices may affect product quality and potency. The responses also provide a foundation to establish standardized manufacturing platforms.     

Assessment of the LOVO device for final harvest of novel cell therapies: a Production Assistance for Cellular Therapies multi-center study

Background aimsThe final harvest or wash of a cell therapy product is an important step in manufacturing, as viable cell recovery is critical to the overall success of a cell therapy. Most harvest/wash approaches in the clinical lab involve centrifugation, which can lead to loss of cells and decreased viability of the final product. Here the authors report on a multi-center assessment of the LOVO Cell Processing System (Fresenius Kabi, Bad Homburg, Germany), a cell processing device that uses a spinning filtration membrane instead of centrifugation.MethodsFour National Institutes of Health Production Assistance for Cellular Therapies cell processing facilities (CPFs) assessed the LOVO Cell Processing System for final harvest and/or wash of the following three different cell products: activated T cells (ATCs), tumor-infiltrating lymphocytes (TILs) and bone marrow-derived mesenchymal stromal cells (MSCs). Each site compared their current in-house, routinely used method of final cell harvest and/or wash with that of the LOVO device.ResultsFinal harvest and/or wash of ATCs, TILs and MSCs using the LOVO system resulted in satisfactory cell viability and recovery with some substantial improvement over the in-house methods of CPFs. Processing time was variable among cell types/facilities.ConclusionsThe LOVO Cell Processing System provides an alternative to centrifuge-based technologies. The system employs a spinning membrane filter, exposing cells to minimal g-forces compared with centrifugation, and is automated and closed. This small multi-center study demonstrated the ability of the LOVO device to yield satisfactory cell viability and recovery of T cells and MSCs.     

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.