The clinical quality management system of advanced therapy medicinal products in the hospital setting: A scoping review

Abstract

Advanced therapy medicinal products (ATMPs) require rigorous quality management to mitigate risks associated with their development and use in hospitals. This study aimed to identify guidelines, standards of practice, and practical experiences in ATMPs quality management in hospital settings. An integrative scoping review under PRISMA guidelines retrieved 14 studies from four databases, 144 quality management guidelines and standards, and risk management reports for approved ATMPs from three government agencies and six organizations. Thirteen models or programs of quality management practices for ATMPs were identified across 25 hospital-based settings in six countries. Major aspects of ATMPs included clinical quality and translation, logistics management, hospital preparation, and patient care. Primary goals of ATMPs management within hospitals involved regulatory compliance and accreditation with national and regional requirements and implementing and maintaining the standardized operational practices. Four priority actions to enhance the quality of ATMPs management were as follows: (1) risk-based procedures and strategies; (2) strengthening of the skills and knowledge of healthcare professionals and technical staff; (3) validation and maintenance of qualified storage, manufacturing, and delivery facilities; and (4) support for a documentation system. In summary, understanding key components of ATMPs management offers valuable insights for developing an adaptive quality management ecosystem supporting clinical translation.

Graphical abstract

This scoping review synthesized existing standards and real-world practices for managing ATMPs in hospitals. It highlights a clinical quality management framework that supports regulatory compliance, risk-based strategies, and workforce training, providing evidence-based insights for hospitals, regulators, and stakeholders to bridge gaps between clinical research and patient care.

Introduction

Advanced therapy medicinal products (ATMPs), a rapidly growing class of therapies that include gene therapy, somatic cell therapy, and tissue-engineered products, offer transformative potentials for treating various complex and previously intractable conditions, such as malignancies, genetic disorders, and degenerative diseases.¹ According to the EU Regulation (EC) No.1394/2007, human cell- and tissue-based products that have undergone substantial manipulation, or those intended to perform functions in the recipient different from those in the donor, are classified as ATMPs.² In recent years, more ATMPs have gained marketing approval from the national regulatory authorities and are currently being used in clinical practice. These ATMPs included chimeric antigen receptor T cell (CAR T cell) therapy products (e.g., idecabtagene vicleucel and tisagenlecleucel) and gene therapy products (e.g., voretigene neparvovec).^3,4,5 However, due to their inherent biological complexity, individualized characteristics, and the cutting-edge technologies involved in their manufacturing and management, the clinical adoption of ATMPs in hospital settings presents significant challenges for healthcare providers, hospital administrators, manufacturers, and regulatory authorities.^6,7

The use of ATMPs in hospitals introduces a range of specific risks related to their intricate manufacturing processes, storage requirements, and administration procedures.^6,8,9 Unlike conventional pharmaceuticals, ATMPs frequently involve live cells or genetically modified materials, necessitating rigorous quality control measures to ensure both patient safety and therapeutic efficacy. Quality-related risks associated with ATMPs in hospitals may include contamination during preparation, loss of product integrity during transportation, improper administration, and insufficient traceability, all of which could result in adverse events or treatment failures.⁶ Given the highly individualized nature of ATMPs, along with variability in hospital infrastructure, workforce capacity, and operational procedures, the need for robust quality management systems to mitigate associated risks is increasingly recognized.

In response, regulatory authorities and professional organizations have introduced specific quality standards and guidelines tailored to the clinical quality management of ATMPs. As outlined in the European Medicines Agency (EMA) guidelines on Good Manufacturing Practice (GMP) specific to ATMPs, strict control measures are recommended to ensure product quality and traceability. These encompass actions for the prevention of mix-up and cross-contamination, proper usage of cleaning agents and air handling units, quality requirements, and detailed documentation for laboratories and storage areas.¹⁰ Similarly, in the United State, the 21 CFR Part 1271 “Guidance for industry- Current Good Tissue Practice (cGTP) and additional requirements for manufacturers of the human cells and tissues and cellular and tissue-based products (HCT/Ps)” specifies that compliance with cGTP is essential to uphold high standards in tissue handling, processing, and distribution, thereby reducing the risk of communicable disease transmission.¹¹ In Asia, regulatory frameworks in Japan and South Korea provide detailed requirements for regenerative medicines and biopharmaceuticals, including specifications for manufacturing sites, laboratory operations, facilities, and equipment.^12,13 The National Medical Products Administration (NMPA) in China has issued a series of policy documents aimed at strengthening oversight across the full life cycle of ATMPs, promoting their research, development, translation, and adoption into medical practices.¹⁴

Quality management standards may exist either as standard-alone documents specific to ATMPs or as components within broader regulatory or accreditation frameworks. Among international professional organizations, one of the earliest quality standards targeting cellular therapy emerged in the mid-1990s in the United States, through initiatives by the Foundation for the Accreditation of Cellular Therapy (FACT) and the American Association of Blood Banks (AABB).¹⁵ In Europe, the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and European Group for Blood and Marrow Transplantation (EBMT), known as JACIE, was established as a non-profit entity with the goals of promoting high-quality patient care and laboratory practices in the field of advanced therapies. JACIE has incorporated risk-based approaches into GMP standards, advocating for the cross-alignment of stringent and consistent quality requirements.¹⁶ Furthermore, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) has issued ATMP-specific GMP guidelines with the objective of promoting globally harmonized quality standards. These guidelines have been adopted or fully implemented by its member countries, contributing to international convergence in ATMPs quality management.¹⁷

Despite the availability of these quality standards, gaps persist in both knowledge and practice regarding the quality management of ATMPs in hospital settings. Current studies primarily focus on the quality control of ATMPs manufacturing or isolated clinical aspects, such as environmental exposure assessments. However, a comprehensive overview of guidelines and standards relevant to quality management of ATMPs in hospitals remains lacking. Additionally, the current practices and experiences of how hospitals and specialized healthcare professionals manage the quality of ATMPs in real-world clinical settings are underreported. In light of the above, the objectives of this study are 2-fold: (1) to identify and summarize the existing quality management guidelines and standards relevant to ATMPs in hospital settings and (2) to explore the real-world experiences and practices employed by hospitals to manage ATMPs. The findings aim to depict the current landscape of tailored quality management system (QMS) frameworks for ATMPs in hospital settings, providing a structured understanding of how hospitals address the complexities associated with ATMPs implementation. In addition, the study seeks to inform hospitals, regulatory bodies, and other stakeholders of the diverse practices and evolving strategies, thereby supporting the development and enhancement of environment-adaptive, risk-based quality systems. These insights will contribute to the broader discourse on the safe, effective, and sustainable integration of advanced therapies into clinical practice and serve as a practical reference for medical institutional decision-making and future policy development.

Results

Study selection

A total of 4,902 potentially relevant articles were identified from 5,779 initial records after removing duplications. An additional 4,847 records were excluded during the title and abstract screening. After full-text screening of the remaining 55 records, 41 records that were not related to the specific quality management experiences of ATMPs in hospitals were excluded. Ultimately, 14 eligible studies were included in this review (Figure 1).

Figure 1.

PRISMA flow-chart of study selection

In addition, 121 technique guidelines about the quality management of ATMPs from the US Food and Drug Administration (FDA) (n = 50), the European Medicines Agency (EMA) (n = 29), the National Medical Products Administration of China (NMPA) (n = 28), and six international professional organizations (n = 14) were also included. As of July 2024, a total of 42 ATMPs had been granted marketing authorization from the FDA, EMA, and NMPA. Specific approved details are summarized in Table S2.

After individual search of the government websites for quality management reports of the approved ATMPs by two authors, a total of 23 quality risk management reports were retrieved, including 5 approved risk evaluation and mitigation strategy (REMS) documents for 6 ATMPs from the FDA, and 18 risk management plan (RMP) reports for 18 ATMPs from the EMA. No quality-management-related reports for ATMPs approved in China were obtained from the NMPA website.

Study characteristics

A total of 14 studies and 148 additional records published between 1994 and 2024 were included in this review. As presented in Table 1, the 14 articles reported about 13 quality management models or programs of ATMPs implemented across 25 hospital-based settings in six countries (including the United States [n = 8], Italy [n = 2], Austria [n = 1], China [n = 1], France [n = 1], and Saudi Arabia [n = 1]). These models or programs, which focused on the cellular therapies (n = 7), ATMPs (n = 3), and CAR T cell therapies (n = 3), were aimed for addressing various aspects of quality management, including driving clinical quality and clinical translation (n = 4), facilitating the quality management process of off-site manufactured cellular therapy (n = 2) and medical products from the cell therapy unit to the pharmacy (n = 1), improving the quality management of GMP facilities (n = 2) and cell therapy laboratory (n = 1) in the hospital settings, and the practice experiences in managing the efficacy and adverse event of cellular therapies (n = 1) and clinical trial network (n = 1). During the synthesis of findings, the practices identified under the seven cQMS elements were further refined and categorized in Table 1, reflecting the quality management processes of ATMPs as outlined below.

Table 1.

Program experiences of ATMPs management at the hospital setting

Author(s)/year of publication	Study location	Program/model involved	Study objectives	cQMS elements involved A: Processes; B: Resources, roles & responsibilities; C: Partnering; D: Risk management; E: Issue management: F: Knowledge management; G: Documentation supporting achievement of quality (the refined code number are detailed in the Figure S1)
Dinh et al., 202418	USA	healthcare-center-based cell therapy laboratories (HC CTLs) supporting off-site manufactured cell therapies program location: academic/research (40%); commercial (60%) target area: cancer immunotherapies and gene therapy	to present the experiences and challenges encountered by a single academic HC CTL through reviewing the 15 off-site manufactured cellular therapy clinical trials	A	•SOPs (A2): each protocol that integrated center-specific and sponsor-provided SOPs • materials shipping and handling (A3.3): - CSM shipping to external manufacturing facilities: cell counts, flow cytometry, and sterility testing - final products received from external manufacturing facilities: (A) container (93% bags, 7% vials); (B) thaw instructions (60% center; 40% protocol); (C) post-thaw expiration and/or product stability time frames (range from 40 min to 24 h); (D) manipulations besides thawing (80% none; 20% dose adjustment). - temperature control: all final products received from the off-site manufacturing facilities were cryopreserved.
				B	•financial supported (B1.4): academic/research and commercial entities •processing staff (B2.2): support off-site manufactured products
				C	•external partnering (C2): off-site manufacturers from academic/research (4, 27%), commercial (11, 73%)
				D	•operation risk assessment (D2.1): mock or dry runs of the process before handling clinical products to identify potential issues and for quality assurance.
				F	•training provider (F2): sponsor •training forms (F2): in-person, virtual meetings, videos, slides, etc.
				G	•format of records (G1.1): electronical with hard copies •information category (G1.2): the subject (identifiers, height, weight) and apheresis product (collection date/time, volume, cell counts, cryoprotectant, etc.), final products (receipt, thaw, and infusion) •specific practices (G1.3): data entered into a web-based form or database
Wiltshire et al., 202219	USA	management of externally manufactured cell therapy products through an administrative unit called the biopharmaceutical unit (BPU) program location: Mayo Clinic target area: Immune, Progenitor and Cell Therapeutics (IMPACT)	to provide the specialized procedures handling IMPACTs from collection to delivery and housing the necessary processes to more easily integrate externally manufactured cell therapies into clinical practice	A	•regulatory (A1): compliance with the US FDA, AABB, and FACT guidelines •SOPs (A2): develop a comprehensive plan •procurement (A3.2): special sample • materials shipping and handling (A3.3): - pick-up location: set up clear communication channels established for pickup and delivery •administrative unit (A4): BPU established to manage the critical quality attributes of cell therapy products •ethics review (A5): BPU Protocol Review Committee
				B	•laboratory equipment (B1.2): a water bath, ambient transport cooler, liquid nitrogen storage tank, vapor phase transport container, temperature tracker and biosafety cabinet •equipment maintenance (B1.2): initial validation (installation qualification, operational qualification, performance qualification), performance tracking and routine preventative maintenance. •workforce involved (B1.3): skilled technicians •financial supported (B1.4): budget development • roles & responsibilities (B2.1/B2.2): - director: MD- or PhD-trained and have ultimate responsibility for critical decisions - managers: work on a broad level to evaluate needs (assign appropriately trained technicians; ensure a safe work environment; ensure sufficient infrastructure, equipment and processes) - technicians: review product manuals, create help sheets and manage products
				C	•internal specific position (C1): managing communication and coordinating activities •internal communication (C1): regular meeting to review updates on trials •external communication (C2): a shared BPU-specific e-mail inbox/a shared phone number for outside contacts
				D	•operation risk mitigation (D2.2): use of PPE while handling patient products •operation risk communication (D2.4): developed processes to streamline communication
				F	•knowledge types (F1): CGMP training and Safety training •training design (F3): evaluate the handling manual to determine if current training is aligned with the tasks required and whether development of new training modules is required. •training implementation (F3): 3 phases, (1) general techniques such as product handling, documentation requirements and aseptic techniques; (2) protocol-specific requirements of sponsor-provided training documents; (3) training reviewed and supplemented to fill in knowledge gaps •training sustain (F4): managers review the workload for the upcoming week per week •training improving (F4): a BPU training tracker for verification of who is trained on part or all of the activities.
				G	•format of records (G1.1): an electronic database solution with scanned paper documents • information category (G1.2): - externally manufactured products: documents mandated by the manufacturer and internal records - equipment recording: all critical equipment recorded and electronically assigned to each product for tracking - label: any paper-based batch records generated are stored in a secure area for the required time • specific practices (G1.3): - information collection: an internal online “BPU Request for Service” form - initial & quality documentation review: ensure feasibility of product data tracking, provenance management and the request for work; and determine whether the proper controls and procedures - trial closure: all files have been reviewed and approved
Talarmin et al. 202020	France	quality risk management of the CAT T cell pharmaceutical circuit program location: Saint-Louis Hospital target area: CAR T cell therapy	to trace the Cell Therapy Unit (CTU) and Pharmacy QMS processes and identify potential risks or failures in the Saint-Louis Hospital CTU and Pharmacy	A	•regulatory (A1): EU regulation 1394/2007& directive 2004/23/EC, ICH Q9, International Standard IEC 60812 • materials shipping and handling (A3.3): - CTU (Pc steps): (i) PBMC receipt from the Apheresis Unit, (ii) PBMC handling (freezing), (iii) PBMC cryopreservation and (iv) PBMC shipment from the CTU to the manufacturer. - Pharmacy (Pp steps): (i) CAR-T cells receipt by the Pharmacy staff in the CTU facility, (ii) CAR-T cells storage in the cryobiology area of the CTU, (iii) CAR-T cells thawing by the Pharmacy staff in the CTU facility, and (iv) CAR-T cells distribution by the Pharmacy staff to the clinical department
				B	•workforce involved (B1.3): the expert group was composed of three pharmacists, two laboratory technicians and one quality assurance manager from the CTU, and three pharmacists from the Hospital Pharmacy
				C	•internal collaboration (C1): Pharmacy and the CTU staff •external partnering (C2): outsourcing activities and the coordinated collaboration with pharmaceutical companies
				D	• operation risk assessment (D2.1): - risk assessment methodology: the “failure mode, effects and criticality analysis” (FMECA) - risk identification: a risk description performed for each elementary step - risk evaluation: the criticality scoring matrix established and validated by the expert group - risk analysis: 9 significant risks (herein), 8 moderate risks, 1 major risks •Pc1R1: confusion between received and shipped products •Pc2R1: non-compliant traceability of received PBMC •Pc3R2: non-compliant delay between the Apheresis and PBMC freezing •Pc4R1: non-compliant traceability of PBMC freezing •Pc6R1: non-compliant traceability of cryopreserved PBMC storage •Pc6R2: deviation of storage temperature not declared to the CAR-T cells manufacturer •Pc7R1: PBMC shipment scheduling without prior CTU agreement •Pc8R2: errors during the shipment step •Pp1R1: CAR-T cells receipt scheduling without the Pharmacy agreement
				E	•compliance CAPA progress (E3.3): herein only present the CAPA of significant risks •Pc1R1: extension and separation of « receipt » and « shipment » areas •Pc2R1/Pc4R1/Pc6R1: development of a software dedicated to the ATMPs activity •Pc3R2: separation of CAR-T cells and HSC transplantation activities •Pc6R2: temperature traceability in the ATMPs software and control before the shipment of PBMC •Pc7R1: creation of dedicated email and systematic appointment •Pc8R2: one shipment per day, by two dedicated CTU staff •Pp1R1: mandatory appointment with the Pharmacy
				F	•training provider (F2): Pharmacy and the CTU staff •training forms (F2): information sheets about the administration procedures for nurses and medical staff
				G	•format of records (G1.1): a traceability system
Greinix et al., 202021	Austria	Austrian CAR-T Cell Network program location: CAR-T cell platform of the Austrian Society of Hematology and Medical Oncology (OeGHO) target area: CAR T cell therapy	to ensure center quality, proper patient selection and fair access to chimeric antigen receptor T cell therapy	A	•regulatory (A1): the registry module for CAR-T cells of the ASCTR and the registry of the EBMT •SOPs (A2): written descriptions, training on and documentation of clinical SOPs, and SOPs available for clinical, radiologic and serologic surveillance for early detection of CRS and ICANS, transfer of patients to the ICU, and management of CRS and neurotoxicity of all grades •patient selection (A3.1): a guidance document produced for patient selection and updated regularly •materials shipping and handling (A3.3): waste disposal within the local regulatory requirements on biologic safety •administrative unit (A4): tumor boards according to the Austrian recommendations (OeSG, Onkologiebeirat) •accreditation compliance (A5): a risk-adapted qualification plan based on regulatory requirements; AGES authorization for production
				B	•location resources (B1.1): Pharmacy/Tissue bank •laboratory equipment (B1.2): all equipment used for harvest, labeling, and storage of blood cells and genetically modified cells •workforce involved (B1.3): medical head, physicians and nursing staff •financial supported (B1.4): producers of CAR-T cells • roles & responsibilities (B2.1): - medical head: medicine and hematology/medical oncology experts, responsible for the coordination and administration of CAR-T cell therapies, - certified medical specialists: constantly available for inpatient/outpatient care of patients - qualified specialists of neurology: immediately participate in the interdisciplinary management of patients - nursing staff: a diploma on nursing care with hematologic–oncologic qualifications or previous fulltime employment for at least 36 months on a hematologic–oncologic ward and have to participate in the center’s internal training program on CAR-T cell therapy
				C	•internal collaboration (C1): interdisciplinary healthcare team
				E	• patient safety CAPA progress (E3.3): - prior to the infusion: prevent the immunosuppression and side effects after lymphodepleting chemotherapy - following therapies: appropriate supportive care needed to prevent the immediate contact isolation
				F	•knowledge types (F1): specialized knowledge on therapy of patients with the malignancies to be treated, competency in cellular therapy including use of gene-modified cells and competency in intensive care
				G	•format of records (G1.1): written documentation •information category (G1.2): descriptions, training on and documentation of clinical SOPs, side effects
Dulan et al., 202022	USA	A Standard-of-Care CAR T cell Clinical Quality and Regulatory Program program location: City of Hope (COH): a National Cancer Institute Comprehensive Cancer Center target area: CAR T cell therapy	to develop the quality structure of cellular therapy program through collaborations between quality, regulatory, and CAR T patient care committees	A	•regulatory (A1): accreditation standards and federal and state requirements, FACT standard B4.7 •SOPs (A2): aligning quality management plan (QMP) and Research and Standard-of-Care Quality Structure •patient selection (A3.1): a form provided by the CCIC meeting to patient referral •administrative unit (A4): Clinical Cellular Immune therapy Committee (CCIC) established at the COH Hematology/HCT Department •accreditation compliance (A5): iterative and annual gap analysis at COH, the Hematology and HCT quality and regulatory program
				B	•workforce involved (B1.3): a program director and 2 designated cochairs; physicians; professionals from clinical and research nursing, regulatory research operations, quality/risk/regulatory management, and administrative operations; and ad hoc multidisciplinary professionals from pharmacy, infectious disease, transfusion medicine, and neurology • roles & responsibilities (B2.1): - NC: prior to enrollment and during the eligibility workup for the patient, the nurse coordinator completes the REMS checklist
				C	•internal collaboration (C1): interdisciplinary healthcare team
				D	•strategic risk assessment (D1.1): Risk Evaluation and Mitigation Strategy (REMS) •compliance risk monitoring (D4.3): a dashboard monitoring system for auditing to screen the EMR documentation
				E	•patient safety CAPA progress (E1.3): specific standard-of-care policies and algorithms implemented for monitoring ICANS and CRS •patient safety issue trending (E1.4): periodic reviews of both the cellular therapy QMP and patient outcomes •data integrity issue documentation (E2.2): develop a new SOP for reporting and tracking deviations for CAR T infusions and a custom electronic application for submitting planned standard-of-care SOP deviations via the CCIC clinical members’ electronic distribution list
				F	•knowledge types (F1): mandatory REMS training •training forms (F2): complete annual competencies checklist and manage a minimum of 2 CAR T cell patients and 2 cellular infusions •training design (F3): a standard work education checklist, encompassing the series of eligibility and screening tests required prior to enrollment, a list of policies to review, including CAR T cell standard-of-care deviations, and SOPs for new patient referrals, authorizations, REMS requirements, and post-CAR T cell infusion care •training implementation (F3): all accreditation-mandated education and 10 h annual training for hematologists required by FACT •training sustain (F4): the annual medical staff competencies checklist and continued education review
				G	•format of records (G1.1): EMR Standardization and a custom navigator for cellular therapy designed by CCIC •information category (G1.2): the growing volumes, adverse events, concomitant therapies, or long-term outcomes in real time • specific practices (G1.3): - reporting criteria: ASTCT consensus to align the CRS and ICANS criteria that apply to all IEC/CAR T cell products - using the custom navigator: an electronic eligibility form to facilitate documentation of the patient’s information (nurse coordinators), document and view the CAR T cell patient’s information in one central place (physicians), document and/or refer to structured neurologic assessment guidelines for rapid evaluation of the patient. •deviation documentation (G3): a custom electronic application for submitting planned standard-of-care SOP deviations
Jenio et al., 201923	USA	clinical outcomes registry model in regenerative medicine program location: NA target area: musculoskeletal regenerative medicine	to be designed for surveillance, tracking, and reporting of efficacy and adverse events of cellular-based therapies	A	•regulatory (A1): local regulatory and GCP •SOPs (A2): the registry framework, the patient cohorts, and quality assurance •patient selection (A3.1): make informed decisions based on the localized data about the population •ethics review (A5): ethical considerations
				B	•equipment maintenance (B1.2): set up and configure the system within the facility •workforce involved (B1.3): all medical staff (clinicians, nursing staff, clinical support, admin staff, and the registry support team) •roles & responsibilities (B2.1): proficiently input data into the registry
				C	•internal collaboration (C1): standardizing treatment pathways, clinical handover processes and shared decision-making with patients
				E	•patient safety CAPA progress (E1.3): quickly identify underperforming products/treatments in use by linking the PROs and AE •patient safety trending and analysis (E1.4): benchmarking of clinical practice through data quality assessment, patient outcomes relative to pre-specified treatment success criteria, and safety relative to external sources •data integrity CAPA progress (E2.3): missing data in key areas that were rectified by refining data fields definition, placement within the operating system, linkage to external supporting documents and response options for users to select during data entry
				F	•knowledge types (F1): management and interaction, clinical documentation and administration processes •training provider (F2): registry support team •training forms (F2): online, in-person, and remote support •training sustain (F4): ongoing training and process correction
				G	•format of records (G1.1): identifiable data was kept electronically on a secure server • specific practices (G1.3): - data integrity: the physical terminal server was located at the facility and was backed up daily. - Data quality control: regular quality control audits at an adequate standard for clinical research, adding registry level completeness audits every 2 weeks
Tanhehco et al., 201824	USA	a standard operating procedure (SOP) to manage cellular clinical trials program location: New York-Presbyterian The University hospitals of Columbia and Cornell target area: cellular therapy	to describe the process and forms used to manage cellular clinical trials in the cellular therapy laboratory (CTL)	A	•regulatory (A1): federal and state regulations on current GMP and GTP •SOPs (A2): an SOP created to describe the roles and responsibilities of the clinical team requesting CTL and CTL staff •ethics review (A5): all CTL staff involved in the conduct of clinical trials in the IRB
				B	•laboratory equipment (B1.2): appropriate facilities, equipment and materials according to the protocol •workforce involved (B1.3): technologists, supervisor and the quality manager, adding the clinical trials coordinator •financial supported (B1.4): hospital or university funds (if resources are deemed inadequate) • roles & responsibilities (B2.1/B2.2): - CTL medical director: involve in all aspects of the clinical trial from the initial meeting to study completion & closure by the sponsors - CTL staff: undergo the protocol training and mock run
				C	•internal collaboration (C1): CTL medical director with the clinical investigators •external partnering (C2): close communication with the sponsors and investigators •external partnering (C2): the sponsors and investigators with the US FDA and other regulatory agencies
				D	•compliance risk monitoring (D4.3): site audit from sponsors to ensure compliance
				E	•patient safety issue documentation (E1.2): document and report any adverse events to the sponsors and investigators •compliance issue documentation (E3.2): document and report any deviations from the protocol
				F	•knowledge types (F1): the roles and responsibilities of CTL staff, and training for processing and manufacturing •training forms (F2): the investigator and sponsor provided to the CTL staff •training design (F3): the clinical trial protocol and lab manual training and mock shipment
				G	•format of records (G1.1): Excel spreadsheet, a study binder •information category (G1.2): study materials such as the protocol and laboratory manual • specific practices (G1.3): - SOP forms: Cellular Therapy Laboratory Research Fee Service Form; the Investigational Cellular Therapy Trial Form
Viganò et al., 201725	Italy	running a GMP facility for regenerative medicine in a public hospital program location: Preventive Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico target area: regenerative medicine/ATMPs	to describe how to deal with some specific issues during our hospital-based GMP experience and to give perspectives on the role of academic entities in the development of ATMPs.	A	•regulatory (A1): EU regulation and the national legal obligations by the Italian Ministry of Health, EMA GMP for ATMPs •leadership commitment (A4): endorsement of the hospital senior management •accreditation compliance (A5): European GMP authorization
				B	•location resources (B1.1): a class A-GMP manufacturing area (e.g., biosafety cabinet) with a class B-GMP surrounding environment; microbiological safety of ATMPs with the standard air cleanliness level •laboratory equipment (B1.2): appropriate bioreactors •workforce involved (B1.3): GMP staff •financial supported (B1.4): economic supported by the charities to the public investment • roles & responsibilities (B2.2): - GMP staff: a medical, biological or biotechnological degree with different levels of experience, and responsible for the production, quality control
				C	•internal communication (C1): the cooperation of the cell-manufacturing unit staff with the hospital unit •external communication (C2): outsourced GMP activities when needed •external communication (C2): academia participation
				D	•strategic risk assessment (D1.1): estimate the size and resources of the GMP facilities •quality risk mitigation (D3.2): efficient layout to minimize the microbiological risks and to optimize the environmental control •quality risk monitoring (D3.3): production process and quality control of the ATMPs manufacturing with the control strategies
				F	•knowledge types (F1): the knowledge of the rules of pharmaceutical standards required for working in a GMP cell manufacturing •training forms (F2): a certification course and personal study
				G	•format of records (G1.1): computerized systems and documents •specific practices (G1.3): a risk-based approach to protect data by duplication and backup
Han et al., 201626	China	innovative and propagable patient-centered translational (PCT) research model established for cell-based therapy program location: cell-processing center (CPC) in Chinese PLA General Hospital target area: cell-based therapy	to establish a feasible and efficacious translation routine and a clinical translational base in Chinese hospitals	A	•SOPs (A2): a series of cellular criteria covering phenotype and magnitude, the safety detection index, and clinical application guidelines •patient care (A3.4): a patient follow-up system •clinical trials design (A3.5): revise content and endpoints designed for large-sample clinical evaluations of the efficacy of cell therapy •administrative unit (A4): set up a new translational medicine research management structure, adding an outpatient service specializing in cell therapy
				B	•workforce involved (B1.3): PCT model involved the creation of an integrated translational medicine research team comprising a laboratory researcher, technicians, physicians, nurses, a statistician, and an ethics and law advisor •financial supported (B1.4): hospital or university funds (if resources are deemed inadequate) • roles & responsibilities (B2.1): - chief scientist: in charge of the overall translational project setting, overall coordination and staff recruitment, task allocation, and administrative management - the appointed chief medical officer (CMO): responsible for patient management and cell preparation - the chief technician officer (CTO): responsible for quality control management - the research and development (R&D) group: clinical sample treatment and special index detection
				C	•internal collaboration (C1): the ward-patient-centered and joint scientist-physician model, several traditional clinical departments •internal communication (C1): a consolidated management system between laboratory scientists and clinical physicians
				E	•patient safety CAPA progress (E1.3): identify the optimal interventions for adoptive immunotherapy by comparison among different tumors and examine the clinical safety and potential concerns of cell therapy through long-term observations •patient safety CAPA progress (E1.3): value of adoptive immunotherapy for chemotherapy-refractory advanced B-cell lymphoma •patient safety issue trending (E1.4): further significant conclusions based on immunotherapy-related clinical research database
				F	•knowledge types (F1): medical safety, clinical research, and patient responses, among other topics •training forms (F2): researcher-clinician meeting, periodic reciprocal education programs
				G	•format of records (G1.1): electronical database •information category (G1.2): an integrated tumor database, including each patient’s complete therapeutic history, status at the time of cell therapy enrollment, transfusion reactions to immune cells, other treatments, and data on regular systematic efficacy evaluations •specific practices (G1.3): set up a data collection office
Montemurro et al., 201527	Italy	a pharmaceutical-grade facility in a public hospital context program location: Fondazione IRCCs Ca’ Granda Ospedale Maggiore Policlinico in Milan target area: ATMPs	to share the solutions to make cell therapy compliant with the requirements for the production and the quality control of a high-standard medicinal product	A	•regulatory (A1): EU GMP •accreditation compliance (A5): Cell Factory certified by the Italian Drug Agency in compliance with European GMP regulations
				B	•location resources (B1.1): GMP facility site in a clean and controlled area, with the air-conditioning system •laboratory equipment (B1.2): the qualification GMP facilities, with cleaning validation and procedures •workforce involved (B1.3): GMP staff, including the management staff and the QP •financial supported (B1.4): budget plan •roles & responsibilities (B2.1): specified in the job descriptions.
				D	•operational risk mitigation (D2.2): specific actions by qualified person (QP) to be taken if the anomalies on the state of efficiency of the components in the HVAC system •quality risk assessment (D3.1): critical systems (“heating, ventilation and air conditioning” (HVAC) system, process systems, and equipment for the storage of materials for the production) all equipped with a 24-h alarm system phone availability •quality risk monitoring (D3.3): the production site is constantly monitored with planned maintenance programs, adding the environmental control monitoring
				E	•patient safety issue documentation (E1.2): document and report any adverse events •compliance issue detection (E3.1): microbiological monitoring •compliance CAPA progress (E3.3): specific SOPs to manage unexpected or unusual events, additional operations on the HVAC system and staff re-training. •compliance trending and analytics (E3.4): every 3 months environmental microbiological, particulate, and staff data are collected in specific forms to prepare the periodic trending reports
				F	•knowledge types (F1): clean room aseptic gowning, stock management, equipment management and environmental monitoring •training forms (F2): theoretical training, practice test, lecture •training design (F3): plan an initial training and an ongoing training with frequent staff performance and training courses
Abumaree et al., 201428	Saudi Arabia	stem cell research and RM program program location: King Abdullah International Medical Research Center target area: stem cell therapy	to coordinate advanced stem cell research and translational outcomes with the goal of treating chronic human diseases	A	•SOPs (A2): FACT standards and national legislations
				B	•location resources (B1.1): KAIMRC Stem Cells and Regenerative Medicine Unit (KSCRMU) •laboratory equipment (B1.2): world-class facilities for cell culture, flow cytometry, microscopy, histology, molecular biology •financial supported (B1.4): the necessary facilities and platform technologies by KAIMRC
				C	•external communication (C2): stem cell scientists and clinicians at KAIMRC and those at the King Abdulaziz Medical City •external partnering (C2): the nonprofit public bank KAIMRC-UCBB
				F	•nowledge types (F1): stem cells and regenerative medicine
Trounson et al., 201229	USA	A Model for Evaluating and Delivering Stem Cell-Based Therapies program location: The Alpha Stem Cell Clinic target area: stem cell therapy	to foster clinical trials, evaluate and establish safe and effective therapies, and develop and maintain the delivery of therapies approved by the FDA or other DRAs	A	•ethics review (A5): Patient safeguards of medical standards, ethical over sight IRBs, and ESCROs
				B	•location resources (B1.1): GMP laboratory •laboratory equipment (B1.2): GMP facilities with that advanced fluorescent activated cell separation equipment, cell culture facilities, molecular biology technology, cell monitoring equipment, and access to appropriate cell handing and manipulation facilities •workforce involved (B1.3): highly qualified clinicians with disease expertise, key clinicians and nursing staff •financial supported (B1.4): sustainable business model
				C	•external partnering (C2): outsourcing service companies, collaborative funding partnerships (CFPs) program
				E	•data integrity issue detection (E2.1): data and safety monitoring •data integrity trending and analytics (E2.4): collect long term, longitudinal data on safety and efficacy of the cell therapy
				F	•knowledge types (F1): challenges and bottlenecks in development and potential approaches •training forms (F2): educational webinars and roundtables
				G	•format of records (G1.1): informatics infrastructure for long-term storage of confidential data
Moyé et al., 201130,31	USA	Cardiovascular Cell Therapy Research Network experience program location: cell therapy and satellite centers target area: cell therapy for cardiovascular	to provide a useful starting model for satellite center accrual in cardiovascular clinical trials	A	•accreditation compliance (A5): same level of regulatory and administrative review of treatment satellites as the main center
				B	•workforce involved (B1.3): treatment satellite’s personnel, PI and medical staff •financial supported (B1.4): negotiated rate in reimbursement for patient care cost • roles & responsibilities (B2.1): - PI: provide an investigator with the sole charge of soliciting and maintaining consistent contact with referring hospitals
				C	•internal communication (C1): regular communication and face-to-face meetings •external partnering (C2): referral versus treatment satellite centers
				D	•patient safety issue documentation (E1.2): time reports on the occurrence of each SAE
				G	•format of records (G1.1): structured reporting mechanisms •specific practices (G1.3): provide adequate support for personnel at the data coordinating center

Theme 1: Process management

All included studies involved the process management within the cQMS framework. Among them, eight studies reported the necessity of conducting clinical practices involving ATMPs in hospital settings in accordance with national and local laws and policies,^{19,20,21,22,23,24,25,27} whereas eight studies highlighted the specific standard operating procedures (SOPs) and detailed work instructions required at the hospital level.^{18,19,21,22,23,24,26,28} The most common reported practices of process management were the logistics and handling of products or materials,^18,19,20,21 followed by the patient selection and therapy evaluation for ATMPs,^21,22,23 along with the product procurement,¹⁹ patient follow-up,²⁶ and clinical trial design.²⁶ The study by Dinh et al. reported on the transport and handling of out-sourced manufactured cell therapies in 15 clinical trials, identifying key considerations when transporting cellular materials to the external manufacturing facilities (including the cell counting, flow cytometry, and sterility testing) and receiving the final product from the outside (covering the containers, thawing instructions, the stability time frame of the product post-thaw, and other manipulations such as dose adjustments).¹⁸ Another study by Wiltshire et al. reported the need for establishing clear communication channels for pickup and delivery when dealing with the transport of externally manufactured products.¹⁹ One study described how pharmacy staff managed the receipt, thawing, and intrahospital distribution of CAR T cell products in a pharmacy setting.²⁰

Considering the specific nature of ATMPs, four studies reported that the establishment of independent cell therapy administrative units at the hospital level contributed to promoting their critical quality attributes.^19,21,22,26 The study by Viganò et al. further emphasized the importance of senior hospital management support in facilitating the adoption of ATMPs.²⁵ In addition, clinical treatment protocols,^19,23 personnel qualifications,²⁴ and patient protection measures²⁹ were all subject to review by hospital ethics committee. The implementation of clinical projects also required the qualification and accreditation in accordance with regional regulatory requirements.^{21,22,25,27,30,31}

Alongside the current guidelines for biologics, Table 2 listed a total of 107 technical guidelines issued by the FDA, EMA, and NMPA, with further details of the content available in the Table S3. These guidelines specifically outlined current regulatory considerations designed for quality management of ATMPs in hospital settings, covering specific ATMPs and indications, as well as the nonclinical, chemistry, manufacturing, and control (CMC) and clinical and post-marketing stages throughout the whole life cycle of ATMPs. It is evident that the FDA has released more technical guidance targeting the use of ATMPs for specific diseases, particularly in the areas of hematopoietic system diseases and rare diseases.

Table 2.

Guidelines included for the quality management of ATMPs in hospital settings

Categories of guidance	US FDA n = 50 (41.3%)	EU EMA n = 29 (24.0%)	China NMPA n = 28 (23.1%)	Professional organizations n = 14 (11.6%)
ATMPsdevelopment stages	41	28	25	14
General (n, %)	11 (26.8)	10 (35.7)	3 (12.0)	1 (7.1)
Non-clinical (n, %)	3 (7.3)	5 (17.9)	5 (20.0)	1 (7.1)
CMC (n, %)	14 (34.1)	6 (21.4)	6 (24.0)	9 (64.3)
Clinical (n, %)	12 (29.3)	4 (14.3)	9 (36.0)	1 (7.1)
Post-marketing (n, %)	2 (4.8)	3 (10.7)	2 (8.0)	2 (14.3)
Indication specific	9	1	3	0
Hematopoietic system diseases (n, %)	3 (33.3)	0	1 (33.3)	0
Rare and serious diseases (n, %)	2 (22.2)	1 (100.0)	1 (33.3)	0
Retinal disorders (n, %)	1 (11.1)	0	0	0
Cardiac diseases (n, %)	1 (11.1)	0	0	0
Others (n, %)	2 (22.3)	0	1 (33.3)	0

Moreover, 14 standards or guidelines from 6 different professional organizations with potential applicability for adoption in cQMS were included in the review. Among them, the ISO 9001 Quality Management System, the GMP issued by the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and relevant quality management guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have been adopted as international standards by the FDA, EMA, and NMPA. The World Health Organization (WHO) has also released GMP guideline specific to biological products. The international standards published by the Foundation for the Accreditation of Cellular Therapy-Joint Accreditation Committee ISCT-Europe & EBMT (FACT-JACIE), along with the standards for cellular therapy services issued by the AABB, also serve as valuable references for quality management of ATMPs in clinical settings.

Theme 2: Resources, roles, and responsibilities

All the included studies reported the management of resources in the cQMS, mainly covering the need for human resources (n = 12), financial resources (n = 11), and requirements for implementation location (n = 5) and equipment (n = 8).

The workforce reported in the included studies involved in the clinical practices of ATMPs included highly qualified clinicians and nursing staff,^{21,23,26,29,30,31} pharmacists,²⁰ clinical trial coordinators,²⁴ skilled GMP technicians,^{19,20,24,25,26,27} statisticians,²⁶ professional managers (e.g., quality assurance manager, regulatory manager, administrative operation),^{20,22,23,24,26,27,30,31} ethics and law advisors,²⁶ and even the ad hoc multidisciplinary professionals from pharmacy, infectious disease, transfusion medicine, and neurology.²² Nine studies reported on the roles and responsibilities of healthcare professionals (HCPs). Medical directors or principal investigators (PIs) involved were required to have ultimate responsibility for key decisions, overseeing the coordination and management of the entire processes.^{19,21,24,26,31,32} Qualified HCPs with extensive work and training were expected to be available to provide care to inpatients/outpatients at any time and to immediately engage in the interdisciplinary management of patients.^21,23,26 The other four studies reported on the roles and responsibilities of other technical staff, including managers working at a wide range of levels, assessing resource needs and quality control management,^19,26,27 and technicians with degrees in medicine, biology, or biotechnology with varying levels of experiences (e.g., mock runs, sample treatment and special index detection).^{18,19,24,25,26,27}

Financial considerations were reported in terms of hospital or academic funds,^18,24,26,28 manufacturer commercial grants,^18,21 and sponsorship by the charities to the public investment.²⁵ Due to the high value of the ATMPs, the development of ongoing budget plan^19,27,29 and negotiation for reimbursement rates related to patient care costs were also included.^30,31

Location aspects primarily included requirements for the GMP manufacturing area (e.g., biosafety cabinet), the GMP environment (e.g., air-conditioning system), and the microbiological safety of ATMPs with the standard air cleanliness level.^{21,25,27,28,29} GMP-qualified equipment mainly covered cell culture, flow cytometry, microscopy, histology, molecular biology facilities, and appropriate bioreactors.^{18,21,24,25,27,28,29} In addition, two studies reported that equipment maintenance practices included initial validation (installation, operational, performance qualification), performance tracking, and routine preventative maintenance.^19,23

Theme 3: Partnering

Thirteen of the included studies reported that internal and external communication and collaboration was essential to the formation of clinical practice network for ATMPs. The reported internal partnering mainly consisted of interdisciplinary HCP communications,^{20,21,22,23,24,26} collaboration between the cell-manufacturing unit and the hospital unit,^25,26 and the regular communication meetings held to review updates.^19,30,31 In contrast, external partnering reported encompassed a range of activities, including outsourcing collaborations,^{18,19,20,25,29,30,31} as well as communication and coordination collaborations with pharmaceutical companies^{20,24,25,28,29} and academic institutions²⁵ and cooperation between sponsors, investigators, and drug regulatory agencies.²⁴ External communication activities also included interactions between scientists and clinicians. For instance, a study by Wiltshire et al. reported that a specific position was set up within the hospital unit to manage communication and coordination activities, with a shared e-mail inbox and phone number for outside contacts.¹⁹

Theme 4: Risk management

Seven of the included studies reported on risk management of ATMPs in hospital settings, including at the strategic,^22,25 operational,^18,19,20,27 quality,^25,27 and compliance^22,24 levels. The study by Dulan et al. reported on overall risk assessment and mitigation strategies,²² whereas the study by Viganò et al. focused on risk assessment for GMP facility sizing and resource planning.²⁵ In terms of operational risk management, one study reported the running of simulation or operational processes to identify potential problems and ensure quality control prior to the handling of clinical products.¹⁸ The study by Talarmin et al. employed the “failure mode, effects, and criticality analysis” (FMECA) approach for risk identification and evaluation, and further analyzed to clarify the significant and major risks of CAR T cell products in cellular therapy units and pharmaceutical processing procedures.²⁰

As reported in two studies, the utilization of personal protective equipment (PPE) components by a qualified person, in conjunction with the implementation of specific actions, was one of the effective strategies for the mitigation of operational risks associated with the handling with ATMPs.^19,27 On the other hand, the study by Wiltshire et al. emphasized the importance of streamlining communication processes for various stakeholders in the management of operational risks.¹⁹ Regarding quality risk management, two studies reported on optimizing the manufacturing environment,²⁵ adopting critical process systems and equipping alarms at storage locations of cellular materials²⁷ to minimize quality risks. Both studies also adopted maintenance schedules to continuously monitor manufacturing sites for quality management.^25,27 With respect to compliance risk management, the sponsors conducted site audits to determine whether the clinical practices in hospital setting met the regulatory requirements of governments and enterprises.^22,24

In addition, as shown in Figure 2, all 23 ATMPs risk management reports from the FDA and EMA included regular reporting and analysis of adverse reactions associated with the use of ATMPs.^{32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54} The most common additional risk minimization measures (aRMMs) identified were educational programs for healthcare professionals (n = 17)^{37,38,39,40,41,42,43,44,45,46,47,49,50,51,52,53,54} and training activities for patients and their caregivers (n = 13).^37,49,50,54 The distribution of patient alert cards,^{37,39,42,43,45,46,48,49,51,52,53} planning and instructions at the time of patient enrollment,^{32,33,34,35,36,37,39,40,45,46,48,51,52,53} as well as the preparation of training materials for pharmacy, cell laboratory, and infusion center^46,52 were also considered effective aRMMs during ATMPs treatment.

Figure 2.

Additional risk minimization activities identified in the risk management reports disclosed by the listed ATMPs from the FDA, EMA, and NMPA

Of the 18 included risk management plans (RMPs) published by the EMA, 16 RMPs reported the specific projects targeting for post-authorization safety studies,^{37,38,39,40,41,42,43,44,45,46,47,48,49,51,52,53} and 15 reported on long-term follow-up studies after ATMPs marketed.^{37,38,39,40,41,43,45,46,47,48,49,50,51,52,54} Besides, the post-market development plan in the six included RMPs that reported the use of questionnaires on safety knowledge and training of ATMPs for HCPs,^40,45 the evaluation of the effectiveness of aRMMs for HCPs,^41,43,49,51 and the safety information in product manuals and alert cards for patients.⁴⁵

Theme 5: Issue management

Ten studies reported on issues management processes covering patient safety (n = 5),^{22,23,24,26,27} data integrity (n = 4),^{22,23,29,30,31} and regulatory compliance (n = 4).^20,21,24,27 In managing patient safety issues, two studies reported the prompt documentation of any patient safety concerns and notification of any adverse events to clinical trial investigators and sponsors.^24,27 Corrective and preventive actions (CAPA) aimed at ensuring patient medication safety included the implementation of specific caring standard, policies, and algorithms,^22,26 along with the rapid identification of underperforming products and treatments.²³ Additionally, regular reviews and benchmarking of quality management plans for ATMPs, as well as patient outcomes, were conducted to analyze trends in patient safety issues.^22,23,26

In terms of data-management-related issues, the study by Dulan et al.²² developed an electronic application for reporting and tracking infusion deviations of CAR T cell products to ensure the integrity of submitted data. Another study established an operating system that refined data field definitions and integrated external supporting documents to address missing data in critical areas.²³ The study by Trounson et al. focused on the ongoing collection and monitoring of long-term longitudinal data to evaluate the safety and efficacy of cellular therapies.²⁹ Compliance management challenges primarily centered on protocol deviations.^20,24,27 For instance, the study by Montemurro et al. conducted routine monitoring of microbiological environmental conditions in accordance with regulatory and protocol requirements, with data on microbial contamination and particulate matter collected to generate periodic compliance trend reports.²⁷

Theme 6: Knowledge management

Twelve studies in the review identified the knowledge management components within the cQMS for ATMPs. The main categories of knowledge required by stakeholders for effective quality management in hospital settings included specialized competencies in treating patients with the malignant tumors and cellular therapies,^21,28,29 GMP training,^19,25,27 personal protective skills,¹⁹ risk management training,²² and clinical documentation and management processes.²³

The main means of knowledge acquisition reported were in-person instruction (including theoretical or certification course training and personal study),^{18,23,24,25,27} practical training and assessment (e.g., completion of an annual competency checklist and management of at least two CAR T cell patients and two cellular infusions),^22,27 and distance-supported training (e.g., virtual meetings, videos, and slide presentation),^18,20,23 in addition to educational webinars and roundtables.^26,27 Only four studies described specific training design and implementation details,^19,22,24,27 whereas three other studies reported the need for continuously updating the training content and regularly reviewing the effectiveness of training.^19,22,23

Theme 7: Documentation supporting achievement of quality

Twelve of the included studies reported about the document management processes to support the achievement of quality. Only one study developed an electronic application for the submission of deviations from SOPs in patient care.²² However, none of the studies were found to report the accountability-related aspects of documentation.

The main format of documentation reported in the included studies were electronic records with hard copy documents or scanned paper,^{18,19,21,22,23,24,25,26,29} as well as structured reports^30,31 and traceability systems.^20,29 Documentation of product-related information was reported in the included two studies as follows: apheresis products (e.g., date/time of collection, volume, cell counts, and cryoprotectants),¹⁸ outsourced manufactured products,¹⁹ and final products (receipt, thawing, and infusion),¹⁸ along with the product label and the recording of all critical equipment.¹⁸ Clinical procedures and protocols,^21,24 subject information,^18,26 and records pertaining to treatment efficacy and long-term follow-up outcomes^22,26 were documented as clinical-related and patient-related information.

Four studies reported the utilization of information collection forms to guarantee data integrity, including the internal online service request form,¹⁹ web-based forms and databases,^18,23 and an electronic customized navigation form.²² The study by Wiltshire et al. reported ensuring the feasibility of product data tracking, provenance management, and work requests during the initial and quality documentation reviews.¹⁹ Several studies reported on the enhancement of document quality through the development and adoption of document reporting criteria,²² and corresponding SOPs,^24,25 as well as the establishment of a separate data collection unit²⁶ or the support of the data coordinating center.^30,31

Discussion

This scoping review identified recommended quality management practices and pragmatic experiences of managing ATMPs in the hospital settings from a wide range of technical guidelines, standards, and risk management reports. Through the application of the cQMS framework, this study identified and categorized key activities essential for quality management of ATMPs, as depicted in Figure 3. The current findings offer a structured approach that guides the regulatory compliance in process management. The interdependencies of coordinating and optimizing resource allocation and collaboration, risk assessment, issue management, and knowledge improvement are vital to maintaining the safety and efficacy of these complex therapies in hospital settings. Although further research and validation are necessary, this study offers valuable insights into improving quality management systems for ATMPs, providing hospitals with a structured, evidence-based framework to assess and enhance their practices.

Figure 3.

The elements of quality management for ATMPs in hospital settings

Quality assurance for ATMPs

The research, development, and use of ATMPs within hospital settings is required to comply with mandatory national regulations, policies, and technical guidelines along with other optional practice standards that collectively form the overall structure of a complex quality management system. In some clinical settings, quality and accreditation requirements are also in place to ensure patient safety, promote best practices, drive process improvements, and standardize procedures throughout the entire patient care continuum in a complementary manner. As reported in the present study, a series of technical guidelines for various ATMPs and their indications had been issued by the FDA, EMA, NMPA, which covered multiple aspects of the full life cycle for ATMPs in hospital settings.

In general, special focus was made on the management practices of clinical trials of cellular therapies, including the manufacturing and delivery of cell products,^18,24,29 patient translational research,²⁶ and clinical trial network building.^30,31 For instance, with patient translational research, the FDA, EMA, and NMPA have all issued specific Good Clinical Practice (GCP) guidelines for ATMPs to standardize the design, implement and report clinical trials, protect trial subjects, and to ensure the reliability of data.^{55,56,57,58,59} Similarly, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has issued GCP guidance for regenerative medicine (RM) products, along with a dedicated procedural document for the remote inspection of clinical trials involving RM products.^60,61 Furthermore, the EMA in its guidance highlights the risks and measures of upstream interventions on subjects, as the process of biopsy or cell extraction may affect not only the safety of the subjects but also the quality of the products.⁵⁵

In addition, considering that most of the ATMPs are manufactured individually for each subject in clinical trials, the FDA had special recommendations to the product manufacturing issues in its early clinical trial design⁵⁶ and clear instructions for the evaluation of multiple investigational therapies within a single overarching protocol under the umbrella clinical trial master protocol.⁵⁷ NMPA has also issued clinical trial guidelines specifically for oncolytic virus products, emphasizing on the design and analysis of shedding studies and the toxicity management of CAR-T cell products.^58,59 Similar actions had been reported in South Korea. The Ministry of Health and Welfare (MoHW) enacted the Act on the Safety of and Support for Advanced Regenerative Medicine and Advanced Biological Products (ARMAB) in 2019, emphasizing stringent oversight from cell collection through to testing, processing, and storage. Guidance issued in 2020 further detailed the requirements for implementing institutions, cell processing facilities, and safety management bodies involved in advanced regenerative therapies.^62,63

On the other hand, given the manufacturing challenges of ATMPs, such as the limited batch sizes and the inherent variability of raw materials, it is crucial for manufacturers or hospital-level entities to implement specific processes and measures that comply with GMP requirements. Guidelines issued by the EMA and FDA focus on preventing the risks of mix-ups and cross-contamination within ATMPs manufacturing facilities and equipment, alongside risks of the spread of related infectious pathogens.^10,11,64 The PIC/S GMP guidelines for ATMPs consist of two parts: part A covers control from seed lots and cell banks to finishing activities and testing, whereas part B contains more specific guidance for selected product types (e.g., animal-derived products).⁶⁵ To this end, the Singapore Health Sciences Authority (HSA) has also published a guidance on ATMPs CMC requirements for both clinical trials and product registration and provided a summary table comparing GMP requirements for an investigational versus registered through subsequent document.^66,67 This phase-appropriate approach to GMP compliance facilitates the alignment of quality standards with the varying requirements throughout the product development life cycle.

Quality accreditation or standards of industry societies are also key elements of the whole quality management ecosystems. The accreditation systems from organizations, such as AABB, FACT, and JACIE, further complement the quality assurance efforts mentioned above, which promote excellence in patient care and operational practices by standardizing cell-based operating procedures.^68,69 Notably, FACT and JACIE are among the peer-driven, voluntary accreditation pathway to high-quality practices such as the “quality management and accreditation standards for hematopoietic stem cell transplantation and cellular therapy,” encompassing clinical programs, collection facilities, and processing laboratories.^69,70,71 The AABB standards provide certification for the processing, storage, and distribution of pluripotent mesenchymal stromal cells expanded ex vivo. Additionally, there are interdependencies among standards. The JACIE standards incorporate the risk analysis section from GMP, allowing them to exist independently or overlap across different regulatory authorities, forming a system that encompasses a wide variety of cell products, sources, and manufacturing processes, promoting donor and patient safety as well as product efficacy.

Risk management for ATMPs

Risk-based management is an essential component in ensuring the safe and appropriate use of ATMPs due to the complexity of biomaterials and operating procedures involved.^15,72 The risks associated with using ATMPs extend beyond immediate side effects and also include long-term concerns, such as complications from the underlying disease and the persistence of the product within the patient.

Risk management documents issued by drug regulatory authorities are designed to report these potential risks and mitigate them through systematic approaches. For instance, the included REMS program for FDA-approved CAR T cell products detailed the necessary risk factors and outlined the medication guidance, prescribing information, hospital enrollment instructions, communication plans with providers, and the dedicated REMS websites designed for the specific products (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). A notable example is the City of Hope National Medical Center in United States, where the Clinical Cellular Immunotherapy Committee (CCIC) collaborated with the department of Hematology’s Quality Management Council to develop an REMS program as a standard-of-care policy and enacted mandatory REMS training.²² The REMS checklist includes a series of pre-enrollment qualifications and screening tests, post-infusion CAR T cell care, and a list of policies to be reviewed (e.g., CAR T cell care standard deviations).²² Similarly, the EMA detailed a list of risks associated with the drugs and their activities in different RMPs of ATMPs. One of the primary tools used by the EMA to continuously monitor the safety of the marketing ATMPs and assess their benefit-risk balance is the Periodic Safety Update Report (PSUR), which compiles and regularly analyzes adverse drug reactions (ADRs) data. All ADRs within the EU are reported through the EudraVigilance system.⁷³

Additionally, post-authorization risk management for ATMPs have focused on safety and long-term follow-up studies to further identify any potential long-term risks associated with the product. Among them, the EMA has detailed relevant risks and provided recommendations on viral vectors in its published guideline on patient follow-up with gene therapy medicinal products.⁷⁴ Viral vectors with integration capabilities or latency require long-term clinical follow-up considerations due to their presence throughout the entire life cycle of target cells or tissues. In January 2020, the FDA released the “Long-term Follow-up After Administration of Human Gene Therapy Products,” which offers guidance on the recommendations on the study design, elements and duration of long-term follow-up observations, and requirements of data collection and reporting.⁷⁵ In December 2021, the NMPA issued the “Guidance for Long-term Surveillance of Gene Therapy Products,”, which clarified that a traceability system for the product and the user should be established after the products approved for marketing.⁷⁶ Moreover, dealing with safety and procedural risks associated with different ATMPs, the CAPA plans and reports provided to regulators and hospitals play a positive role in systematically collecting and analyzing information leading to issues, thereby ensuring the reliability of systems and processes and facilitating continuous improvement.⁷⁷

Workforce capacity building for ATMPs

The successful implementation of ATMPs in hospital settings requires a skilled and diverse workforce, with varying demands for human resources depending on the specific practices employed. Healthcare professionals (e.g., clinicians, nurses, pharmacists, and clinical trial coordinators), technical staff (e.g., laboratory technicians, GMP, and support staff), and related managers (e.g., quality assurance and regulatory staff) constitute the core workforce involved in the manufacturing, delivery, and patient care associated with ATMPs. The field of cell, gene, and tissue therapies require expertise across diverse scientific disciplines (e.g., cell and molecular biology and bioinformatics) and biomedical areas (e.g., oncology, hematology, and emergency medicine). Additionally, strict adherence to legal standards and regulatory affairs related to preclinical trials, manufacturing, and clinical use imposes heighted demands on their knowledge and skills.

As ATMPs increasingly demonstrate disruptive effects in clinical practice, HCPs need to be more prepared for the use of such therapies in hospitals. The readiness of physicians refers to their ability to accurately assess the safety of new treatment modalities for patients and effectively apply validated techniques to address unmet needs.⁷⁸ In this context, the study by Terzic et al. underscored the necessity of establishing rigorous early training programs within medical teams.^79,80 Their study proposed a patient-center training model for working physicians that integrated evolving real-world experience with the curriculum, covering topics from laboratory to clinical translation, as well as the supplementary knowledge in ethics, regulatory affairs, and production supply chain.⁸¹ Likewise, hospital pharmacy departments need to prepare for emerging ATMPs by collaborating with multidisciplinary colleagues to ensure the adequacy of pharmacy facilities and practices.^82,83 A study reported the critical role of pharmacists in institutional preparedness and management of gene therapy, particularly in the proper handling of gene replacement therapies, risk level management, institutional environment preparation, and the development of appropriate policies and procedures.⁸⁴

For technical staff, successful GMP compliance hinges on the ability of production operators to execute tasks with the highest precision and without deviation in the specific sequence outlined in batch records.⁸⁵ These demands not only procedural rigor but also a thorough understanding of both the manufacturing process and the product themselves, enabling operators to identify and address deviations encountered during actual operations. To meet these demands, manufacturers and hospitals must facilitate the technical staff with specialized training, either directly from manufacturers or through internal programs, to equip them for the complexities of ATMPs manufacturing. Green et al. proposed the establishment of continuing education courses tailored for the regenerative medicine biomanufacturing workforce, suggesting this as a pathway to address critical skill gaps in the field.⁸⁶ Programs like the Austin Community College (ACC) biotechnology initiative serve as an illustrative example, offering advanced training in areas such as cell culture, bioprocessing, bioinformatics, next-generation sequencing, and quality control.⁸⁷ The recent study by Wu et al. advocates for the adoption of electronic QMS in academic cell and gene therapy GMP facilities to enhance operational efficiency and adaptability through the utilization of digital workflows, advanced analytics, and comprehensive staff training in a rapidly evolving field.⁸⁸ These efforts underscore the importance of developing comprehensive training pipelines to equip technical staff with the competencies necessary for operating in regulated environments.

Moreover, accreditation and professional societies play an indispensable role in fostering workforce development by offering strategic frameworks, resources, and collaborative opportunities that enhance talent capabilities. For instance, the ISCT at its 2022 Annual Meeting has outlined a value chain for education and training in cell and gene therapy, emphasizing the shared responsibility among academia, public-private partnerships, and public initiatives (e.g., hospitals and academic institutions) to deliver training programs that are aligned with industry goals for market approvals and workforce readiness.⁸⁶ Acting as a bridge between regulators, academia, and industry, scientific societies such as the ISCT connect multidisciplinary experts, promote the translational work of their work, and are establishing a Workforce Development Committee to guide training initiatives and competency-based programs with global applicability.⁸⁷

Strengths and limitations

Based on the concepts and frameworks of quality management to implement data retrieval, extraction, and evidence synthesis of various literature, guidelines, standards, and related reports, this scoping review provides a systematic visual representation of the quality management system in the development and utilization of ATMPs in hospital settings. The cQMS conceptual framework is designed to offer a consistent, streamlined, and proactive approach to achieving clinical quality goals of the product throughout all development phases. Therefore, adopting the framework provides significant value by fostering a more standardized and consistent evidence base for the development and management of ATMPs in broader clinical settings. The findings of this study could be used to proactively identify and mitigate quality risks during the use of ATMPs, while promoting the elements of QMS to a wider range of healthcare institutions and their stakeholders, pharmaceutical manufacturers, and regulatory agencies and ultimately promoting patient accessibility and safety of products.

However, there are still some limitations in this study. One of the limitations was that, due to a lack of quantitative data in the included literature, we were not able to measure or review the quality management practice and its outcomes. The cQMS of ATMPs in real-world settings encompass multifaceted factors across structural, procedural, implementational, and outcome-related dimensions. Future efforts involve the development and adoption of standardized and evidence-based benchmarking tools and quality indicators for the comprehensive and continuous monitoring, performance assessment, and improvement of clinical quality management practices of ATMPs. Additionally, the included literature may present limitations in reflecting real-world quality management practices within hospital settings, such as time lags and gaps in data comprehensiveness. Unpublished quality-related data from different regulatory agencies, medical institutions, or undisclosed internal data from pharmaceutical manufacturers may inevitably affect the completeness of data collection and result in the omission of certain normative practices. Furthermore, this study mainly included technical guidelines and reports about ATMPs from the United States, the European Union, and China, serving as typical cases for analysis. The exclusion of regulatory practices in other regions may have led to information gaps and limited representativeness. Future research may expand the scope to present a more comprehensive regulatory landscape.

Overall, this scoping review systematically summarized and mapped the key processes and elements critical to the quality management of ATMPs within hospital settings, covering resource allocation, staff responsibilities, risk and issues management, and related supporting knowledge and documentation. The main driving factors for high-quality management of ATMPs in hospitals include regulatory compliance, adherence to technical guidelines, and standards issued by national regulatory authorities and internationally recognized professional organizations, the implementation of risk-based management strategies, and the development of specialized workforce capabilities alongside multidisciplinary coordination. The findings provide practical references for healthcare institutions to evaluate existing clinical quality management practices and identify areas for improvement or adaptation, particularly as more ATMPs transition into routine clinical practice. Moving forward, a key contribution to implementing and developing an adaptive quality management ecosystem will be to bridge the gap between clinical research and clinical care of ATMPs, which will help promote the safe and effective delivery of these innovative therapies to patients.

Materials and methods

This scoping review identified publicly available information on the quality management of ATMPs in hospital settings sourced from literature and documents in electronic databases and related government and official websites. This study was conducted and reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The study protocol has been registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) under registration number INPLASY202480117.⁸⁹ Data extraction, compilation, and analysis were guided by the elements of the clinical quality management system (cQMS) conceptual framework.

Theoretical framework

The use of an effective QMS is essential for systematically organizing and standardizing processes, resources, and responsibilities involved in the development of pharmaceuticals.⁹⁰ The theoretical, research, and conceptual frameworks for quality management have been proven in many practices to guide organizations and institutions to better comply with regulatory requirements and reduce risk in the development and use of products. A risk-based, clinical-focused QMS is recognized as being particularly effective in addressing or preventing quality challenges within the complex clinical environments.^91,92

Based on the existing international quality standards, TransCelerate has developed a clinical QMS framework (cQMS) applied in the clinical development settings.⁹² This framework facilitates the transition of clinical institutions from reactive to proactive, aiming to prevent risks from becoming issues during clinical development activities. The framework takes into account the diversity of organizations that may be interested and capable of implementing it, as well as the inherent variability in clinical development. Within this framework, seven key elements have been reported to contribute to success in the clinical area, namely, processes; resources, roles, and responsibilities; partnering; risk management; issue management; knowledge management; and documentation supporting achievement of quality. The adoption of the cQMS framework has the potential to transform the concept of quality into the “what to do” in clinical operations and decision-making processes within the medical institutions.

Eligibility criteria

Literature published in English was included if it directly discussed about the real-world experiences in the quality management of ATMPs within a hospital setting. Articles that did not involve empirical research or quality management practices of ATMPs conducted in a hospital setting were excluded. In addition, technique guidelines and reports relevant to ATMPs issued by regulatory authorities in the United States, the Europe Union, and China that pertain to cQMS were included.

Data retrieval and collection

The data retrieval and collection was conducted in July 2024 to search the publicly available regulatory guidelines, documents, standard operating procedures (SOPs), related literature, and reports. Four databases (PubMed, Web of science, Scopus and Science Direct) were searched for eligible literature from January 1, 2004 to July 31, 2024. The primary concepts in this scoping review included “quality management,” “advanced therapy medicinal products,” and “hospital”. After the preliminary research of the potential synonyms, a pilot search for each term was conducted in PubMed and Web of Science to determine the included search keywords as described in the Table S1. Selected synonyms, keywords, and Medical Subject Headings (MeSH) terms related to the three concepts were used to develop a comprehensive search strategy. In addition, to identify the potentially eligible studies, a search of gray literature was conducted using Google Scholar, and the reference lists and citations of included studies were reviewed.

The United States, the European Union, and China were targeted for search due to their extensive issuance of technique guidelines for ATMPs at various development stages. The official websites of the abovementioned drug regulatory authorities and other international professional organizations that had published publicly accessible documents involving the quality management of ATMPs were searched for eligible records. Information as of July 2024 was also retrieved from their respective official websites for inclusion in this review.

Data extraction and analysis

The included literature, technique guidelines, and reports were extracted and analyzed following the specific categories of the cQMS conceptual framework. For eligible full-text articles, the following items were extracted into an Excel table: the name of the first author, year of publication, study location, the purposed of studies, and the quality management program or model involved (including the name of the program/model, the specific implementation place, type of ATMPs, and the practice content). The types of practices were categorized based on the seven elements of the cQMS framework: (A) processes; (B) resources, roles, and responsibilities; (C) partnering; (D) risk management; (E) issue management; (F) knowledge management; and (G) documentation supporting achievement of quality. Guidelines and related SOPs for the quality management of ATMPs in hospital settings, as well as information reports on specific marketed ATMPs were also incorporated into the cQMS framework for analysis.

The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All records were submitted to a public reference manager (Zotero software) to remove the duplications. Then, two authors independently (J.S. and C.O.L.U.) screened the titles and abstracts to identify the inclusion literatures. Full texts of potentially relevant articles, guidance, and reports were retrieved for detailed assessment (J.S. and J.Y.). Any discrepancy was resolved through discussion by agreement in consultation with two other authors (H.H. and C.O.L.U.).

Acknowledgments

This work was supported by a grant from University of Macau (MYRG-GRG2023-00087-ICMS, MYRG-GRG2024-00147-ICMS-UMDF, MYRG-CRG2024-00024-ICMS-IAS), and the Science and Technology Development Fund, Macao SAR (file no. 005/2023/SKL). The authors would like to express their sincere gratitude to the Centre for Pharmaceutical Regulatory Sciences and the Institute of Chinese Medical Sciences, both at the University of Macau, for their support to this research.

Author contributions

J.S., conceptualization, data acquisition, analysis, methodology, writing/original draft, and writing/review and editing; J.Y., data acquisition, analysis, and writing/review and editing; Y.Z., review and editing; P.H.H.W., review and editing; H.H., data acquisition, analysis, methodology, and writing/review and editing; C.O.L.U., conceptualization, data acquisition, analysis, methodology, writing/original draft, and writing/review and editing.

Declaration of interests

The authors report no competing interests.