Advanced therapy medicinal products (ATMPs), encompassing gene therapy, somatic cell therapy, and tissue-engineered products, represent a rapidly expanding class of therapies offering transformative potential for treating complex and previously intractable conditions such as malignancies, genetic disorders, and degenerative diseases. Defined by EU Regulation (EC) No.1394/2007, these products involve human cell- and tissue-based materials that have undergone substantial manipulation or are intended to perform functions in the recipient different from those in the donor. With increasing marketing approvals, ATMPs like chimeric antigen receptor T cell (CAR T cell) therapy and gene therapy products are now integrated into clinical practice.
However, the clinical adoption of ATMPs in hospital settings presents significant challenges due to their inherent biological complexity, individualized characteristics, and the cutting-edge technologies involved in their manufacturing and management. The use of ATMPs introduces specific risks related to intricate manufacturing processes, stringent storage requirements, and complex administration procedures. Unlike conventional pharmaceuticals, ATMPs often involve live cells or genetically modified materials, necessitating rigorous quality control measures to ensure both patient safety and therapeutic efficacy. Quality-related risks include contamination, loss of product integrity during transportation, improper administration, and insufficient traceability, all of which could lead to adverse events or treatment failures. This underscores the critical need for robust quality management systems (QMS) to mitigate these risks, especially given the variability in hospital infrastructure, workforce capacity, and operational procedures.
In response to these challenges, regulatory authorities and professional organizations have introduced specific quality standards and guidelines tailored to the clinical quality management of ATMPs. Examples include the European Medicines Agency (EMA) guidelines on Good Manufacturing Practice (GMP) for ATMPs, recommending strict control measures for product quality and traceability. Similarly, the US Food and Drug Administration (FDA) specifies compliance with Current Good Tissue Practice (cGTP) for human cells and tissues and cellular and tissue-based products (HCT/Ps) to reduce communicable disease transmission risks. Regulatory frameworks in Asia (Japan, South Korea, China) also provide detailed requirements for regenerative medicines and biopharmaceuticals. Beyond national regulations, international professional organizations such as the Foundation for the Accreditation of Cellular Therapy (FACT), the American Association of Blood Banks (AABB), and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and European Group for Blood and Marrow Transplantation (EBMT) (JACIE) have established quality standards for cellular therapy, often incorporating risk-based approaches. The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has also issued ATMP-specific GMP guidelines to promote globally harmonized quality standards.
Despite the availability of these standards, persistent gaps exist in both knowledge and practice regarding ATMP quality management in hospital settings. Current studies often focus on manufacturing quality control or isolated clinical aspects, lacking a comprehensive overview of guidelines and real-world experiences. This scoping review aims to address these gaps by identifying and summarizing existing quality management guidelines and standards relevant to ATMPs in hospital settings, and by exploring the real-world experiences and practices employed by hospitals to manage ATMPs. The study was conducted as an integrative scoping review following PRISMA guidelines, retrieving 14 studies from four databases, 144 quality management guidelines and standards, and risk management reports from government agencies and organizations. Data extraction and analysis were guided by the clinical quality management system (cQMS) conceptual framework, which systematically organizes processes, resources, and responsibilities, and facilitates a proactive approach to prevent risks from becoming issues during clinical development activities.
The review identified thirteen models or programs of quality management practices for ATMPs across 25 hospital-based settings in six countries. Major aspects covered included clinical quality and translation, logistics management, hospital preparation, and patient care, with primary goals of regulatory compliance and accreditation, and maintaining standardized operational practices. The findings were categorized into seven key elements of the cQMS framework:
- Process Management: All included studies addressed process management, emphasizing adherence to national and local laws and policies, along with establishing specific standard operating procedures (SOPs) and detailed work instructions at the hospital level. Key practices included logistics and handling, patient selection and evaluation, procurement, follow-up, and clinical trial design. The establishment of independent cell therapy administrative units and support from senior hospital management were reported to promote critical quality attributes of ATMPs. Regulatory compliance and accreditation were crucial for clinical projects.
- Resources, Roles, and Responsibilities: This theme covered human resources, financial resources, and requirements for implementation location and equipment. The workforce was diverse, including clinicians, nurses, pharmacists, clinical trial coordinators, GMP technicians, statisticians, professional managers, and ethics and law advisors. Medical directors or principal investigators (PIs) held ultimate responsibility for key decisions and overall process coordination. Financial considerations involved hospital/academic funds, manufacturer grants, and charitable support, necessitating ongoing budget planning and reimbursement rate negotiations. Location requirements emphasized GMP manufacturing areas, biosafety cabinets, and air-conditioning systems, with equipment covering cell culture, flow cytometry, and bioreactors. Equipment maintenance included initial validation, performance tracking, and routine preventative maintenance.
- Partnering: Internal and external communication and collaboration were deemed essential for ATMP clinical practice networks. Internal partnering included interdisciplinary healthcare professional communications and collaboration between cell-manufacturing and hospital units. External partnering encompassed outsourcing collaborations, communication with pharmaceutical companies, academic institutions, and cooperation with sponsors, investigators, and drug regulatory agencies. Streamlining communication processes was highlighted for operational risk management.
- Risk Management: Seven studies addressed risk management across strategic, operational, quality, and compliance levels. Methods included overall risk assessment and mitigation strategies, and specific approaches like Failure Mode, Effects, and Criticality Analysis (FMECA) for risk identification and evaluation. Mitigation strategies involved personal protective equipment (PPE) and streamlining communication. Quality risk management focused on optimizing manufacturing environments and equipping alarms at storage locations. Compliance risk management included site audits by sponsors to ensure adherence to regulatory requirements. Risk management reports from FDA and EMA consistently included regular reporting and analysis of adverse reactions. Common additional risk minimization measures (aRMMs) included educational programs for healthcare professionals, training for patients and caregivers, patient alert cards, and detailed planning at patient enrollment. Post-authorization risk management focused on safety and long-term follow-up studies, especially for viral vectors.
- Issue Management: This theme covered patient safety, data integrity, and regulatory compliance. Prompt documentation of patient safety concerns and adverse event notification was reported. Corrective and preventive actions (CAPA) aimed at patient medication safety included implementing specific caring standards, policies, and algorithms, and rapidly identifying underperforming products. Data integrity issues were addressed by electronic applications for reporting deviations and refining data field definitions. Compliance challenges, such as protocol deviations, were managed through routine monitoring of environmental conditions.
- Knowledge Management: Twelve studies highlighted knowledge management components, identifying specialized competencies in treating malignant tumors and cellular therapies, GMP training, personal protective skills, risk management training, and clinical documentation and management processes as key knowledge types. Knowledge acquisition methods included in-person instruction, practical training, distance-supported training, educational webinars, and roundtables. The need for continuous updating and effectiveness review of training was also noted.
- Documentation Supporting Achievement of Quality: This element was reported in twelve studies, with formats primarily being electronic records, often with hard copies or scanned paper, structured reports, and traceability systems. Documentation included product-related information (e.g., apheresis products, outsourced products, final products, equipment records) and clinical/patient-related information (e.g., procedures, protocols, subject information, treatment efficacy, and long-term outcomes). Information collection forms and internal online service request forms were used to guarantee data integrity.
In summary, this scoping review offers valuable insights for developing an adaptive quality management ecosystem supporting clinical translation of ATMPs. It systematically summarizes key processes and elements crucial for ATMP quality management in hospitals, including resource allocation, staff responsibilities, risk and issues management, and supporting knowledge and documentation. The primary drivers for high-quality ATMP management in hospitals include adherence to regulatory compliance, technical guidelines, and international standards, along with implementing risk-based strategies and developing specialized workforce capabilities with multidisciplinary coordination. These findings serve as practical references for healthcare institutions to evaluate and enhance their existing clinical quality management practices as more ATMPs integrate into routine clinical care, ultimately promoting patient accessibility and product safety.
One limitation acknowledged by the authors is the lack of quantitative data in the included literature, which prevented measuring or reviewing the quality management practice and its outcomes. Future efforts should focus on developing standardized benchmarking tools and quality indicators for comprehensive monitoring and assessment of ATMP clinical quality management. The scope was also limited to guidelines and reports from the United States, European Union, and China, potentially leading to information gaps from other regions.
Reference: Shi, J., Yang, J., Zheng, Y., Wong, P. H. H., Hu, H., & Ung, C. O. L. (2025). The clinical quality management system of advanced therapy medicinal products in the hospital setting: A scoping review. Molecular Therapy: Methods & Clinical Development, 36, 101485.