Navigating Point-of-Care Cell Therapy Manufacturing: A 2025 Guide to EU Regulations and Decentralized Production

Abstract

This article provides a comprehensive analysis of the evolving regulatory landscape for point-of-care (POC) and decentralized manufacturing of cell and gene therapies in Europe. Tailored for researchers, scientists, and drug development professionals, it explores the UK's pioneering regulatory framework, examines the current EU guidance ecosystem, and addresses key methodological and operational challenges. By comparing global approaches and outlining future directions, this guide serves as a strategic resource for navigating the technical and regulatory complexities of bringing advanced therapies closer to the patient.

The Rise of Decentralized Manufacturing: Redefining Production for Advanced Therapies

The field of advanced therapy medicinal products (ATMPs) is undergoing a significant transformation in its manufacturing and regulatory paradigms. For years, the production of cell and gene therapies has relied predominantly on centralized manufacturing models, where therapies are produced in large-scale, Good Manufacturing Practice (GMP)-compliant facilities often located far from the patient treatment site [1]. This model, while benefiting from economies of scale and centralized quality control, presents substantial challenges including complex logistics, lengthy turnaround times, and limited patient access to these life-saving therapies [2]. Recognizing these limitations, regulatory bodies and industry stakeholders are now actively shaping a shift toward more flexible manufacturing approaches, notably point-of-care (POC) and modular manufacturing solutions [3] [4].

This paradigm shift is particularly evident in the European regulatory context, where authorities are developing frameworks to accommodate the specific requirements of decentralized production. The European Medicines Agency (EMA) maintains a centralized authorization procedure for all ATMPs but recognizes the need for tailored guidance to support innovation while ensuring patient safety [5]. Simultaneously, national regulators like the UK's Medicines and Healthcare products Regulatory Agency (MHRA) have introduced groundbreaking legislation—the Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025—that establishes a formal pathway for manufacturing therapies at or near the patient care setting [3] [4]. This regulatory evolution aims to balance the need for regulatory oversight with the flexibility required to deliver personalized therapies in a timely manner, ultimately expanding patient access to these transformative treatments.

Current Regulatory Frameworks in the EU and UK

European Medicines Agency (EMA) Framework

The European Medicines Agency provides a centralized authorization procedure for all advanced therapy medicinal products within the European Union, with the Committee for Advanced Therapies (CAT) playing a pivotal role in their scientific assessment [5]. The regulatory framework for ATMPs in the EU continues to evolve, with recent updates focusing on good manufacturing practice guidelines to address technological advancements. Notably, the European Commission is currently undertaking a stakeholder consultation on EudraLex Volume 4, which covers GMP guidelines including Chapter 4, Annex 11, and a new Annex 22 specifically addressing artificial intelligence applications in pharmaceutical manufacturing [3]. This revision aims to support innovation while ensuring regulatory harmonization, with the consultation period open until 7th October 2025 [3].

The EMA has also demonstrated commitment to supporting ATMP development through initiatives like the ATMP pilot for academia and non-profit organizations, which provides dedicated regulatory assistance and fee reductions for developers targeting unmet medical needs [5]. Furthermore, the EMA and Heads of Medicines Agencies (HMA) have jointly set ambitious new targets for clinical trials in the EU, aiming to add an additional 500 multinational trials and ensure two-thirds begin patient recruitment within 200 days of application submission [6]. These efforts are part of the broader Accelerating Clinical Trials in the EU (ACT EU) initiative to create a more supportive environment for clinical research.

UK Medicines and Healthcare Products Regulatory Agency (MHRA) Framework

The UK has positioned itself as a pioneer in decentralized manufacturing regulation with the implementation of the Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025 in July 2025 [3] [4]. This world-first framework establishes formal pathways for manufacturing advanced therapies at the point of care, allowing hospitals, clinics, and local care settings to complete final manufacturing steps using regulated protocols [4]. The legislation also supports mobile manufacturing units and applies to a wide range of products including cell and gene therapies, tissue-engineered treatments, blood products, and 3D-printed therapies [4].

The MHRA provides oversight through a central control site and has issued complementary guidance developed in collaboration with the National Health Service, industry, and healthcare professionals to clarify practical implementation [4]. More recently, in September 2025, the MHRA published further guidance on decentralized manufacturing through a blog post that outlines emerging considerations and key requirements for the new manufacturing and supply framework, which encompasses both point-of-care and modular manufacturing elements [6].

Table: Key Regulatory Developments Supporting Point-of-Care and Modular Manufacturing

Regulatory Body	Regulatory Development	Key Features	Implementation Timeline
UK MHRA	Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025	Permits manufacturing at hospitals, clinics, local care settings; supports mobile units; central control site oversight	Effective July 2025 [3]
European Commission	EudraLex Volume 4 Revision (Chapter 4, Annex 11, New Annex 22)	Addresses AI in pharmaceutical manufacturing; ensures GMP guideline relevance to digital technologies	Consultation until October 2025 [3]
EMA/HMA	Clinical Trials Targets	Additional 500 multinational trials; 66% of trials to begin recruitment within 200 days	5-year implementation plan [6]
MHRA	Route B Notification Pilot	Streamlined substantial modifications process with 14-day response time	Launched October 2025 [6]

Comparative Analysis of Manufacturing Models

Centralized Manufacturing Model

The centralized manufacturing model remains the dominant approach for commercial cell and gene therapies, characterized by large-scale GMP facilities that produce therapies for distribution to multiple treatment centers [7] [1]. This model offers significant advantages in infrastructure efficiency, as high fixed costs for cleanrooms, specialized equipment, and qualified personnel are amortized across multiple product batches [2] [1]. Centralized facilities enable rigorous standardization and safety protocols, ensuring consistency and product quality through established supply chains and comprehensive testing before product release [2]. Additionally, centralized models typically utilize cryopreservation, allowing for scheduled administration and creating backup doses when necessary [2].

However, the centralized approach presents substantial limitations, particularly for autologous therapies where patient-specific starting materials must be transported to the manufacturing facility and the final product shipped back to the treatment center. This logistics chain results in lengthy turnaround times—often several weeks—which can be problematic for patients with rapidly progressing diseases [2] [1]. The complexity of global logistics also introduces risks of shipping delays, temperature excursions, and high associated costs [1]. Furthermore, access limitations are significant, with estimates suggesting that less than 20% of eligible B-cell lymphoma patients in the U.S. receive CAR-T therapy, due in part to the infrastructure limitations of centralized manufacturing [1].

Point-of-Care and Modular Manufacturing Models

Point-of-care and modular manufacturing represent a paradigm shift that addresses many limitations of centralized production. The POC model involves manufacturing therapies at or near the patient treatment location, potentially within hospital settings or specialized local facilities [2]. This approach significantly reduces turnaround time by eliminating complex logistics, enabling faster treatment for patients with aggressive diseases [2] [1]. The UK's new regulatory framework specifically supports this model, allowing "hospitals, health clinics and local care settings in the UK now have a pathway to carry out the manufacturing steps for these personalised or time-sensitive treatments near or on-site" [3].

Modular manufacturing, often implemented through self-contained GMP cleanroom modules, offers flexibility and scalability while maintaining manufacturing standards [8]. Companies like Valicare offer turnkey solutions such as the cult.tainer—a modular cleanroom module up to 470 square meters that can be configured for specific manufacturing processes and rapidly deployed [8]. These modular systems can be implemented within hospital settings or as mobile units, creating manufacturing capabilities without the need for permanent infrastructure construction [4] [8].

The EU-funded Facer project has developed an autonomous cell culture platform that exemplifies advanced POC manufacturing technology. This system can "autonomously manufacture billions of high-quality cells starting from a small biopsy of cells" using single-use cartridges with continuous monitoring and minimal human intervention [9]. The platform's modular design allows simultaneous production of cells from five different sources without cross-contamination, demonstrating the potential for standardized yet flexible manufacturing at the point of care [9].

Table: Comparative Analysis of Centralized vs. Point-of-Care Manufacturing Models

Factor	Centralized Manufacturing	Point-of-Care Manufacturing
Turnaround Time	Several weeks due to logistics [1]	Significantly reduced (days) [2]
Manufacturing Costs	High fixed costs but lower per-batch costs at scale [1]	Lower logistics costs but potential for higher per-batch costs [1]
Quality Control	Standardized across facilities; batch testing before release [2]	Requires harmonization across multiple sites; real-time monitoring [1]
Regulatory Oversight	Established pathways; single-site inspection [5]	Evolving frameworks; multi-site oversight challenges [3] [1]
Patient Access	Limited to centers near manufacturing facilities or with robust logistics [1]	Potentially broader access, including remote locations [2]
Therapy Applicability	Suitable for less aggressive diseases and off-the-shelf products [1]	Critical for aggressive diseases and highly personalized therapies [1]

Experimental Protocols for Point-of-Care Manufacturing Implementation

Protocol 1: Technology Implementation and Process Validation

Objective: Establish and validate a point-of-care manufacturing system for autologous cell therapies within a hospital setting.

Materials and Equipment:

• Autonomous cell culture platform (e.g., Facer platform) or comparable system [9]
• Single-use bioreactor cartridges designed for the specific cell type [9]
• Closed processing systems to minimize contamination risk [1]
• Environmental monitoring equipment for continuous air quality assessment
• Quality control instruments for in-process testing (flow cytometer, viability analyzer)

Methodology:

• Site Assessment and Preparation:
  • Evaluate hospital space for modular cleanroom installation (e.g., cult.tainer) [8]
  • Ensure utility requirements are met (electrical, HVAC, gases)
  • Verify classification of cleanroom areas according to GMP standards

• Technology Implementation:

  • Install autonomous cell expansion platform with continuous monitoring capabilities [9]
  • Configure single-use cartridge systems for specific cell therapy products
  • Establish closed-system connections between process steps to minimize open manipulations

• Process Validation:

  • Conduct three consecutive validation runs using donor materials
  • Monitor critical process parameters (cell density, viability, metabolite levels)
  • Compare final product quality to historical centralized manufacturing data
  • Validate product identity, potency, and purity using established assays

• Staff Training and Qualification:

  • Train hospital technicians on automated system operation and monitoring
  • Establish competency assessments for critical manufacturing steps
  • Implement ongoing training program for process updates

Data Analysis: Compare process consistency through statistical analysis of critical quality attributes (CQAs) across validation runs. Process is considered validated if all CQAs fall within pre-established specifications for three consecutive runs.

Protocol 2: Quality Management System Implementation

Objective: Establish a quality management system (QMS) suitable for point-of-care manufacturing that ensures regulatory compliance and product quality.

Materials:

• Document management system for standard operating procedures (SOPs)
• Electronic batch record system with identity preservation capabilities
• Deviation and CAPA management system
• Environmental monitoring software

Methodology:

• QMS Framework Development:
  • Adapt existing QMS from centralized manufacturing for POC requirements
  • Develop site-specific SOPs for manufacturing, testing, and release
  • Establish change control procedures appropriate for multi-site operations

• Batch Record Design:

  • Create simplified electronic batch records with built-in compliance checks
  • Implement identity preservation protocols throughout manufacturing process
  • Incorporate real-time data collection and review capabilities

• Product Release Protocol:

  • Define release criteria based on critical quality attributes
  • Establish rapid testing methodologies compatible with shorter vein-to-vein times
  • Implement two-tier release process: local review followed by central quality assurance

• Multi-Site Harmonization:

  • Develop standardized training materials across all POC sites
  • Establish process performance qualification (PPQ) protocol for new sites
  • Create centralized monitoring system for tracking performance metrics across sites

The implementation of these protocols should align with the emerging regulatory considerations outlined by the MHRA, which emphasizes the importance of harmonized operations and consistent quality across decentralized manufacturing networks [6].

Technological Solutions and Research Reagent Considerations

Automated and Modular Manufacturing Platforms

The successful implementation of point-of-care manufacturing depends heavily on technological innovations that enable robust, standardized processes in decentralized settings. Automated cell culture systems represent a critical advancement, with platforms like the Facer system providing autonomous expansion of cells from small biopsies with continuous monitoring and minimal human intervention [9]. These systems utilize single-use cartridges where cells are expanded under controlled conditions, maintaining homogeneity and batch-to-batch consistency while eliminating cross-contamination risks between different cell sources [9].

Modular cleanroom solutions offer practical infrastructure for POC manufacturing without requiring permanent facility modifications. The cult.tainer concept developed by Valicare provides turnkey GMP-compliant cleanroom modules specifically designed for ATMP manufacturing [8]. These modules can be configured to include all necessary process and quality control rooms, with optional storage, airlocks, and office facilities [8]. The modular approach significantly reduces implementation time, with providers offering "3-month planning and 9-month implementation" timelines for establishing manufacturing capabilities [8].

Closed processing systems and automation are essential technologies for POC manufacturing, reducing facility footprint requirements and environmental controls needed for compliance [1]. When processes are closed and automated, the need for classified cleanroom space is reduced, making implementation in hospital settings more feasible [1]. Furthermore, automation addresses the challenge of technical staffing at multiple sites by reducing manual interventions and standardizing operations across networks [1].

Essential Research Reagent Solutions

Table: Key Research Reagent Solutions for Point-of-Care Cell Therapy Manufacturing

Reagent/Category	Function	Point-of-Care Considerations
GMP-grade cytokines and growth factors	Direct cell differentiation and expansion	Pre-qualified for use in closed systems; reduced endotoxin levels [1]
Serum-free, xeno-free media formulations	Support cell growth without animal components	Formulated for consistency across multiple sites; stability during storage [1]
Single-use bioreactor cartridges	Provide scaffold for cell expansion	Designed for autonomous systems with integrated monitoring [9]
Rapid quality control test kits	Assess critical quality attributes	Designed for use near manufacturing site; reduced turnaround time [2]
Cryopreservation solutions	Maintain cell viability during storage	Formulated for direct use without dilution; compatible with rapid thaw protocols [2]

Workflow Visualization of Point-of-Care Manufacturing

The following diagram illustrates the integrated workflow for point-of-care cell therapy manufacturing, highlighting the coordination between clinical, manufacturing, and regulatory activities:

POC Manufacturing Workflow Integration

This workflow visualization demonstrates the streamlined process for point-of-care manufacturing compared to traditional centralized models. The integration of clinical, manufacturing, and regulatory activities within the same facility or nearby locations significantly reduces vein-to-vein time and eliminates complex logistics associated with shipping patient materials [2]. The diagram highlights the continuous regulatory oversight and documentation requirements that remain essential despite the decentralized nature of manufacturing [3] [6].

The paradigm shift from centralized factories to point-of-care and modular manufacturing units represents a transformative development in the field of advanced therapy medicinal products. Regulatory bodies in both the UK and EU are establishing frameworks that enable this transition while maintaining appropriate oversight for patient safety [3] [4] [5]. The UK's world-first legislation specifically supporting point-of-care manufacturing demonstrates the growing recognition that alternative production models are necessary to address the limitations of centralized approaches [4].

The future landscape of ATMP manufacturing is likely to evolve toward hybrid models that strategically combine centralized and decentralized approaches based on specific therapy and patient needs [2] [7] [1]. Centralized manufacturing will continue to play a crucial role for standardized products with predictable demand, while point-of-care approaches will be particularly valuable for therapies treating aggressive diseases where turnaround time is critical, or for geographically dispersed patient populations [1]. Market analysis supports this trend, projecting that "hybrid delivery models are projected to grow fastest" among cell and gene therapy infrastructure components [7].

Successful implementation of decentralized manufacturing will require ongoing collaboration between technology developers, manufacturers, and regulators to establish harmonized standards and interoperable systems [1]. As noted in regulatory analyses, "Seamless connectivity requires technical expertise and changes in business practices, which will increase overhead. Regulatory harmonization across regions is crucial for implementing common manufacturing practices" [1]. The continued development of automated, closed-system technologies and standardized quality control approaches will be essential to ensuring that point-of-care manufacturing can deliver consistent, high-quality therapies to patients regardless of location.

This paradigm shift ultimately holds the promise of expanding access to transformative cell and gene therapies, ensuring that these innovative treatments can reach patients safely, swiftly, and equitably. By embracing flexible manufacturing approaches supported by evolving regulatory frameworks, the field can overcome current limitations and realize the full potential of personalized regenerative medicines.

Advanced Therapy Medicinal Products (ATMPs), which include cell and gene therapies, represent a groundbreaking category of treatments with the potential to address previously untreatable conditions [10]. Within the European regulatory framework, ATMPs are classified as gene therapy medicinal products, somatic cell therapy medicinal products, or tissue-engineered products [11]. A significant characteristic of many ATMPs, particularly autologous therapies like CAR-T cells, is their personalized nature; they are derived from a patient's own cells, manipulated ex vivo, and then returned to the same patient [12]. This personalized paradigm, combined with the inherently short shelf-lives of living cellular products, creates unique supply chain and manufacturing hurdles that conventional pharmaceutical models cannot adequately address [13] [14]. Point-of-care (POC) manufacturing, where products are finalized at or near the patient's treatment location, emerges as a critical strategy to overcome these challenges, enhancing patient access while navigating complex regulatory requirements [15] [16].

Core Challenges in ATMP Development and Commercialization

The development and commercialization of ATMPs are fraught with technical and logistical obstacles that directly impact their viability and patient accessibility. The table below summarizes the primary challenges associated with short shelf-lives, personalization, and supply chain complexities.

Table 1: Core Challenges in ATMP Commercialization

Challenge Category	Specific Challenges	Impact on Therapy Delivery
Short Shelf-Life	Inability to conduct conventional sterility testing due to time constraints; complex cryopreservation and storage requirements; limited time for quality control (QC) and release [13] [15].	Requires final product release before full sterility results are available, demanding exceptional aseptic process control [15].
Personalization (Autologous)	Bespoke manufacturing for individual patients; variability in starting material from sick patients; complex logistics coordinating apheresis, manufacturing, and reinfusion [14] [11].	Precludes traditional scale-up and batch production; leads to high costs and operational complexity; requires "just-in-time" manufacturing [14].
Supply Chain & Manufacturing	Need for closed, aseptic systems (cannot be sterile-filtered); stringent control of raw materials; scaling complexities and high cost of goods [13] [11] [12].	Only ~20% of eligible patients are currently reached due to infrastructural and cost barriers; requires highly integrated and synchronized supply chains [14].

The Scalability and Access Gap

A central tension in the ATMP field lies in balancing scientific innovation with the infrastructure required for delivery. While therapy approvals are increasing, the industry currently reaches only approximately 20% of the eligible patient population across the U.S. and Europe [14]. This access gap is shaped by interrelated factors, including the cost of goods, reimbursement hurdles, cold chain logistics, treatment scheduling, and the physical proximity of patients to qualified clinical sites. Scalability must be designed into therapy development from the beginning, not added as an afterthought, as early-stage developers grappling with complexity at low volumes risk stalled launches and missed patients when moving to commercialization [14].

Regulatory Framework for Point-of-Care ATMPs in the EU and UK

The European Medicines Agency (EMA) and the UK's Medicines and Healthcare products Regulatory Agency (MHRA) provide pathways for the legal supply of ATMPs, recognizing the need for flexible manufacturing models.

Established EU Pathways

In the EU, ATMPs can only be supplied legally under one of three conditions:

• Centralized Authorization: The product is authorized via the EMA [17].
• Clinical Trial Authorization: The product is administered as part of a clinical trial authorized by a national authority [17].
• Hospital Exemption: A national authority grants a special exemption for the product to be used under certain conditions within a specific hospital [17].

The EudraLex Volume 4, Part IV provides specific GMP guidelines for ATMPs, acknowledging their unique manufacturing requirements [12].

Innovative UK Framework for POC Manufacturing

In a significant regulatory advancement, the MHRA introduced a new framework in 2025 for "decentralized manufacturing," which includes Modular Manufacturing (MM) and Point of Care (POC) manufacturing [16]. This framework, effective July 2025, creates two new license types:

• Manufacturer's License (MM)
• Manufacturer's License (POC)

Under this model, a central "control site" holds the manufacturing license and creates a Master File (MF) containing full instructions for the final manufacturing or assembly steps at satellite MM or POC units [16]. Crucially, product release occurs at the central control site, not at the patient's bedside, which streamlines the process and enhances regulatory oversight [16]. This framework is designed to simplify operations, reduce costs, and improve patient access to personalized ATMPs while maintaining stringent quality controls.

Experimental Protocols for ATMP Manufacturing and Control

This section outlines detailed protocols for key processes in ATMP development and manufacturing, with a focus on addressing shelf-life and personalization challenges.

Protocol: Point-of-Care CAR-T Cell Manufacturing

The following protocol details the manufacturing of CAR-T cells in a decentralized, GMP-compliant setting, suitable for a POC facility [15].

Objective: To manufacture autologous CAR-T cells from patient leukapheresis material over an 8-12 day process within a closed system. Starting Material: Non-mobilized leukapheresis product with minimum targets of 20 x 10^8 Total Nucleated Cells (TNCs) and 10 x 10^8 CD3+ T cells [15].

Table 2: Key Reagents and Materials for CAR-T Manufacturing

Research Reagent/Material	Function/Purpose
Leukapheresis Product	Source of patient's CD3+ T cells, the starting material for the therapy.
Viral Vector (e.g., Lentivirus)	Gene delivery vehicle used to transduce T cells with the Chimeric Antigen Receptor (CAR) gene [15].
Cell Culture Media & Cytokines (e.g., IL-2)	Supports T cell activation, expansion, and viability during the ex vivo culture process [15].
Activation Beads (e.g., anti-CD3/CD28)	Stimulates T cell activation and proliferation, a critical step before genetic modification [15].
Closed System Bioreactor	Provides a controlled, aseptic environment for cell culture, minimizing contamination risk (e.g., Miltenyi CliniMACS Prodigy) [15].

Methodology:

• T Cell Activation: Isolated T cells from leukapheresis material are stimulated using activation beads (e.g., anti-CD3/CD28) in a GMP-grade culture medium [15].
• Genetic Transduction: Activated T cells are transduced with the lentiviral vector encoding the CAR construct. This step is typically performed within 2-3 days of activation [15].
• Cell Expansion: Transduced cells are cultured in a closed-system bioreactor for approximately 7-10 days to expand the population of CAR-T cells to a therapeutically relevant dose [15].
• Formulation and Cryopreservation: The final product is formulated into a saline-based solution containing cryoprotectants (e.g., DMSO) and cryopreserved in vapor-phase liquid nitrogen for storage and transport [15].

Quality Control and Release: A Certificate of Analysis (CoA) is generated prior to release. Critical quality attributes are summarized in the table below.

Table 3: Critical Quality Attributes for CAR-T Cell Release

Quality Attribute	Target/Specification	Test Method
Viability	Typically >70-80%	Flow cytometry (e.g., 7-AAD exclusion)
Identity (CAR Expression)	Specification set per product (e.g., >20% CAR+ T cells)	Flow cytometry
Potency	Demonstrated cytotoxic activity against target cells	In vitro co-culture assay
Purity (CD3+ Population)	Specification set per product	Flow cytometry
Sterility	No microbial growth	BacT/ALERT or equivalent
Endotoxin	Below threshold (e.g., <5 EU/kg)	LAL assay
Vector Copy Number	Within predefined safety limits	qPCR

Protocol: Risk-Based Contamination Control Strategy

Given the short shelf-life of ATMPs often precludes end-product sterility testing, a robust, process-based contamination control strategy is essential [13] [12].

Objective: To design and implement a contamination control strategy for aseptic ATMP manufacturing, aligning with PIC/S and EMA guidelines [12]. Methodology:

• Process Simulation (Media Fill): Perform a minimum of three consecutive successful media fills that mimic the entire aseptic manufacturing process, using a microbial growth medium like Tryptic Soy Broth [13].
• Environmental Monitoring: Establish a comprehensive program monitoring viable and non-viable particulates in the critical processing environment (Grade A biosafety cabinet with Grade B background) [13] [12].
• Raw Material Control: Implement a risk-based approach for testing raw and ancillary materials (e.g., cytokines, media) per USP <1043> and Ph.Eur. 5.2.12, focusing on viral safety and freedom from adventitious agents [11].
• Supplier Qualification: Enact quality agreements with suppliers of critical materials (e.g., plasmids, vectors) to ensure GMP-grade quality and traceability [11].
• Closed System Processing: Utilize closed or functionally closed systems (e.g., closed tubing sets, bioreactors) wherever possible to minimize human intervention and open processing steps [15] [12].

Diagram 1: POC CAR-T manuf. workflow with critical control points.

Strategic Solutions and Future Perspectives

Overcoming the core challenges in ATMP delivery requires a multi-faceted approach that integrates regulatory innovation, technological advancement, and strategic supply chain planning.

Embracing Regulatory Innovation

The MHRA's new framework for MM and POC manufacturing provides a viable model for the EU to consider [16]. By allowing product release at a central control site rather than the bedside, it alleviates a major logistical bottleneck for autologous therapies. Companies should proactively engage with regulators through early scientific advice protocols to align on development plans, ensuring compliance with evolving standards for decentralized manufacturing [10].

Leveraging Technology and Partnership

• Automation and Closed Systems: Investing in semi-automated, closed-system platforms (e.g., CliniMACS Prodigy) enhances process robustness, reduces contamination risk, and improves inter-facility standardization, which is crucial for multi-site POC networks [15].
• Strategic Supply Chain Partners: Developers need end-to-end integrated partners who provide more than logistics—offering regulatory guidance, GMP biostorage, Qualified Person (QP) release services, and continuous condition monitoring [14]. The supply chain thus becomes a strategic driver of success.

Implementing a Lifecycle Evidence Strategy

For market access, manufacturers should adopt a long-term, proactive evidence generation plan that extends beyond initial regulatory approval [10]. This includes:

• Post-approval studies and patient registries to collect long-term efficacy and safety data.
• Real-world evidence (RWE) generation to demonstrate therapeutic value in broader patient populations.
• Health economic studies to substantiate cost-effectiveness, which is critical for reimbursement in a landscape of high-cost therapies.

The successful widespread adoption of ATMPs hinges on directly addressing the intertwined challenges of short shelf-lives, personalization, and complex supply chains. Point-of-care manufacturing, supported by progressive regulatory frameworks like the MHRA's decentralized manufacturing model, offers a promising pathway forward. By implementing robust, risk-based manufacturing protocols, leveraging automation, and fostering deep collaboration across the development and supply chain ecosystem, the industry can transform these formidable challenges into opportunities. The ultimate goal is clear: to build resilient, patient-centered systems that can reliably deliver on the groundbreaking promise of advanced therapies to the patients who need them.

The paradigm for manufacturing advanced therapeutic medicinal products (ATMPs), such as cell and gene therapies, is shifting from centralized factories to decentralized models. This transition is driven by the need to manage products with very short shelf-lives, high levels of personalization, and complex logistics that are inherent to novel therapies like CAR-T cells [18] [16]. The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has established a pioneering regulatory framework for these decentralized manufacturing (DM) approaches, which came into force on 23 July 2025 [18]. This framework formally recognizes and regulates three interconnected models: Point-of-Care (POC), Modular Manufacture (MM)—which includes mobile micro-factories—and establishes the concept of a "Control Site" to oversee a network of manufacturing "spokes" [18] [16] [19]. For researchers and drug development professionals, particularly those operating within or in collaboration with the UK, understanding these models is critical for designing compliant and efficient manufacturing strategies for advanced therapies. These models are not mandatory but represent an alternative to centralized production where justified by clinical need, such as improving timeliness of access or overcoming geographical barriers to innovative medicines [19].

Table 1: Core Definitions of Decentralised Manufacturing Models

Model	Formal Definition	Primary Justification	Typical Applications
Point-of-Care (POC)	A medicinal product that, for reasons relating to method of manufacture, shelf life, constituents, or method/route of administration, can only be manufactured at or near the place of use or administration [18].	Product can only be made at/near the patient [18] [20].	Therapies with shelf-lives of "seconds or minutes"; highly personalised ATMPs; some 3D-printed products; blood products [18].
Modular Manufacture (MM)	A medicinal product that, for reasons related to deployment, the licensing authority determines it is necessary or expedient to be manufactured in a relocatable unit (modular unit) [18].	Public health requirement and/or significant clinical advantage relating to deployment [18] [20].	Prefabricated manufacturing units moved every few months/years; deployment to various clinical or factory sites [18].
Mobile Micro-Factories	A subset of MM, defined as "mobile manufacture": mobile micro-factories deployable at clinical centres or military fields when required [18].	Operational expediency and clinical need for rapid, temporary deployment [18].	On-demand manufacturing in remote, temporary, or emergency settings [18].

Regulatory Framework and Application Workflow

The UK's regulatory framework for DM is built upon amendments to The Human Medicines Regulations 2012 (HMR 2012) via The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025 (SI 2025 No. 87) [18]. A cornerstone of this framework is the "hub and spoke" structure, where a central Control Site holds the manufacturing license and oversees the quality and operations of the decentralized manufacturing sites (the POC or MM sites) [16] [19]. The Control Site is responsible for generating and managing a Decentralised Manufacturing Master File (DMMF), which is a detailed description of the arrangements for the manufacture or assembly of the product at the remote sites [18] [20]. This file, analogous to a Drug Master File, is submitted to the MHRA and must be rigorously followed by all satellite sites [16].

A critical first step for any sponsor is the Designation Step, a formal process where the MHRA evaluates whether a product is suitable for POC or MM designation [20] [19]. The justification must be anchored in clinical benefit, such as improved clinical outcomes, equity of access, or timeliness of treatment within a narrow clinical window. The MHRA emphasizes that convenience and cost reduction alone are not sufficient justifications [19]. The designation application should be submitted early in development and can be part of a Clinical Trial Authorisation (CTA), Marketing Authorisation Application (MAA), or a variation to an existing authorization [20]. Upon a positive designation, the sponsor must then apply for or vary a manufacturing license to become the Control Site, specifying the product and the type of DM activity (POC or MM) [18] [19]. This process triggers a Good Manufacturing Practice (GMP) inspection to ensure robust procedures are in place for overseeing the decentralized network [19].

Diagram 1: Regulatory pathway for POC/MM product approval.

Model-Specific Operational Protocols

Point-of-Care (POC) Manufacturing Protocol

The POC model is designed for products whose fundamental characteristics necessitate manufacture immediately before administration [18]. The protocol execution happens at the POC site (e.g., a hospital pharmacy or clinical lab), but the overall responsibility lies with the distant Control Site.

Experimental/Methodological Protocol: POC Product Final Assembly and Release

• Objective: To aseptically complete the final manufacturing steps of a POC-designated ATMP (e.g., a CAR-T cell therapy) at a hospital site, ensuring the product meets all pre-defined Critical Quality Attributes (CQAs) and is safely administered to the intended patient.

• Pre-requisites:

  • The POC site must be listed in the approved DMMF and have a technical agreement with the Control Site [19].
  • Personnel must be trained and certified by the Control Site on the specific procedures outlined in the DMMF [20].
  • All starting materials (e.g., patient cells, viral vector, media) must be received and verified against the patient-specific identifier.
  • The manufacturing environment must be verified (e.g., room classification, viable particle monitoring) as per the DMMF and GMP requirements [20].

• Materials and Equipment:

  • Patient-specific apheresis material.
  • GMP-grade transduction reagents (e.g., viral vector, activation agents).
  • Cell culture media and supplements.
  • Bioreactor or cell culture vessel (e.g., static culture bag, automated closed-system bioreactor).
  • Labelling kit supplied by the Control Site (if product is not for immediate administration) [20].

• Procedure:

  • Identity Verification: Confirm the identity of the patient's starting material against the patient identifier and manufacturing order. This is a critical step to prevent mix-ups [20].
  • Initiation of Manufacture: Initiate the final process steps (e.g., cell activation, transduction, expansion) as defined in the DMMF. All process parameters (e.g., temperature, gas exchange, culture duration) must be recorded in a batch-specific record.
  • In-Process Controls (IPCs): Perform IPCs (e.g., cell count, viability, metabolite analysis) according to the DMMF. Data must be recorded and any deviations reported immediately to the Control Site.
  • Harvest and Formulation: Upon completion of culture, harvest and formulate the final product into the administration vessel.
  • Real-Time Release Testing (RTRT): The Control Site's Qualified Person (QP) releases the batch based on RTRT data and verification that all steps were performed correctly. This relies on process validation and surrogate measures (e.g., critical process parameters) as a proxy for traditional end-product testing [20].
  • Administration: The product is administered to the patient immediately. For POC products administered within minutes of manufacture, labelling is exempt; otherwise, pre-labelled containers should be used [20].

Modular and Mobile Manufacturing Protocol

The MM model involves manufacturing within a relocatable, self-contained unit that can be deployed for months or years, whereas mobile micro-factories are a highly mobile subset for shorter, more urgent deployments [18]. The protocol focuses on the qualification, movement, and operation of these units.

Experimental/Methodological Protocol: Deployment and Operation of a Mobile Micro-Factory

• Objective: To deploy a mobile micro-factory to a clinical centre, qualify its operational status, and commence GMP-compliant manufacturing.

• Pre-requisites:

  • The mobile unit and its deployment location are specified in the approved MM Master File [18].
  • The Control Site has validated the transportation, set-up, and qualification process for the unit.
  • All necessary utilities (e.g., power, water, data) at the deployment site are confirmed to be compatible.

• Materials and Equipment:

  • Mobile manufacturing unit (modular unit).
  • Calibrated manufacturing and testing equipment.
  • Quality-critical raw materials.
  • Environmental monitoring equipment.
  • Data capture and communication systems for remote oversight by the Control Site.

• Procedure:

  • Pre-Departure Checks: At the previous location, document the state of the unit, decontaminate equipment, and secure all materials for transport.
  • Transportation and Siting: Transport the unit to the new clinical site and connect it to the required services. The transportation must not compromise the unit's integrity.
  • Qualification and Calibration:
    • Perform installation qualification (IQ) to verify correct installation.
    • Perform operational qualification (OQ) to ensure the unit functions as intended in the new environment.
    • Re-calibrate critical equipment as per the validated schedule.
    • Verify the classified manufacturing environment meets specified cleanroom standards [19].
  • Process Performance Qualification (PPQ): If required per the validation strategy, execute a PPQ run (e.g., a media fill or a simulated run) to demonstrate the integrated system works in the new location.
  • Commencement of GMP Manufacturing: Once fully qualified, the unit can begin manufacturing patient-specific or batch products under the supervision of the Control Site. All batch records and data are reviewed by the Control Site, and the QP at the Control Site releases the product [16].

Table 2: Key Comparisons Between POC and MM Operational Protocols

Aspect	Point-of-Care (POC) Protocol	Modular/Mobile (MM) Protocol
Product Shelf-life	Very short (seconds/minutes/hours) [18] [19].	Can be longer, similar to centralized products.
Primary Justification	Product can only be made at/near patient [18].	Necessary/expedient for deployment and clinical access [18].
Site Location Permanence	Fixed location at/near clinical facility.	Relocatable; sequential deployment to different sites [18].
Product Release	Real-Time Release Testing (RTRT) by Control Site QP is common [20].	QP release from the distant Control Site, based on data review [16].
Labelling	Exempt if administered immediately (e.g., within 2 minutes) [20].	Standard labelling requirements apply.

The Scientist's Toolkit: Essential Research Reagent Solutions

Successfully implementing a DM strategy requires careful selection of reagents and systems that ensure consistency and quality across multiple sites. The following toolkit outlines critical components for developing and controlling POC and MM processes.

Table 3: Essential Research Reagent Solutions for Decentralised Manufacturing

Tool/Reagent	Function/Explanation	Consideration for DM
Closed, Automated Bioreactor Systems	Automated platforms for cell expansion, transduction, and differentiation with minimal open steps.	Reduces operator-dependent variability; enables standardized execution across non-expert sites; critical for ensuring comparability [19].
GMP-Grade, Defined Cell Culture Media	Serum-free, xeno-free media formulations that support consistent cell growth and product quality.	Eliminates batch-to-batch variability of serum; essential for achieving a robust and transferable process across a decentralized network.
Critical Process Parameter (CPP) Probes	In-line or at-line sensors for parameters like pH, dissolved oxygen, glucose, and cell density.	Provides real-time data for RTRT; serves as a surrogate for product quality, enabling release from the Control Site without traditional end-testing [20] [21].
Standardized Analytical Methods	Kit-based or platform assays for potency, identity, purity, and safety (e.g., flow cytometry, qPCR).	Methods must be validated for transfer and use at multiple locations or centralized at a contract lab to ensure data comparability for the Control Site [20].
Unique Patient & Product Identifiers	A robust tracking system (e.g., barcodes, RFID) for patient apheresis, intermediates, and final product.	Paramount for traceability and preventing mix-ups in a hub-and-spoke model; directly supports pharmacovigilance activities [20].

Quality Management and Pharmacovigilance

A robust Quality Management System (QMS) orchestrated by the Control Site is the backbone of successful DM. The Control Site must treat all POC and MM sites as outsourced activities, governed by technical agreements that clearly define responsibilities [20] [19]. The QMS must cover the entire lifecycle, from onboarding and training of remote site personnel to ongoing oversight, which includes audits, data monitoring, and management of changes to the DMMF [20]. The MHRA will inspect the Control Site's systems for overseeing the network and may inspect a selection of the remote sites to verify control [19].

Pharmacovigilance (PV) for DM products follows standard principles but is heightened by the potential for process interpretation differences across many sites [20]. A robust Pharmacovigilance System Master File (PSMF) is required. The license holder (at the Control Site) is responsible for collecting, processing, and reporting safety data [16] [20]. Product traceability is critical, as the PV system must be able to link any adverse event not only to a product batch but potentially to the specific site and personnel involved in its final manufacture [20]. This enables effective signal management and the issuance of Periodic Safety Update Reports (PSURs) that account for the distributed nature of the manufacturing process.

Diagram 2: Quality and safety oversight in the hub-and-spoke model.

Advanced Therapy Medicinal Products (ATMPs), encompassing gene therapies, somatic cell therapies, and tissue-engineered products, represent a groundbreaking shift in medical treatment [5]. Unlike traditional pharmaceuticals, many ATMPs, particularly autologous cell therapies, are personalized medicines manufactured for individual patients. This fundamental characteristic creates unprecedented regulatory challenges as production shifts from centralized facilities to distributed points of care [13] [16].

The conventional regulatory framework for medicinal products was designed for mass-produced, off-the-shelf pharmaceuticals with stable shelf lives and standardized manufacturing processes [22]. This framework struggles to accommodate the dynamic, small-scale, and geographically dispersed nature of point-of-care ATMP manufacturing [23]. The core regulatory imperative is clear: existing frameworks require substantial adaptation to ensure patient safety without stifling innovation in distributed ATMP production [13].

This application note examines the specific limitations of current regulatory approaches, analyzes emerging frameworks addressing these gaps, and provides detailed protocols for implementing compliant distributed manufacturing systems within the European context.

Current Regulatory Gaps and Distributed Manufacturing Challenges

Limitations of Traditional Frameworks

Traditional Good Manufacturing Practice (GMP) regulations assume centralized production with linear, scalable processes [22]. This creates significant mismatches with distributed ATMP manufacturing:

• Batch Definition Challenges: Conventional batch definition and release procedures are poorly suited to patient-specific therapies where each unit constitutes a separate "batch" [16].
• Site Licensing Complexity: Under current EU law, each production site must hold a separate manufacturing authorization, creating prohibitive complexity for decentralized networks [23].
• Infrastructure Requirements: Traditional GMP demands specialized facilities and equipment that are impractical and cost-prohibitive for point-of-care settings like hospital labs or mobile units [13] [23].

Specific Hurdles in ATMP Production

The transition from non-clinical (Good Laboratory Practice - GLP) to clinical (Good Manufacturing Practice - GMP) environments presents particular challenges for ATMPs [13]:

Challenge Domain	Specific Hurdle	Impact on Distributed Manufacturing
Manufacturing Consistency	High variability in biological starting materials; complex, multi-step processes [13]	Difficult to ensure identical processes and product quality across multiple decentralized sites
Supply Chain & Logistics	Extremely short shelf life (hours to days); maintenance of cold chain; sterility assurance during transport [23]	Limits geographical distribution options; increases risk of product failure
Quality Control & Release	Limited sample sizes for testing; need for rapid release methods; complex analytical methods [13] [23]	Traditional QC approaches are too slow; requires development of rapid, non-destructive testing methods
Personnel & Training	Shortage of qualified personnel with specialized expertise in aseptic processing and cell culture [22] [23]	Difficult to maintain consistent expertise across multiple decentralized locations
Facility Design	Need for aseptic processing environments; environmental monitoring; contamination control [13]	Challenging to implement in clinical settings not designed for pharmaceutical manufacturing

Emerging Regulatory Solutions for Distributed Manufacturing

The UK's Innovative Approach: Modular and Point-of-Care Frameworks

In July 2025, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) implemented a world-first regulatory framework specifically designed for modular manufacture and point-of-care production of ATMPs [3] [4]. This innovative approach introduces two new licensing categories:

• Manufacturer's License (MM): For modular manufacturing units that may be relocatable [16]
• Manufacturer's License (POC): For manufacturing at or near the place of product administration [16]

The framework employs a Master File (MF) system where a central "control site" holds the manufacturing license and creates detailed protocols that satellite sites must follow [16]. This allows for standardized processes across distributed locations while maintaining centralized oversight and quality responsibility.

UK Point-of-Care Regulatory Model

EU Regulatory Evolution and Ongoing Challenges

The European regulatory system is also evolving to address distributed manufacturing challenges:

• Proposed Directive Reforms: The 2023 Proposal for a Directive reforming the Union code relating to medicinal products contains provisions allowing decentralized production sites to operate under the responsibility of a qualified person at a central site, without requiring separate manufacturing authorizations [23].
• EMA Support Initiatives: The European Medicines Agency offers scientific advice, protocol assistance, and specific support for ATMP developers, including an ATMP pilot for academia and non-profit organizations [5].
• GMP Adaptation: The European Commission has issued detailed guidelines on GMP specific to ATMPs, acknowledging their unique characteristics and manufacturing challenges [23].

However, significant hurdles remain in the EU system, particularly regarding the requirement for each manufacturing site to hold its own authorization, creating barriers to establishing truly distributed manufacturing networks [23].

Essential Protocols for Compliant Distributed Manufacturing

Protocol 1: Quality Management System Implementation for Multi-Site Operations

Objective: Establish a unified Quality Management System (QMS) across all manufacturing sites that ensures consistent product quality while complying with EU GMP requirements [24] [23].

Materials and Equipment:

• Document management system (electronic preferred)
• Change control management software
• Deviation and CAPA tracking system
• Training competency records database
• Environmental monitoring equipment
• Quality risk management tools

Procedure:

• Central QMS Establishment
  • Develop master quality documents at the control site
  • Define standardized procedures for all critical processes
  • Establish quality metrics and reporting requirements

• Site Qualification

  • Conduct initial audits of all proposed satellite sites
  • Verify facility design, equipment qualification, and environmental controls
  • Assess personnel competencies and training records

• Process Validation

  • Perform process validation runs at each satellite site
  • Demonstrate process consistency across all locations
  • Establish site-specific validation acceptance criteria

• Ongoing Monitoring

  • Implement continuous environmental monitoring
  • Conduct regular internal audits across all sites
  • Perform comparative testing between sites quarterly

Acceptance Criteria: All satellite sites must demonstrate equivalent performance in critical quality attribute testing, environmental monitoring, and process consistency.

Protocol 2: Rapid Sterility Testing and Product Release for Short Shelf-Life ATMPs

Objective: Implement a rapid microbiological testing strategy that enables product release within the constrained timeframe of short shelf-life ATMPs while maintaining sterility assurance.

Materials and Equipment:

• Rapid microbial detection system (e.g., growth-based or viability-based technologies)
• Sterility test kits validated for cell therapy products
• Environmental monitoring equipment
• Process analytical technology (PAT) tools
• Automated culture systems

Procedure:

• Pre-Manufacturing Controls
  • Perform extended sterility testing on raw materials
  • Conduct media fills to validate aseptic processes
  • Implement real-time particle monitoring

• In-Process Testing

  • Collect samples at critical process steps
  • Initiate rapid microbiological testing parallel to final manufacturing steps
  • Monitor critical process parameters in real-time

• Final Product Assessment

  • Perform abbreviated final product testing focused on critical quality attributes
  • Utilize rapid sterility methods with reduced incubation times
  • Implement parametric release where justified and validated

• Data Review and Release

  • Quality Person reviews all manufacturing and testing data
  • Assess trend data from previous batches manufactured at the site
  • Authorize release based on comprehensive data package

Acceptance Criteria: Sterility testing results must demonstrate no microbial growth, and all critical process parameters must remain within validated ranges.

The Scientist's Toolkit: Essential Research Reagent Solutions

Successful implementation of distributed ATMP manufacturing requires carefully selected reagents and materials that meet regulatory standards while maintaining functionality across multiple sites.

Reagent/Material	Function	GMP Requirements	Considerations for Distributed Manufacturing
CRISPR Components (gRNA, Cas nuclease) [22]	Genome editing for gene therapies	True GMP-grade, not "GMP-like"; comprehensive documentation	Standardized across all sites; single-source supplier preferred
Cell Culture Media [13]	Support cell growth and maintenance	GMP-grade, endotoxin tested, performance qualified	Identity testing at each site; consistent formulation critical
Critical Raw Materials (e.g., cytokines, growth factors) [13]	Direct cell differentiation and function	GMP-grade, vendor qualification, traceability	Supplier qualification essential; reserve sourcing strategy needed
Process Analytical Technology [13]	Real-time monitoring of critical quality attributes	Qualified/validated systems; data integrity	Standardized across sites; centralized data management
Primary Cell Starting Materials [23]	Patient-specific therapeutic agents	Donor screening, procurement controls, traceability	Standardized collection protocols across clinical sites

Implementation Roadmap and Future Perspectives

The transition to distributed ATMP manufacturing requires careful planning and execution. The following workflow outlines the key stages for implementing a compliant point-of-care manufacturing network:

Distributed Manufacturing Implementation Workflow

The regulatory landscape for distributed ATMP manufacturing continues to evolve rapidly. Emerging trends include:

• AI and Digital Solutions: Artificial intelligence systems are being incorporated into pharmaceutical manufacturing guidelines, with the EU revising GMP Annex 11 and introducing a new Annex 22 specifically addressing AI in manufacturing [3].
• Harmonization Efforts: Regulatory bodies are increasingly collaborating through initiatives like the International Coalition of Medicines Regulatory Authorities (ICMRA) to align approaches to decentralized manufacturing [16].
• Advanced Monitoring Technologies: Implementation of real-time release testing and process analytical technology enables the level of control necessary for distributed manufacturing [13].

The successful implementation of distributed ATMP manufacturing requires embracing these new regulatory frameworks while maintaining focus on the fundamental goal: ensuring patient access to safe and effective advanced therapies through robust, compliant manufacturing systems.

Operationalizing POC Production: A Deep Dive into the UK's Regulatory Blueprint

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has established a pioneering regulatory framework for decentralised manufacturing (DM) of medicinal products, enacted through The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025 (Statutory Instrument 2025 No. 87) which came into force on 23 July 2025 [18] [25] [26]. This framework creates two distinct categories: Point of Care (POC) and Modular Manufacture (MM), governed by specific license types and controlled through a central Decentralised Manufacturing Master File (DMMF) [18] [19]. This regulatory innovation addresses critical challenges in delivering advanced therapies, particularly those with very short shelf lives or requiring high personalization, by enabling manufacture at or near the patient location [18]. For researchers and drug development professionals operating within the broader European context, understanding this UK-specific framework is essential for navigating the evolving transatlantic regulatory landscape for point-of-care cell therapies.

Regulatory Framework and Key Definitions

The MHRA's framework introduces legally distinct pathways for decentralized production, moving beyond the traditional single-site factory model to a distributed "scale-out" approach [18] [19].

Core Definitions and Legislative Basis

The Human Medicines Regulations 2012 (HMR 2012) have been amended to incorporate the following key definitions [18]:

• POC (Point of Care): Manufacture and supply at or near the place where the product is to be used or administered, justified by factors such as extremely short shelf-life (seconds or minutes), constituent nature, or method of administration [18].
• POC Medicinal Product: A medicinal product that, for reasons relating to method of manufacture, shelf life, constituents or method or route of administration, can only be manufactured at or near its point of use [18].
• MM (Modular Manufacture): Relocatable manufacturing units (modular units) deployed for reasons related to product deployment, as determined necessary or expedient by the licensing authority [18].
• MM Medicinal Product: A product deemed necessary to be manufactured in a relocatable unit for deployment reasons, with the MHRA taking a broader approach not limited to starting materials or short shelf life [25].
• Decentralised Manufacturing Master File (DMMF): A detailed description of the arrangements for the manufacture or assembly of a POC or MM medicinal product, required for all DM products [18].

Table: Key Terminology in the MHRA's Decentralised Manufacturing Framework

Term	Definition	Key Justification
Point of Care (POC)	Manufacture at/near patient administration site [18]	Product can only be made at point of use due to shelf-life/characteristics [18]
Modular Manufacture (MM)	Manufacture in relocatable units [18]	Necessitated by reasons relating to deployment (e.g., pandemic response) [25]
POC/MM Control Site	Premises for supervising/controlling DM activities [18]	Central oversight location specified on the manufacturer's licence [18]
POC/MM Site	Individual location where manufacture/assembly occurs [18]	Secondary sites authorized via the Master File [25]
Master File (DMMF)	Detailed description of manufacturing arrangements [18]	Single reference document for all decentralized sites and processes [19]

Legislative Context and Readiness Pillars

The framework's implementation is built on three fundamental pillars of readiness [19] [26]:

• Regulatory Pillar: The MHRA's responsibility encompassing the new legislation and guidance documents, which will evolve with accumulated experience.
• Institutional Pillar: The preparedness of healthcare providers (e.g., NHS), and other relevant bodies (e.g., Human Tissue Authority, NICE) to adopt these disruptive changes.
• Technical Pillar: The responsibility of innovators to ensure their manufacturing processes and testing procedures are suitable for novel, decentralized environments.

License Types and Application Process

The MHRA has established specific license categories for decentralized manufacturing, requiring a formal designation process to justify the need for POC or MM approaches.

License Categories and Requirements

A POC or MM medicinal product must be manufactured under a specific manufacturer's licence [18]:

• Manufacturer’s Licence (POC): A manufacturer’s licence that relates to the manufacture or assembly of the POC medicinal products specified in that licence [18].
• Manufacturer’s Licence (MM): A manufacturer’s licence that relates to the manufacture or assembly of the MM medicinal products specified in that licence [18].

These can be either a Manufacturer’s Licence (MIA) for a licensed POC/MM medicinal product or a Manufacturer’s Specials Licence if the product is a special medicinal product [18]. Existing licence holders can apply to vary their licence to include POC or MM activities [18].

Table: Comparison of POC and MM Licence Requirements

Aspect	Point of Care (POC) Licence	Modular Manufacture (MM) Licence
Primary Justification	Product can only be made at point of use [18]	Reasons relating to deployment [18]
Typical Products	ATMPs, 3D-printed products, ultra-short shelf-life products [18]	Vaccines for pandemic response, military field deployments [25]
Shelf-Life Consideration	Very short (seconds/minutes/hours); no portion retained post-administration [19]	Not a limiting factor; broader justification based on deployment need [25]
Labelling Exemption	Yes, for immediate administration with no retained product [25]	Standard labelling requirements apply [25]
Site Mobility	Fixed but distributed POC sites (e.g., hospitals, homes) [18]	Relocatable modular units moved between clinical/factory sites [18]

Designation Process and Clinical Benefit Justification

Centralized manufacture remains the default, and POC/MM is not mandatory [19]. Applicants must pass a designation process requiring justification anchored in clinical benefit [19]. The MHRA provides the following guidance [25] [19]:

• Application Timing: Applicants are encouraged to apply early once data indicate their product meets DM criteria.
• Designation Decision Timeline:
  • 60 days if no additional information or meeting is required.
  • 90 days if a meeting or further information is needed.
• Justification Requirements: The application must provide background and justification for meeting legal criteria. Justification must be based on clinical benefit, incorporating:
  • Improved clinical outcomes
  • Equity and timeliness of access
  • Elimination of geographical barriers
  • Data or published literature supporting claims
• Exclusions: Justifications based solely on cost are not suitable and should be directed to NICE [19].

Diagram: MHRA POC/MM Designation and Licensing Application Process

The Decentralised Manufacturing Master File (DMMF)

The Decentralised Manufacturing Master File serves as the central document governing all decentralized production activities, providing the necessary flexibility while maintaining regulatory oversight [18] [25].

Role and Function of the DMMF

The DMMF is a mandatory requirement for manufacturing any POC or MM medicinal product [18]. It functions as a single reference document that captures [25]:

• All authorized manufacturing locations and their status
• Contact details for all sites
• Approved products, processes, and procedures
• The approved designation reference

Critically, the DMMF provides operational flexibility. Manufacturers are not required to submit a variation to notify the MHRA of new or decommissioned sites; however, they must notify the MHRA of any material alteration to the control site or modular units [25]. This allows for scalability without constant regulatory submissions.

DMMF Maintenance and Oversight

Licence holders have specific obligations for maintaining the DMMF [25]:

• Annual Reporting: License holders must maintain the DMMF and keep it up to date with annual reporting of updates and changes to the MHRA.
• Quality System Integration: The DMMF must be integrated into the manufacturer's quality system, with clear procedures for updates and version control.
• Inspection Readiness: The DMMF is subject to review during MHRA inspections, and manufacturers must demonstrate effective oversight of all processes described within it.

GMP, Quality Control, and Pharmacovigilance

While the manufacturing model is innovative, the fundamental requirements for quality, safety, and efficacy remain unchanged [19].

Good Manufacturing Practice (GMP) Considerations

The Control Site for any DM product must hold an appropriate manufacturing licence and a DMMF [19] [26]. Any addition of DM processes will trigger an MHRA inspection [19]. Key GMP considerations include [25] [19]:

• Qualified Person (QP) Release: The QP can nominate an individual independent of the manufacturing and clinical team to release a POC product, but the license holder must demonstrate consistency in the release process and how the QP maintains oversight.
• Technical Agreements: Developers need engagement with healthcare providers covered by technical agreements aligning with GMP Chapter 7 principles.
• Environmental Control: Manufacturers must demonstrate that non-standard locations can maintain appropriate environmental conditions for product quality.

Pharmacovigilance and Traceability

Robust pharmacovigilance systems are essential for DM products [25]:

• Adverse Event Monitoring: Manufacturers must have processes to collect, allocate, and evaluate adverse events across multiple sites, with clear oversight of contracts and agreements.
• Batch Traceability: Throughout the product's lifecycle, manufacturers must demonstrate integration of healthcare settings to maintain complete product and batch traceability.
• PSMF Inclusion: Decentralized medicines, including control and manufacturing site lists, must be included in the Pharmacovigilance System Master File (PSMF).
• QPPV Oversight: The Qualified Person for Pharmacovigilance must maintain oversight of all processes and sites, linking to other departments such as the Responsible Person or quality department.

Experimental Protocol: Implementing a POC Framework

For researchers establishing point-of-care manufacturing capabilities, the following protocol outlines key implementation steps.

Protocol: MHRA POC Designation and Licensing

Objective: To successfully obtain MHRA designation as a Point of Care manufacturer and secure the appropriate manufacturing licence for a novel autologous cell therapy product.

Materials and Reagents Table: Essential Research Reagents and Materials for POC Implementation

Item	Function/Application
DM Designation Application Template	MHRA-provided format for justification submission [25]
DMMF Template	Framework for documenting all manufacturing arrangements [18]
GMP-Grade Automated Cell Processor	Closed-system instrument for reducing cleanroom space needs [27]
Quality Management System (QMS)	System for ensuring consistent quality and safety oversight [25]

Methodology:

• Pre-Application Phase (Weeks 1-4)

  • Feasibility Assessment: Confirm product meets POC criteria (short shelf-life, requires proximity to patient).
  • Clinical Benefit Dossier: Compile data supporting improved outcomes, access equity, or timeliness.
  • Stakeholder Engagement: Consult with healthcare providers (e.g., NHS Specialist Pharmacy Service) regarding site suitability.

• Designation Application (Weeks 5-8)

  • Submit Designation Request: File application with MHRA including full justification and supporting data.
  • MHRA Interaction: Respond to any requests for additional information within the 90-day maximum timeline.

• Licence Application/Variation (Weeks 9-16)

  • DMMF Preparation: Develop comprehensive master file documenting all manufacturing locations, processes, and procedures.
  • Submit Licence Application: Apply for new Manufacturer's Licence (POC) or vary existing licence to include POC dosage form.
  • Inspection Preparation: Prepare for MHRA GMP inspection of control site and review of DMMF.

• Post-Authorization (Ongoing)

  • Annual Reporting: Submit annual updates on DMMF changes to MHRA.
  • Site Management: Add new POC sites via DMMF updates without variation submission.
  • Pharmacovigilance Maintenance: Ensure adverse event monitoring and traceability across all sites.

Troubleshooting:

• Insufficient Clinical Benefit Justification: Strengthen with real-world data on treatment delays or access barriers in centralized models.
• DMMF Deficiencies: Implement robust quality systems for multi-site control before inspection.
• QP Release Challenges: Establish clear procedures for remote or delegated QP release activities.

The MHRA's framework for decentralized manufacturing represents a significant advancement in regulatory science, creating a flexible but controlled pathway for delivering innovative therapies directly to patients. The distinction between POC and MM licenses acknowledges different clinical and logistical needs, while the DMMF provides the necessary structure for oversight at scale. For researchers and developers, success in this new paradigm requires not only technical excellence but also rigorous justification of clinical benefit and robust quality systems capable of managing distributed manufacturing networks. As these frameworks evolve in the UK, EU, and United States, professionals must stay informed of converging and diverging requirements to ensure global compliance and patient access to groundbreaking cell and gene therapies.

Decentralized manufacturing has emerged as a transformative approach for autologous cell therapies, mitigating challenges related to logistics, timeliness, and scalability inherent in centralized models [28]. This paradigm involves manufacturing therapeutic products at multiple locations, including regional facilities or certified treatment centers close to the patient's bedside [28]. The successful implementation of this network hinges on a robust regulatory and quality framework, the cornerstone of which is the Control Site [28] [16].

The Control Site acts as the central regulatory nexus, ensuring consistency, quality, and compliance across all decentralized manufacturing points, often referred to as Point-of-Care (POCare) or Modular Manufacturing (MM) sites [28] [16]. Its establishment is critical for maintaining the principles of Current Good Manufacturing Practice (cGMP) in a geographically dispersed manufacturing network. This model is designed to ensure that advanced therapy medicinal products (ATMPs) manufactured at or near the patient bedside possess the same assurances of quality, safety, and efficacy as those produced in conventional, centralized facilities [28]. Regulatory bodies like the UK's Medicines and Healthcare products Regulatory Agency (MHRA) have formally incorporated the Control Site model into their legislative framework, creating new manufacturer's licenses specifically for Modular Manufacture and Point of Care, effective from July 2025 [3] [16].

Regulatory Framework and the Control Site

The regulatory landscape for decentralized manufacturing is rapidly evolving, with the MHRA leading the implementation of a tailored framework. The core principle is the division of responsibilities between a central Control Site and the individual POCare manufacturing locations.

Table 1: Regulatory Framework for Control and POCare Sites

Component	Description	Regulatory Reference (MHRA)
Manufacturer's License (POC/MM)	Held by the Control Site, granting permission to supervise decentralized manufacturing.	Manufacturer’s License (Point of Care) and Manufacturer’s License (Modular Manufacture) [16]
Master File (MF)	A comprehensive document created and maintained by the Control Site, containing full instructions for manufacture/assembly at the POCare site.	Submitted with the license application; must be followed by the POCare site [16]
Supervision & Control	The legal responsibility of the Control Site to oversee all satellite POCare manufacturing locations.	Mandated by the manufacturer's license [16]
Regulatory Interaction	The Control Site serves as the single point of contact for competent authorities.	Primary focus point for interaction with regulatory agencies [28]

Core Regulatory Documents and Submissions

The regulatory submission for a decentralized manufacturing network is built around two key documents managed by the Control Site:

• The Manufacturer's License Application: This application, for either a "Manufacturer’s License (MM)" or "Manufacturer’s License (POC)," is submitted by the entity intending to act as the Control Site. It must describe the satellite sites to be used and the overall quality management system [16].
• The Master File (MF): This product-specific file, referenced in the license, is the foundational document that guarantees standardization. It provides the detailed, step-by-step protocols that each POCare site must follow, ensuring process consistency and product comparability across the network [16]. The Control Site is responsible for creating and updating this file.

Detailed Supervisory Responsibilities of the Control Site

The Control Site's oversight extends across the entire product lifecycle, from technology transfer and training to batch release and pharmacovigilance.

Table 2: Supervisory Responsibilities of the Control Site

Responsibility Area	Specific Functions of the Control Site
Quality Assurance & QMS	Establishment and maintenance of a comprehensive Quality Management System (QMS) applicable to the entire network [28].
Regulatory Liaison	Acting as the primary focus point for all interactions with regulatory agencies (e.g., MHRA, EMA, FDA) [28].
Personnel & Training	Provision of an overarching training platform to guarantee standardized skill sets and quality standards across all POCare sites [28].
Documentation Control	Maintaining the POCare Master File for the individual POCare GMP manufacturing sites and ensuring it is current [28] [16].
Process Standardization	Leveraging automated, closed-system technologies and standardized GMP manufacturing platforms to minimize process variability [28].
Quality Control & Batch Release	Housing the Qualified Person (QP) who is ultimately responsible for certifying and releasing each batch of the product before it is administered [28] [16].
Pharmacovigilance	Collecting, processing, and reporting post-administration safety and efficacy data for all products from the network [16].
Audit & Compliance	Conducting regular audits of the POCare sites to ensure adherence to the Master File and GMP principles.

Protocol for Control Site Oversight and POCare Site Auditing

Objective: To verify that all POCare manufacturing sites within the network consistently adhere to the approved processes, quality specifications, and GMP standards defined in the Master File and the Control Site's QMS.

Methodology:

• Audit Planning (Frequency: Annually or based on risk assessment):

  • Define the audit scope, objectives, and criteria based on the Master File and QMS requirements.
  • Select a qualified audit team with expertise in cell therapy manufacturing and GMP.
  • Develop a detailed audit plan and checklist covering:
    • Facility and equipment maintenance.
    • Staff training and competency records.
    • Documentation and record-keeping practices.
    • Adherence to aseptic processing and environmental monitoring.
    • Raw material and starting material control.
    • In-process control and testing.
    • Final product handling and storage.
    • Deviation, corrective and preventive action (CAPA) management.

• On-Site Audit Execution:

  • Conduct an opening meeting with the POCare site management.
  • Perform a physical inspection of the manufacturing facility, including isolator-based systems or cleanrooms [29].
  • Review batch manufacturing records, quality control data, and personnel training files.
  • Interview key personnel to assess their understanding of the Master File procedures.

• Reporting and CAPA:

  • Document all observations and classify them by criticality (Critical, Major, Minor).
  • Hold a closing meeting to present the findings.
  • Issue a formal audit report to the POCare site management and the Quality leadership at the Control Site.
  • The POCare site is required to provide a CAPA plan with defined timelines for addressing the findings.
  • The Control Site is responsible for reviewing and approving the CAPA plan and verifying its effectiveness upon closure.

• Management Review:

  • Audit outcomes and trends are reviewed periodically by the Control Site's senior management to assess the overall health and compliance of the decentralized network.

The following diagram illustrates the logical relationship and workflow between the Control Site and a POCare manufacturing site.

Experimental Protocols for Ensuring Product Comparability

A foundational responsibility of the Control Site is to demonstrate that a comparable product is manufactured at each POCare location [28]. This requires a structured, data-driven approach.

Protocol for Process Performance Qualification (PPQ) Across Multiple POCare Sites

Objective: To generate objective evidence that the manufacturing process, when executed at different POCare sites using the same Master File, consistently produces a product meeting its pre-determined quality attributes.

Methodology:

• Experimental Design:

  • Sites: Select a minimum of three POCare sites that are representative of the planned network.
  • Runs: Execute a minimum of three consecutive successful manufacturing runs per site, using the same lot of critical raw materials (e.g., cell culture media, activation reagents) where possible.
  • Sample Plan: Define the number and timing of in-process and final product samples for testing.

• Critical Process Parameters (CPPs) and Key Analytical Assays:

  • Monitor and record CPPs (e.g., temperature, gas concentrations, bioreactor agitation) in real-time.
  • Subject final products to a comprehensive panel of quality control tests, as detailed in the table below.

• Data Analysis:

  • Use statistical process control (SPC) charts to monitor CPPs and demonstrate they remain within validated ranges across all sites and runs.
  • Perform statistical analysis (e.g., ANOVA) on CQAs to confirm there are no significant differences in the final product attributes between the different POCare manufacturing sites.

Table 3: Key Analytical Methods for Product Comparability Assessment

Research Reagent / Assay Solution	Function in Comparability Testing
Flow Cytometry Panels	Quantifies cell identity, purity (e.g., % CAR-positive T cells), and the presence of impurities (e.g., residual non-target cells).
Cell Counting & Viability Assays (e.g., Trypan Blue)	Determines total nucleated cell count, viable cell count, and viability percentage.
Potency Assays (e.g., Cytokine Release, Cytotoxicity)	Measures the biological activity of the product, a critical quality attribute for efficacy.
Sterility Test Kits (BacT/ALERT)	Detects the presence of aerobic and anaerobic microorganisms.
Endotoxin Detection Assays (LAL)	Quantifies bacterial endotoxins to ensure product safety.
Molecular Assays (qPCR/ddPCR)	Detects and quantifies specific genetic elements (e.g., vector copy number for genetically modified therapies).
Glucose/Lactate Metabolite Assays	Serves as an indicator of metabolic activity during the manufacturing process.

Protocol for Real-Time Quality Control (RT-QC) and Batch Release

Objective: To implement a rapid, near-real-time quality control strategy that supports the short vein-to-vein time of POCare manufacturing while ensuring patient safety.

Methodology:

• In-process Controls (IPCs):

  • The Control Site defines critical IPCs in the Master File (e.g., cell viability and concentration at specific days, glucose consumption rates).
  • POCare sites perform these IPC tests using standardized, often automated, equipment.
  • Data is digitally recorded and transmitted to the Control Site for real-time monitoring.

• Final Product Testing:

  • Tests with short turnaround times (e.g., viability, cell count, identity by flow cytometry) are performed at the POCare site.
  • Tests with longer turnaround times (e.g., sterility) are initiated, but the product can be released based on negative Gram stain results or other rapid sterility indicators, with the full sterility test serving as a confirmatory test post-release [29].

• Batch Review and Release:

  • All manufacturing and QC data from the POCare site is electronically transmitted to the Qualified Person (QP) at the Control Site.
  • The QP performs a comprehensive review of the data against the product specification file.
  • Upon confirming compliance, the QP certifies the batch for release, and the authorization is communicated to the POCare site.

The following workflow diagram details the batch release process under the Control Site model.

The Centralized Control Site model, with its clearly defined and extensive supervisory responsibilities, provides the essential structural and regulatory framework to make decentralized cell therapy manufacturing a viable and safe reality. By acting as the central hub for quality, regulatory interaction, and oversight, the Control Site ensures that the critical principles of GMP are not diluted across a distributed network. The implementation of detailed protocols for audit, comparability assessment, and batch release, supported by standardized technologies and rigorous documentation, is paramount. As regulatory frameworks like the MHRA's new legislation mature, the Control Site model is poised to become the global standard, enabling broader, faster, and more cost-effective access to life-saving personalized cell therapies without compromising on quality or patient safety.

Point-of-Care (POC) cell therapy manufacturing represents a paradigm shift in advanced therapy medicinal product (ATMP) production, moving critical manufacturing steps closer to patients. This approach is particularly transformative for autologous therapies like CAR-T cells, which are personalized for each patient using their own cells [16]. The regulatory landscape is evolving rapidly to accommodate this innovation, with the UK's Medicines and Healthcare products Regulatory Agency (MHRA) establishing the first comprehensive framework in 2025, while the European Medicines Agency (EMA) maintains specific Good Manufacturing Practice (GMP) requirements for ATMPs [3] [30] [31].

The core advantage of POC manufacturing lies in addressing critical challenges of traditional centralized models. For therapies with very short shelf-lives or those manufactured using patient-specific cells, POC production can dramatically reduce the time between cell collection and treatment administration [32]. This can potentially reduce costs and expand patient access to transformative therapies [33]. The regulatory framework for these novel approaches requires specialized submission dossiers that demonstrate both therapeutic efficacy and a robust, decentralized quality system.

Key Regulatory Pathways and Designation

UK MHRA Pathway

The MHRA's innovative framework, effective July 2025, introduces two distinct manufacturing categories: Point of Care (POC) and Modular Manufacture (MM) [3] [16]. POC products are those that, due to method of manufacture, shelf life, constituents, or route of administration, can only be manufactured at or near where the product is used. MM products are those where deployment makes it necessary or expedient to manufacture in modular units [20]. The regulatory journey begins with a crucial designation step, where sponsors petition the MHRA to evaluate whether their product qualifies for these pathways [20].

The designation application must include comprehensive justification based on product characteristics, including quality and clinical data where appropriate. According to MHRA guidance, convenience and cost alone are not sufficient criteria; the designation must be driven by technical and clinical necessities [20]. The MHRA aims to provide a preliminary decision within 30 days, with full approval potentially within 60 days, provided all required information is submitted [20]. This designation is a prerequisite for subsequent Marketing Authorisation Application (MAA) or Clinical Trial Authorisation (CTA) submissions, and failure to obtain it can result in rejection of the main application [20].

EU EMA Pathway

While the EU has not yet established a dedicated pathway equivalent to the MHRA's POC framework, ATMPs including those manufactured at point-of-care fall under the centralised authorization procedure and must comply with specific GMP guidelines for ATMPs outlined in EudraLex Volume 4, Part IV [5] [30]. The EMA's Committee for Advanced Therapies (CAT) plays a central role in evaluating these advanced products, preparing draft opinions on quality, safety, and efficacy that inform the Committee for Medicinal Products for Human Use (CHMP) recommendations [5].

The EU system requires manufacturers to hold a manufacturing authorization from the national competent authority of the Member State where manufacturing occurs [31]. For POC manufacturing, this would present challenges under the traditional framework, as each production site would typically require listing on the authorization and individual GMP inspections [32]. The EMA is currently undertaking revisions to its ATMP-specific GMP guidelines, with a concept paper outlining proposed changes released for public consultation until July 2025 [34].

Table 1: Comparison of Regulatory Pathways for POC Therapies

Aspect	UK MHRA Pathway	EU EMA Pathway
Framework Status	Implemented July 2025	Traditional ATMP framework with ongoing updates
Key Concept	Control site with POC/MM master file	Manufacturing authorization for each site
Oversight Focus	Control site and quality system	Individual manufacturing sites
GMP Application	Through control site to satellite locations	Direct application at each manufacturing site
Submission Requirements	Designation application + DMMF + MAA/CTA	Standard MAA with site-specific information

Core Components of the Submission Dossier

Quality and Manufacturing Documentation

The quality and manufacturing section forms the cornerstone of any POC therapy submission dossier. For the UK MHRA pathway, this centers on the Decentralized Manufacturing Master File (DMMF), which describes how to complete manufacturing at decentralized sites under the oversight of a control site [20]. The control site must be located in the UK and hold a manufacturing license, maintaining a pharmaceutical quality system that treats remote sites like contracted manufacturing organizations (CMOs) with appropriate oversight, audits, and quality agreements [20] [16].

Critical elements to document include a comprehensive control strategy for decentralized operations, procedures for onboarding, suspending, and pausing remote sites, equipment calibration and maintenance programs, training systems for personnel at all sites, and product release procedures [20]. For POC products administered immediately after manufacture, labeling requirements are waived; however, pre-labeling containers is encouraged [20]. The dossier must demonstrate process validation and comparability between products manufactured across different remote sites, which is particularly challenging for autologous products [20].

In the EU context, manufacturers must comply with GMP specific to ATMPs as outlined in EudraLex Volume 4, Part IV, with particular attention to the unique characteristics of these products, including the use of substances of human origin such as blood, tissues, and cells [31]. The pharmaceutical quality system must ensure that medicinal products are consistently produced and controlled in accordance with quality standards appropriate to their intended use [31].

Clinical Development and Trial Documentation

For Clinical Trial Authorisations (CTAs) involving POC manufacturing, the submission must address unique considerations related to decentralized production. The MHRA requires that CTA applications reference the POC/MM designation and indicate that it hasn't changed [20]. A control site must be designated, typically where components are manufactured, and a Manufacturing Importation Authorisation Application (MIA) must be submitted with supporting data [20].

A critical challenge in clinical trials involving POC manufacturing is maintaining trial integrity, particularly blinding. The submission must detail mechanisms for preserving blinding despite potential differences in manufacturing time, appearance, or administration procedures between active and placebo products [20]. The dossier should document specialized procedures to address factors that could potentially unblind the study, such as variations in manufacturing processes between treatment arms, differences in time required for manufacture or preparation, and variations in product characteristics or administration procedures [20].

For both clinical and marketing applications, the submission must include comprehensive pharmacovigilance systems with enhanced traceability to monitor safety and efficacy across multiple manufacturing sites. The MHRA emphasizes that with numerous potential manufacturing sites interpreting instructions differently, the pharmacovigilance program must be "acutely sensitive" to subtle differences and able to track them effectively [20].

Pharmacovigilance and Risk Management

The pharmacovigilance system for POC therapies requires particular attention in the submission dossier due to the decentralized nature of manufacturing. The MHRA mandates that general principles of pharmacovigilance apply to decentralized manufacturing, but with enhanced measures to address the complexity of multiple manufacturing sites [20]. A robust risk management plan is paramount, with additional risk minimization measures where warranted [20].

The submission must include a Pharmacovigilance System Master File and designate a Qualified Person for pharmacovigilance to oversee the program [20]. The system must enable precise product traceability not only for safety monitoring but to ensure the correct medicine reaches the correct patient—a critical consideration for autologous therapies [20]. Traditional pharmacovigilance activities including signal management and periodic safety update reports should be managed commensurately with the risks associated with these novel products [20].

For therapies made available through early access schemes such as the UK's Early Access to Medicines Scheme (EAMS), the submission must demonstrate appropriate risk consideration to ensure adequate patient monitoring [20]. The same vigilance standards apply to "specials" (one-off medicines) manufactured under the POC framework [20].

Experimental Protocols for POC Therapy Development

Process Validation and Comparability Protocols

Objective: To validate the POC manufacturing process and demonstrate comparability between products manufactured at different sites under the control site's oversight.

Methodology:

• Process Validation: Conduct at least three consecutive successful batches at multiple representative POC sites to demonstrate process robustness [20]. Include worst-case scenario testing for critical process parameters.
• Comparability Study: Implement a standardized testing protocol across all manufacturing sites. For autologous cell therapies, this includes:
  • Cell Viability and Potency: Standardized assays measuring specific biological activity
  • Identity Testing: Flow cytometry for cell surface markers or genetic identity testing
  • Purity and Impurity Profiles: Testing for process-related impurities and contaminants
• Real-Time Release Testing (RTRT) Validation: For therapies employing RTRT, validate all analytical methods per ICH guidelines and demonstrate reliability across all sites [20].

Data Analysis: Establish acceptance criteria for all critical quality attributes (CQAs) prior to study initiation. Use statistical methods to demonstrate that inter-site variability does not exceed pre-defined limits and does not impact product safety or efficacy.

Environmental Monitoring and Aseptic Processing Validation

Objective: To demonstrate maintenance of aseptic conditions across all POC manufacturing sites, including those in hospital settings.

Methodology:

• Site Qualification: Perform comprehensive environmental monitoring at each proposed POC manufacturing location, including:
  • Viable Airborne Particle Monitoring: Using volumetric air samplers
  • Surface Monitoring: Contact plates and swabs for critical surfaces
  • Personnel Monitoring: Finger dabs and gowning assessments
• Media Fill Simulation: Perform process simulation using microbial growth media instead of product materials to validate aseptic processing under actual conditions [32]. Include all personnel who would normally participate in manufacturing.
• Ongoing Monitoring Program: Establish a continuous environmental monitoring program with alert and action limits based on initial qualification data.

Acceptance Criteria: All sites must meet predetermined microbial quality standards consistent with EU GMP Annex 1 requirements for aseptic processing [34]. Media fill simulations must yield zero contamination for validation.

Essential Research Reagent Solutions

The development and quality control of POC therapies requires specialized reagents and materials to ensure consistent manufacturing across multiple sites. The following table details critical reagents and their functions in POC therapy development and manufacturing.

Table 2: Essential Research Reagent Solutions for POC Therapy Development

Reagent/Material	Function	Quality Requirements
Cell Separation Media	Isolation of specific cell populations from patient samples	GMP-grade, endotoxin tested, consistent performance across lots
Activation/Transduction Enhancers	Improve genetic modification efficiency of patient cells	Defined composition, pre-qualified for use with specific vector systems
Cell Culture Media	Support cell growth and expansion during manufacturing	Serum-free or xeno-free formulation, GMP-grade, composition fully defined
Viral Vectors	Delivery of genetic material to patient cells	Produced under GMP, thoroughly characterized, high titer, replication-incompetent
Critical Process Reagents	Cytokines, growth factors, antibodies used in manufacturing	Recombinant origin, GMP-grade, full characterization and viral safety data
Final Formulation Solutions	Preparation of final product for administration	Sterile, pyrogen-free, compatible with cellular product

Regulatory Strategy and Documentation Workflow

The following diagram illustrates the key stages and documentation requirements in the regulatory approval pathway for POC therapies:

The regulatory landscape for point-of-care cell therapies is rapidly evolving, with the UK MHRA establishing a pioneering framework that could influence global regulatory approaches. The successful submission dossier for a POC therapy must demonstrate not only safety and efficacy but also a robust, decentralized quality system capable of maintaining product consistency across multiple manufacturing sites. As regulatory agencies worldwide continue to adapt to these innovative manufacturing paradigms, developers should engage early and often with regulators through scientific advice procedures and designated pathway consultations. The potential for POC manufacturing to expand patient access to transformative therapies makes navigating this complex regulatory environment a worthwhile endeavor for developers of advanced cell and gene therapies.

The advent of point-of-care (POC) and modular manufacturing for Advanced Therapy Medicinal Products (ATMPs) represents a paradigm shift in cell and gene therapy production. This new model, exemplified by the UK's world-first regulatory framework that came into effect in July 2025, enables manufacturing steps to be completed at hospitals, clinics, or near patients' homes [3] [4]. While this decentralization dramatically improves patient access to personalized treatments, it simultaneously creates significant challenges for maintaining consistent quality control across multiple, geographically distributed sites. A Unified Quality Umbrella architecture addresses these challenges by establishing centralized oversight and standardized processes across all manufacturing locations, ensuring compliance with stringent regulatory requirements while enabling operational flexibility.

This architecture adapts the umbrella system architectural pattern—well-established in telecommunications for managing complex, multi-vendor ecosystems—to the specific needs of ATMP manufacturing [35]. In this model, a central "umbrella" system provides orchestration and control over modular subsystems, ensuring coherence across the network while allowing specialized functions at each node. For POC cell therapy manufacturing, this translates to a quality system that maintains centralized control and standardization while permitting necessary local adaptation of manufacturing processes.

Regulatory Framework for Distributed Manufacturing

The regulatory landscape for decentralized ATMP manufacturing is evolving rapidly, with recent developments creating both requirements and opportunities for unified quality systems.

Table: Key Regulatory Developments for Distributed ATMP Manufacturing

Regulatory Body	Development	Key Provisions	Effective Date
UK MHRA	The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025	Establishes "Manufacturer's License (MM)" and "Manufacturer's License (POC)" with central "Control Site" responsibility [16].	July 23, 2025 [3] [4]
UK MHRA	Modular Manufacture and Point of Care Regulations	Allows medicines manufacturing closer to patients using regulated protocols; supports mobile manufacturing units [4].	July 23, 2025
European Medicines Agency (EMA)	Advanced Therapy Medicinal Products Framework (Regulation 1394/2007)	Centralized evaluation for ATMPs; Hospital Exemption clause for non-routine hospital production [36].	Ongoing
FDA Center for Biologics Evaluation and Research (CBER)	Public listening meeting on leveraging knowledge for CGT development	Seeking input on using prior knowledge to facilitate product development and review [3].	September 18, 2025

The UK's pioneering framework introduces two distinct but related models for decentralized manufacturing:

• Modular Manufacturing (MM): Manufacturing activities performed away from the primary licensed facility, potentially at a clinic or hospital laboratory, to address short shelf life or personalized nature of treatments [16].

• Point of Care (POC) Manufacturing: Manufacturing performed at or near the place of administration to the patient, immediately before use [16].

Under both models, the Control Site holds the manufacturing license and maintains ultimate responsibility for quality assurance through a Master File (MF) that specifies processes for satellite sites to follow. This regulatory structure explicitly mandates the type of unified quality architecture described in this document [16].

Architectural Framework for Quality Integration

Core Components of the Quality Umbrella

The Unified Quality Umbrella employs a centralized orchestration model with modular execution nodes, creating a system that ensures consistency while accommodating necessary local adaptations.

The architecture follows an event-driven design pattern where quality events (deviations, environmental excursions, out-of-specification results) are detected locally and communicated to the central quality system for orchestrated response [37]. This approach enables real-time quality monitoring and rapid intervention while maintaining comprehensive data collection for trend analysis and continuous improvement.

Data Integration and Communication Framework

Effective integration of distributed sites requires robust data architecture that provides a "single source of truth" for all quality-related information [37]. A Unified Namespace (UNS) architecture serves as this foundation, creating a centralized repository for real-time data from all sites while maintaining contextual relationships.

This data architecture enables real-time quality monitoring across all distributed sites while supporting regulatory requirements for data integrity, traceability, and confidentiality. The UNS serves as the communication backbone, using standardized protocols like MQTT to facilitate seamless data exchange between the central quality system and distributed manufacturing nodes [37].

Implementation Protocols

Protocol 1: Quality Management System Implementation for Distributed Manufacturing

Objective: Establish a comprehensive QMS that maintains centralized control while enabling compliant operations across distributed manufacturing sites.

Table: QMS Implementation Requirements and Specifications

Component	Requirement	Implementation Specification	Regulatory Reference
Quality Manual	Documented scope, procedures, and process interactions	Single quality manual covering all sites with site-specific appendices	ISO 9001:2015 [38]
Document Control	Uniform data recording methods and version control	Electronic QMS with unique identifiers and automated version control	EU GMP Chapter 4 [3]
Record Management	Traceability and retrievability of all records	Centralized electronic repository with controlled access and backup	EU GMP Annex 11 [3]
Management Review	Periodic assessment of system effectiveness	Quarterly reviews with standardized metrics from all sites	ICH Q10 [39]
Training System	Consistent training and competency assessment	Centralized training records with site-based practical assessment	EU GMP Annex 11 [3]

Methodology:

• Gap Analysis and Planning

  • Conduct current state assessment of all potential manufacturing sites using standardized audit protocol
  • Establish implementation timeline with defined milestones and deliverables
  • Allocate resources for central and site-specific implementation activities

• Documentation Development

  • Create document templates with consistent styles and formats [38]
  • Develop top-level quality manual defining scope and exclusions
  • Establish hierarchy for managing QMS documentation: Quality Manual → Policies → Procedures → Work Instructions → Records [38]
  • Implement electronic quality management system (eQMS) for document control

• System Deployment and Integration

  • Phase deployment starting with pilot site before full implementation
  • Conduct comprehensive training for personnel at all sites
  • Establish change control procedures for system modifications
  • Implement monitoring mechanisms for system performance

• Performance Monitoring and Continuous Improvement

  • Define and track key quality indicators across all sites
  • Conduct periodic internal audits and management reviews
  • Implement corrective and preventive action (CAPA) system
  • Establish process for regular system updates and improvements

Protocol 2: Site Qualification and Auditing Under the Unified Quality Umbrella

Objective: Ensure all distributed manufacturing sites maintain consistent quality standards through standardized qualification and auditing processes.

Methodology:

• Pre-Qualification Assessment

  • Conduct feasibility assessment evaluating site capabilities, resources, and compliance history [36]
  • Review scope of authorized activities and certifications
  • Assess ability to perform specific procedures and environmental controls
  • Verify availability of requested equipment and qualified personnel

• Qualification Audit Execution

  • Perform comprehensive on-site audit prior to collaboration commencement [36]
  • Examine site documentation and quality system robustness
  • Interview personnel across functional areas
  • Inspect facility infrastructure and key process locations
  • Evaluate quality management system implementation

• Audit Response and Corrective Action

  • Document findings using standardized classification system (minor, major, critical)
  • Develop corrective action plans with defined timelines and responsibilities
  • Verify effectiveness of implemented corrective actions
  • Formalize site qualification status based on audit outcomes

• Ongoing Surveillance

  • Conduct periodic surveillance audits every 2-3 years [36]
  • Perform for-cause audits in response to significant deviations or compliance issues
  • Monitor quality performance metrics between audits
  • Maintain qualification through continuous compliance demonstration

Protocol 3: Quality Control Testing and Product Release for Distributed Manufacturing

Objective: Implement standardized quality control testing and product release processes that ensure consistency across distributed manufacturing sites while complying with regulatory requirements for POC manufacturing.

Table: Quality Control Testing Requirements for Distributed ATMP Manufacturing

Test Category	Test Parameters	Frequency	Acceptance Criteria	Site Execution Capability
Identity	Cell surface markers, Genetic modification confirmation	Each batch	Consistent with product specifications	Centralized or distributed based on complexity
Potency	Cytotoxicity, cytokine secretion, transduction efficiency	Each batch	Meets validated acceptance criteria	Primarily centralized with point-of-care indicators
Viability	Cell count, viability, exclusion dyes	Each batch	≥ required minimum viability	Distributed with centralized verification
Purity	Endotoxin, mycoplasma, sterility	Each batch	Meets pharmacopeial requirements	Mixed (distributed sampling with centralized testing)
Safety	Replication competent virus, adventitious agents	Selected batches	Absence of contaminants	Centralized specialized testing

Methodology:

• Test Method Standardization

  • Develop and validate test methods at central control site
  • Transfer qualified methods to distributed sites following established protocols
  • Establish method equivalency and performance monitoring
  • Implement reference standards and controls across all sites

• Sample Management Protocol

  • Define sample collection, preservation, and transportation requirements
  • Establish chain of identity and custody procedures
  • Implement sample tracking and reconciliation systems
  • Define sample retention and disposal requirements

• Results Management and Reporting

  • Establish electronic data capture and reporting system
  • Define critical result notification and investigation procedures
  • Implement data trending and performance monitoring
  • Establish results review and approval hierarchy

• Product Release Process

  • Centralized batch release by qualified person at control site [16]
  • Review of all manufacturing and testing data from distributed sites
  • Verification of compliance with established specifications
  • Documentation of release decision and final product certification

The Scientist's Toolkit: Essential Research Reagent Solutions

Table: Key Reagents and Materials for Quality System Implementation

Reagent/Material	Function	Quality Requirements	Application in Unified Quality System
Reference Standards	Calibration and qualification of analytical methods	Certified reference materials with established traceability	Method validation and transfer across sites; system suitability testing
Cell Counting and Viability Assays	Assessment of cell quantity and quality	Validated methods with established precision and accuracy	In-process controls and final product testing at distributed sites
Vector Titer Assays	Quantification of gene delivery vectors	Standardized against reference materials with defined potency	Critical quality attribute monitoring across manufacturing network
Process Residual Testing Kits	Detection of process-related impurities	Validated sensitivity and specificity for target analytes	Lot release testing and process validation studies
Environmental Monitoring Materials	Assessment of manufacturing environment quality	Growth promotion testing and qualification for intended use	Aseptic process validation and continuous monitoring at all sites
Chain of Identity Systems	Patient sample tracking and identification	100% accuracy with redundant verification systems	Maintenance of product identity across distributed manufacturing process
Quality Control Cells	System suitability testing for potency assays	Well-characterized with established performance characteristics	Inter-site comparison and method performance verification
Data Integrity Solutions	Secure data capture, storage, and transmission	21 CFR Part 11/Annex 11 compliance with audit trail functionality	Real-time quality data aggregation across distributed network

Compliance and Validation Considerations

Implementing a Unified Quality Umbrella for distributed ATMP manufacturing requires careful attention to regulatory compliance and validation requirements across multiple jurisdictions.

The European ATMP framework under Regulation 1394/2007 establishes specific requirements for advanced therapies, including cell-based immunotherapies [36]. The recent updates to Good Manufacturing Practice guidelines, including Chapter 4, Annex 11, and the new Annex 22 on Artificial Intelligence, provide specific guidance for pharmaceutical manufacturing utilizing digital technologies and distributed models [3]. These regulations emphasize the importance of data integrity, process validation, and quality risk management in decentralized manufacturing environments.

Under the UK's new regulatory framework, the Control Site maintains ultimate responsibility for quality assurance, requiring robust technical agreements and quality contracts with all distributed manufacturing locations [16]. This includes:

• Validation Protocols: Comprehensive process validation across all manufacturing sites, including comparability studies demonstrating consistency between central and distributed operations.
• Data Integrity Measures: Implementation of ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate) across the distributed network, with particular attention to electronic data systems.
• Quality Risk Management: Application of ICH Q9 principles to identify, assess, and control risks associated with distributed manufacturing models [39].
• Change Control Systems: Standardized procedures for managing changes across all sites, ensuring consistent implementation and documentation of modifications.

The successful implementation of a Unified Quality Umbrella enables manufacturers to maintain the high standards of pharmaceutical quality required for ATMPs while leveraging the benefits of distributed manufacturing models to improve patient access to these transformative therapies.

Overcoming Implementation Hurdles: Quality Control, Tech Transfer, and Workforce Strategy

Ensuring Product Consistency and Quality Across Multiple Decentralized Sites

The paradigm of cell therapy manufacturing is shifting from centralized facilities toward decentralized, point-of-care (POC) production to improve patient access and address logistical challenges of autologous therapies [28]. This transition introduces significant challenges in maintaining consistent product quality and critical quality attributes (CQAs) across multiple manufacturing sites [28]. The European regulatory landscape is evolving to accommodate this new paradigm, with recent guidelines emphasizing the need for robust quality management systems (QMS) and comparability demonstrations between sites [3] [28].

The implementation of a Control Site model, which serves as the regulatory nexus maintaining POCare Master Files and ensuring consistency across manufacturing locations, provides a framework for standardized operations [28]. This application note outlines specific protocols and analytical strategies to ensure product consistency across decentralized manufacturing networks, with particular emphasis on meeting evolving EU regulatory expectations for point-of-care manufacturing.

Regulatory Framework and Quality Systems

EU Regulatory Context

The European regulatory framework for decentralized manufacturing is evolving rapidly, with several key developments:

• Revised GMP Guidelines: The European Commission is consulting on updates to EudraLex Volume 4, covering GMP guidelines for Chapter 4, Annex 11, and a new Annex 22 addressing artificial intelligence in pharmaceutical manufacturing [3]. The consultation period extends until October 7, 2025, with implementation expected shortly thereafter.

• Control Site Model: The European framework emphasizes a Control Site model where a central facility maintains regulatory responsibility through POCare Master Files that standardize processes across all manufacturing sites [28]. This central site holds primary responsibility for quality assurance, Qualified Person (QP) designation, and serves as the single point of contact for competent authorities [28].

• Harmonized Technical Standards: The European Pharmacopoeia is gradually implementing new primary labeling for reference standards to include additional information such as CAS numbers, chemical names, and safety pictograms, improving standardization across testing locations [3].

• EMA-HMA Network Strategy: The 2025 network strategy prioritizes availability and accessibility of medicines, explicitly acknowledging decentralized manufacturing as an approach for customized products designed for individual patients [28].

Quantitative Comparison of Regulatory Frameworks

Table 1: Comparative Analysis of Key Regulatory Parameters for Decentralized Manufacturing

Parameter	EU Framework	UK MHRA Framework	FDA Approach
Licensing Structure	Control Site with POCare Master Files [28]	Manufacturer's License (POC) with Master File [16]	Distributed Manufacturing Platform [28]
Product Release Location	Control Site [28]	Main Manufacturing Site [16]	Manufacturing Facility
Key Regulatory Document	POCare Master File [28]	Master File (MF) [16]	Risk Evaluation and Mitigation Strategies (REMS) [3]
Site Qualification	Demonstration of comparability across all sites [28]	Specification in Master File [16]	Comparability data required for each facility [28]
Timeline for Implementation	Consultation on key guidelines until Oct 2025 [3]	Effective July 2025 [3] [16]	Ongoing through emerging technology programs [28]

Critical Quality Attributes and Analytical Methods

Defining Critical Quality Attributes

Ensuring consistency across decentralized manufacturing sites requires precise definition and monitoring of CQAs. For autologous cell therapies, these attributes must account for both product-specific characteristics and process-related parameters.

Table 2: Essential Critical Quality Attributes for Cross-Site Consistency

Category	Critical Quality Attribute	Target Range	Acceptance Criteria
Identity	Cell surface marker expression	>90% positive for target markers	Consistent profile across sites (±5%)
Viability	Cell viability post-manufacturing	>80%	Consistent recovery rates (±5%)
Potency	Functional activity in validated assays	EC50 within predefined range	Parallel dose-response curves
Purity	Percentage of target cell population	>85%	Statistically equivalent across sites
Safety	Sterility (bacteria, fungi)	No growth	Equivalent testing methods
Genetic Stability	Karyotype normality	Normal diploid karyotype	Consistent genomic integrity

Cross-Site Analytical Method Harmonization

The foundation of reliable comparability data is analytical method harmonization across all manufacturing sites:

• Reference Standards: Implement common reference standards and controls across all sites, utilizing European Pharmacopoeia standards with new labeling requirements [3].
• Method Transfer Protocols: Establish rigorous method transfer protocols including parallel testing and statistical equivalence demonstrations.
• Centralized Data Management: Utilize centralized data systems with standardized analytical procedures to minimize inter-site variability.
• Proficiency Testing: Implement regular cross-site proficiency testing to ensure continued analytical consistency.

Experimental Protocols for Cross-Site Validation

Protocol: Cross-Site Comparability Study Design

Purpose: To demonstrate manufacturing consistency and product comparability across multiple decentralized manufacturing sites.

Materials:

• Common cell source (same donor/donor pool)
• Standardized reagents qualified for GMP use
• Identical equipment platforms across sites
• Harmonized analytical instruments and reagents

Procedure:

• Site Preparation: Ensure all sites have equivalent facility classification, environmental monitoring, and equipment qualification.
• Reagent Qualification: Use a common lot of critical reagents across all sites to minimize variability.
• Parallel Processing: Process identical starting material simultaneously at all sites following standardized procedures.
• In-Process Monitoring: Collect identical in-process samples at predetermined critical process steps.
• Comprehensive Testing: Perform full panel of quality control tests on final products from all sites.
• Statistical Analysis: Apply equivalence testing with predefined margins using appropriate statistical methods.

Acceptance Criteria:

• No statistically significant differences in CQAs between sites (p > 0.05)
• All CQAs within predefined equivalence margins (typically ±10-15%)
• Similar process parameter ranges across all sites (e.g., growth rates, metabolic profiles)

Protocol: Automated Cell Processing System

Purpose: To standardize cell isolation and processing across sites using closed, automated systems.

Materials:

• Gibco CTS DynaCellect Magnetic Separation System [40]
• Gibco CTS Dynabeads CD3/CD28 beads [40]
• Gibco CTS Detachable Dynabeads [40]
• Gibco CTS OpTmizer Serum-Free Medium [40]

Procedure:

• Cell Isolation: Program CTS DynaCellect system with standardized protocol for cell isolation (~100 minutes) [40].
• Cell Activation: Use consistent bead-to-cell ratio across all sites with CTS Dynabeads CD3/CD28.
• Bead Removal: Implement standardized detachment protocol using CTS Detachable Dynabeads (reduce bead removal from ~5 hours to <1 hour) [40].
• Cell Expansion: Culture cells in CTS OpTmizer SFM with standardized feeding schedule.
• Process Monitoring: Record key parameters including cell counts, viability, and metabolic rates.

Quality Control:

• Cell purity >95% [40]
• Cell viability >90% post-isolation
• Consistent bead removal efficiency (>98%)

Visualization of Decentralized Manufacturing Framework

Control Site Oversight Structure

Control Site Oversight: This diagram illustrates the regulatory architecture for decentralized manufacturing, with a central Control Site maintaining POCare Master Files and providing oversight to multiple manufacturing sites [28].

Cross-Site Validation Workflow

Cross-Site Validation: This workflow outlines the systematic approach for demonstrating product comparability across multiple manufacturing sites, emphasizing parallel processing and statistical equivalence testing.

Research Reagent Solutions

Table 3: Essential GMP-Compliant Reagents for Decentralized Manufacturing

Product Category	Specific Product	Function	Importance for Cross-Site Consistency
Cell Separation	Gibco CTS Dynabeads CD3/CD28 [40]	T cell isolation and activation	Standardized bead-to-cell ratio ensures consistent activation across sites
Cell Processing	Gibco CTS Detachable Dynabeads [40]	Rapid bead removal	Reduces processing time from 5 days to under 1 hour, minimizing variability [40]
Cell Culture Media	Gibco CTS OpTmizer Serum-Free Medium [40]	T cell expansion	Defined formulation eliminates serum variability, maintains cell phenotype
Automated System	Gibco CTS DynaCellect System [40]	Automated cell processing	Closed system reduces operator-dependent variability, improves reproducibility
Electroporation	Gibco CTS Xenon Electroporation System [41]	Non-viral transfection	Standardized protocols ensure consistent gene modification efficiency

Implementing robust strategies to ensure product consistency across decentralized manufacturing sites requires integrated approach addressing regulatory, technical, and operational challenges. The Control Site model with POCare Master Files provides regulatory structure, while standardized automated platforms, harmonized analytical methods, and rigorous comparability protocols enable technical implementation. As regulatory frameworks evolve, particularly in the EU with upcoming GMP guideline revisions, maintaining focus on critical quality attributes and statistical equivalence will be essential for successful decentralized manufacturing of cell therapies. The protocols and frameworks outlined provide a foundation for researchers and drug development professionals to establish compliant, consistent decentralized manufacturing networks.

Addressing Aseptic Processing and Environmental Control in Non-Traditional Settings

The development of point-of-care (POC) manufacturing for Advanced Therapy Medicinal Products (ATMPs) represents a paradigm shift in biopharmaceutical production, moving from centralized facilities to decentralized settings near patients [29]. This transition introduces unique challenges for maintaining aseptic processing and environmental control, particularly in hospital clinics and non-traditional manufacturing environments with higher microbial burdens [29]. The recent European Union regulatory landscape, including new frameworks from the Medicines and Healthcare products Regulatory Agency (MHRA), has evolved to address these challenges while ensuring patient safety [3] [16]. This application note provides detailed protocols and considerations for implementing robust aseptic processing and environmental control systems within POC cell therapy manufacturing facilities, aligned with current EU regulatory expectations.

Regulatory Context for POC Manufacturing

EU Regulatory Framework Evolution

The regulatory landscape for decentralized manufacturing of ATMPs has recently undergone significant modernization to address the unique challenges of POC production:

• New MHRA Framework: Effective July 2025, the UK MHRA implemented new regulations for modular manufacture and point-of-care production, creating pathways for medicines to be manufactured closer to patients [3] [16]. This framework introduces two new license types: "manufacturer's license (MM)" for modular manufacture and "manufacturer's license (POC)" for point-of-care production [16].

• Control Site Model: Under the new regulations, the license holder (control site) maintains responsibility for product quality and creates a Master File (MF) that satellite manufacturing sites must follow [16]. This enables product release at the centralized manufacturing site rather than at the bedside [16].

• GMP Adaptation: The European Commission is currently consulting on updates to EudraLex Volume 4, including revisions to GMP Annex 11 and the introduction of a new Annex 22 addressing Artificial Intelligence in pharmaceutical manufacturing [3]. The deadline for this consultation is October 7, 2025 [3].

Rationale for Regulatory Modernization

The drive toward regulatory innovation for POC manufacturing addresses several critical challenges in ATMP production:

• Logistical Constraints: Centralized manufacturing models for autologous cell therapies involve transporting patient cells over long distances, causing delays in treatment and potential compromise of cell viability [29] [33].

• Economic Pressures: Conventional CAR-T therapies can cost hundreds of thousands of pounds per dose, while POC manufacturing approaches have demonstrated potential for significant cost reduction [33].

• Patient Access: POC manufacturing can expand access to lifesaving treatments for rare diseases and conditions with limited treatment options [33].

Table 1: Comparison of Centralized vs. Point-of-Care Manufacturing Models

Aspect	Centralized Manufacturing	Point-of-Care Manufacturing
Production Location	Distant specialized facilities	Hospital, clinic, or near patient
Supply Chain Complexity	High (international logistics)	Low (local logistics)
Time to Treatment	Weeks to months	Potentially days
Regulatory Framework	Traditional GMP	Emerging decentralized frameworks
Cost Structure	High (often >£200,000 per dose)	Potentially significantly lower
Product Release	At manufacturing site	At control manufacturing site

Aseptic Processing Strategies for Non-Traditional Settings

Isolator-Based Systems

Closed-system isolator technologies represent the cornerstone of aseptic processing in non-traditional settings, providing physical separation between operators and the manufacturing environment [29]:

• System Classification: Positive pressure isolators protect sterile products from external contamination, while negative pressure isolators handle hazardous substances to protect operators [29]. POC manufacturing typically employs positive pressure configurations.

• Critical Components: Modern isolators incorporate integral glove ports, rapid transfer ports (RTPs) for material transfer, integrated decontamination systems (e.g., vaporized hydrogen peroxide), and independent HVAC filtration modules that enable ISO Class 5 environments within non-classified hospital rooms [29].

• Comparative Advantage: Unlike biological safety cabinets (BSCs) which require classified cleanrooms, isolators provide fully sealed workspaces with integrated decontamination and can operate effectively in non-classified backgrounds [29]. This fundamental difference makes isolators particularly advantageous for POC manufacturing where full GMP cleanroom infrastructure is often unavailable.

Comparative Barrier System Technologies

Table 2: Comparison of Aseptic Processing Technologies for POC Manufacturing

Technology	Separation Level	Background Environment Requirement	Integrated Decontamination	Suitability for POC
Open Benches	None	ISO Class 5 cleanroom required	No	Poor
Biological Safety Cabinets (BSCs)	Partial (open front)	ISO Class 7 cleanroom required	No	Limited
Restricted Access Barrier Systems (RABS)	Partial (solid walls)	ISO Class 7 cleanroom required	Sometimes	Moderate
Isolators	Complete (fully sealed)	No specific classification required	Yes (integrated cycles)	Excellent

Environmental Monitoring Protocols

Implementing robust environmental monitoring is essential for demonstrating aseptic process control in non-traditional settings. The following protocol outlines a comprehensive approach:

Viable Particle Monitoring Protocol

Objective: To routinely assess and document microbial contamination levels within the critical processing environment.

Materials:

• Active air samplers with appropriate volumetric collection capacity
• Settling plates (90-100mm) with soybean-casein digest agar
• Surface contact plates (RODAC plates) with appropriate culture media
• Glove/finger tip testing kits
• Incubator capable of maintaining 20-25°C and 30-35°C

Methodology:

• Active Air Sampling: Place samplers at predetermined locations within the isolator, operating for the duration of critical processing. Sample volume should be sufficient to detect contamination at levels consistent with ISO Class 5 environments [42].
• Sedimentation Monitoring: Position settling plates in areas representing worst-case scenarios for particulate settlement, including during maximum activity periods. Expose plates for approximately 4 hours [42].
• Surface Monitoring: Use contact plates to monitor critical surfaces (work surfaces, equipment, container surfaces) at the conclusion of processing activities.
• Personnel Monitoring: Implement regular glove and gown monitoring for operators following aseptic manipulations.

Incubation and Analysis:

• Incubate plates at 30-35°C for 3-5 days, followed by 20-25°C for additional 2-3 days
• Identify and enumerate all microbial growth
• Investigate any excursions beyond alert/action levels
• Maintain trend analysis data for continuous monitoring program improvement

Non-Viable Particle Monitoring

Objective: To continuously monitor airborne particulate levels in critical processing zones.

Methodology:

• Install continuous non-viable particle monitoring systems with remote probes within the isolator environment
• Set alert limits at 3,520 particles/m³ for ≥0.5μm particles
• Set action limits at 3,520 particles/m³ for ≥0.5μm particles (consistent with ISO Class 5 standards)
• Document and investigate all excursions beyond established limits

workflow Diagram: Aseptic Processing Implementation

Critical Considerations for POC Implementation

Personnel Training and Qualification

Personnel factors represent the most variable component in POC aseptic processing and require rigorous control:

• Comprehensive Training Programs: Effective training must extend beyond basic aseptic techniques to include fundamental understanding of microbiology, contamination control, cleanroom operations, and quality systems [42]. Personnel should possess both technical skills and professional ethics appropriate for aseptic processing [42].

• Gowning Qualification: Implement validated gowning procedures with regular qualification assessments. For isolator operations, focus on proper glove port technique and material transfer procedures.

• Behavioral Monitoring: Establish programs for regular assessment of aseptic technique, including media fills that simulate worst-case intervention scenarios.

Facility Design and Material Flow

Proper facility design is crucial for maintaining contamination control in space-constrained POC environments:

• Unidirectional Flow: Design personnel and material flows to be unidirectional where possible, with separate entry and exit airlocks to minimize contamination risk [42].

• Material Management: Implement robust systems for status identification and management of materials to prevent use of improperly processed components [42]. This is particularly critical given the high volume of materials processed in aseptic facilities.

• Cleaning and Disinfection: Develop and validate cleaning procedures specifically designed for the facility layout and equipment configuration. Process support rooms (ISO 7 and ISO 8) typically require more frequent cleaning than critical processing areas [42].

Quality Systems and Documentation

Adapting quality systems to the POC manufacturing model requires specific considerations:

• Master File System: Under the MHRA POC framework, the control site must create and maintain a comprehensive Master File specifying manufacturing processes for satellite sites [16].

• Change Management: Implement robust change management procedures that allow for process improvements while maintaining regulatory compliance. The MHRA framework permits updates to the Master File without requiring license variations [16].

• Documentation Practices: Establish batch record systems that accommodate the decentralized model while maintaining data integrity and product traceability.

The Scientist's Toolkit: Essential Research Reagent Solutions

Table 3: Key Materials and Reagents for POC Aseptic Processing

Item	Function	Application Notes
Vaporized Hydrogen Peroxide (VHP)	Isolator decontamination	Sporicidal agent for full isolator decontamination cycles; requires validation of concentration, distribution, and contact time
Soybean-Casein Digest Agar	Culture media for environmental monitoring	General purpose media for bacteria and fungi; used in settle plates, contact plates, and active air sampling
Neutralizing Agar	Culture media for sanitized surfaces	Contains neutralizers for chemical disinfectants; used when monitoring after cleaning activities
Rapid Transfer Port (RTP) Systems	Material transfer into isolators	Maintain contamination control during material ingress/egress; requires operator training for proper use
Particle Counters	Non-viable particle monitoring	Remote probes for continuous monitoring of ISO 5 environments; require regular calibration
Single-Use Assemblies	Fluid transfer and bioprocessing	Pre-sterilized components reduce cleaning validation burden and contamination risk

Implementing robust aseptic processing and environmental control in non-traditional POC settings requires a holistic approach integrating appropriate technologies, rigorous protocols, and adapted quality systems. Isolator-based systems provide the foundation for maintaining sterility in non-classified environments, while comprehensive environmental monitoring programs demonstrate state of control. The emerging regulatory frameworks for decentralized manufacturing, including the MHRA's point-of-care and modular manufacturing licenses, provide pathways for implementing these approaches while maintaining product quality and patient safety. By adopting these strategies, researchers and drug development professionals can advance the field of POC cell therapy manufacturing while meeting regulatory expectations.

Building a Skilled Workforce and Navigating the Complexities of Staff Training and Competency

The regulatory landscape for point-of-care (POC) cell therapy manufacturing is undergoing significant transformation, creating parallel demands for an equally evolved and highly skilled workforce. The recent enactment of new frameworks, such as the UK's "The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025", specifically aims to transform the manufacture of innovative medicines at the point of patient care [16] [4]. This shift from centralized to decentralized manufacturing models introduces new operational complexities. This Application Note addresses the critical workforce training and competency requirements essential for navigating this new regulatory and manufacturing environment, ensuring both compliance and the safe delivery of advanced therapy medicinal products (ATMPs).

Regulatory Context for Point-of-Care Manufacturing

Understanding the regulatory structure is the first step in building a compliant training program. The new framework for POC manufacturing delineates specific legal responsibilities and introduces novel licensing categories that directly impact workforce organization.

Key Regulatory Frameworks

• EU Regulatory Environment: The European framework for ATMPs is complex, governed by the ATMP Regulation (EC 1394/2007), and involves a intricate legal landscape that can vary between Member States [43]. The recently effective EMA Guideline on investigational ATMPs provides a multidisciplinary reference, though differences in requirements like allogeneic donor eligibility and GMP compliance persist compared to other regions [44].
• UK's Pioneering Framework: The UK's MHRA has introduced a world-first regulatory framework for the modular and point-of-care manufacture of ATMPs, effective July 2025 [16] [33] [4]. This framework is designed to support quicker and cheaper manufacturing of therapies like CAR-T by allowing final manufacturing steps at or near the hospital [33].

The "Control Site" and Satellite Model

The UK's new regulations create a novel operational model centered on a Manufacturer’s License for POC or Modular Manufacture (MM) [16]. The holder of this license, the "Control Site," bears full responsibility for generating the Master File (MF) that details the manufacturing process and for the supervision and control of all satellite POC or MM units [16]. This model fundamentally shifts the paradigm, moving product release from the bedside back to the main manufacturing site, but distributes the manufacturing activities across satellite locations [16]. This structure necessitates clearly defined roles, responsibilities, and chains of command between the central control site and the point-of-care units.

Core Competency Framework

A successful POC manufacturing workforce requires a multi-faceted competency profile that blends deep technical skill with robust quality and regulatory knowledge. The following table outlines the primary competency domains and their practical applications.

Table 1: Core Competency Domains for POC Cell Therapy Manufacturing

Competency Domain	Key Knowledge/Skill Requirements	Application in POC Context
Technical & GMP Proficiency	- Aseptic processing & closed-system manipulation.- Cell culture, cryopreservation, and analytics.- Phase-appropriate GMP and Good Documentation Practices (GDP).	Executing the technical steps outlined in the Master File consistently and safely at a decentralized location, often for an n-of-1 (personalized) therapy [16] [44].
Quality Management Systems (QMS)	- Understanding of Pharmaceutical Quality System principles (EU GMP Ch.1) [30].- Deviation, CAPA, and change management.- Self-inspection and internal audit execution.	Implementing local QMS activities under the oversight of the central Control Site, managing local deviations, and participating in internal and regulatory inspections [16].
Regulatory & Compliance	- Knowledge of EudraLex Volume 4, specifically the GMP for ATMPs guideline [30].- Understanding the Hospital Exemption pathway and national variations [43] [45].	Ensuring all local practices strictly adhere to the approved MF and overarching EU or national GMP requirements for ATMPs, ensuring regulatory compliance at the point-of-care [16] [44].
Digital Literacy & AI Tools	- Use of AI and data analytics for regulatory monitoring and process control.- Interpreting outputs from Machine Learning (ML) models used in manufacturing.	Using digital tools for real-time documentation, leveraging AI for regulatory intelligence (e.g., scanning 9,000 regulations/day [46]), and managing electronic batch records.

Experimental Protocol for Staff Training & Competency Assessment

This protocol provides a detailed methodology for establishing and maintaining a qualified workforce for POC cell therapy operations, aligning with regulatory expectations for training and competency.

Protocol: A Risk-Based Training and Competency Assurance Program

Objective: To ensure all personnel involved in POC manufacturing are demonstrably competent to perform their assigned tasks in compliance with the approved Master File and GMP standards.

Materials:

• SOPs and the Master File (MF) for the specific ATMP.
• Training curricula and lesson plans for each role.
• Classroom and practical training facilities (including a GMP mock-up area).
• Assessment forms (for knowledge, practical skill, and behavioral competencies).

Procedure:

• Role Definition & Training Needs Analysis (TNA):
  • Define each job role within the POC unit (e.g., POC Aseptic Operator, POC Quality Person).
  • Perform a TNA for each role, mapping required competencies from the Core Competency Framework (Table 1) against specific tasks in the MF.

• Curriculum Development:
  • Develop a multi-modular curriculum based on the TNA. The diagram below illustrates a logical training pathway that progresses from foundational knowledge to final authorization.

• Training Delivery:

  • Module 1: Foundational. Deliver training on core GMP, ATMP regulations, and the specific POC model, including the responsibilities of the Control Site [16].
  • Module 2: Role-Specific & Technical. Provide hands-on technical training on the specific manufacturing process (e.g., cell washing, formulation) using the exact equipment and procedures from the MF.
  • Module 3: Practical Application. Conduct simulated manufacturing runs in a GMP mock-up environment, incorporating common errors and deviations to train problem-solving skills.

• Competency Assessment:

  • Employ a three-pronged assessment strategy for each critical task:
    • Knowledge Assessment: Written or oral exams on theoretical principles.
    • Practical Skill Assessment: Direct observation of the candidate performing the task against a pre-defined checklist (e.g., media preparation, aseptic connection).
    • Behavioral Assessment: Evaluation of GMP comportment, documentation practices, and response to simulated deviations.

• Authorization & Certification:

  • Designate a qualified Trainer/Assessor (approved by the Control Site) to review all assessment results.
  • Upon successful completion, issue a formal "Letter of Authorization" or certification, specifying the exact tasks the individual is approved to perform. This authorization must be documented in the personnel training file.

• Maintenance of Competency:

  • Perform annual performance requalification for all critical aseptic and operational tasks.
  • Mandate annual GMP and procedural refresher training.
  • Manage and document re-training following major deviations, process changes, or observations during inspections.

The Scientist's Toolkit: Essential Research Reagent Solutions

The transition from research to GMP-compliant POC manufacturing requires careful planning and selection of materials. The following table details key reagents and materials, highlighting critical considerations for clinical-stage development.

Table 2: Key Reagent Solutions and GMP Considerations for POC ATMPs

Reagent/Material	Research Function	Critical GMP & POC Considerations
Cell Culture Media	Supports cell growth, expansion, and viability.	- Quality (e.g., xeno-free, serum-free formulations) and regulatory status of raw materials [39].- Comparability studies required for any change in source or formulation [44].
Growth Factors & Cytokines	Directs cell differentiation, expansion, and activation.	- Use of GMP-grade materials where possible.- Justification of quality and purity in the IMPD. Robust and standardized QC testing upon receipt at the POC unit.
Viral Vectors	Gene delivery for genetic modification of cells (e.g., CAR-T).	- Sourced from a GMP-compliant manufacturer.- The vector is typically provided by the Control Site to the POC unit as the "bulk substance" [16]. Strict chain of identity and custody must be maintained.
Ancillary Materials	Includes reagents like cytokines, antibodies, and separation media.	- Comprehensive vendor qualification is required.- Rigorous incoming quality control at the POC unit is essential for lot-to-lot consistency and patient safety.
Final Formulation Buffers	Creates the final injectable product suspension.	- Must be prepared and sterile-filtered under GMP conditions, often in advance by the Control Site.- Requires strict management of shelf-life and stability data at the POC.

The successful implementation of POC cell therapy manufacturing is inextricably linked to the development of a robust, well-trained, and highly competent workforce. As regulatory frameworks like the UK's new legislation and the EMA's clinical trial guideline evolve, the human factor remains the most critical component for ensuring product quality and patient safety. By adopting a structured, risk-based approach to training and competency assessment—centered on a clear understanding of the Control Site and satellite unit model—organizations can navigate this complex landscape effectively. This will ultimately fulfill the promise of POC manufacturing: to provide patients with quicker, more sustainable, and equitable access to transformative Advanced Therapy Medicinal Products.

Regulatory Horizons: Comparing EU, UK, and US Pathways and Future Trends

Advanced Therapy Medicinal Products (ATMPs), encompassing gene therapies, somatic-cell therapies, and tissue-engineered products, represent a paradigm shift in medicine towards potentially curative, personalized treatments [5]. The conventional centralized manufacturing model, where products are made in large-scale, distant facilities, poses significant challenges for autologous ATMPs (patient-specific). These include complex logistics, lengthy vein-to-vein times, and high costs due to the lack of economies of scale [28]. Decentralized manufacturing has emerged as a transformative strategy, moving production closer to the patient—either in regional facilities or at the point of care (POC) within certified hospital settings [28]. This approach aims to improve patient access, reduce delays, and enhance the affordability of these life-changing therapies [33].

The European regulatory framework, steered by the European Medicines Agency (EMA), is evolving to accommodate these innovative manufacturing paradigms. While the EU is actively refining its guidelines, the core principle remains that any decentralized model must adhere to the same rigorous standards of quality, safety, and efficacy as centralized production [47] [28]. This document provides application notes and detailed protocols for navigating and implementing the existing EU ATMP guidelines within decentralized manufacturing scenarios, serving as a practical resource for researchers and drug development professionals.

EU Regulatory Framework and Key Concepts

Foundational EU Regulations and Guidelines

The regulation of ATMPs in the EU is anchored by Regulation (EC) No 1394/2007, which provides the legal definition and central marketing authorization pathway for these products [47] [5]. The EMA's Committee for Advanced Therapies (CAT) is pivotal in their scientific assessment, providing classification recommendations and expert guidance [5]. Although the EU's specific GMP annex for decentralized manufacturing is under development, several existing documents provide the necessary regulatory bedrock, as outlined in Table 1.

Table 1: Key EU Regulatory Documents Applicable to Decentralized ATMP Manufacturing

Document Title	Scope & Relevance to Decentralized Manufacturing	Key Points for Application
EudraLex Volume 4, GMP Guidelines [3]	General Good Manufacturing Practice standards for medicinal products.	Forms the non-negotiable foundation for all manufacturing activities, regardless of location.
Annex 1: Sterile Medicinal Products	Specific requirements for sterile product manufacture.	Critical for aseptic processing at POC; mandates validated processes and environmental monitoring.
Guideline on GMP specific to ATMPs [28]	Elaborates GMP principles tailored to the unique characteristics of ATMPs.	Addresses control strategies for variable starting materials, a key challenge in autologous POC manufacture.
EMA/HMA Network Strategy to 2025 [28]	Strategic vision acknowledging decentralized manufacturing as a future priority.	Signals regulatory openness to innovative models and guides long-term development planning.

The Control Site Model for Regulatory Oversight

A cornerstone of implementing decentralized manufacturing within the current EU framework is the Control Site model [28]. This model establishes a single, centralized entity that assumes ultimate responsibility for the quality of the ATMP produced across a network of decentralized manufacturing units (DMUs). The Control Site acts as the primary interface with regulatory authorities, ensuring centralized oversight and consistency. Figure 1 illustrates the logical relationships and regulatory responsibilities within this model.

Figure 1: Regulatory Oversight in a Decentralized ATMP Manufacturing Model. The diagram illustrates the central role of the Control Site in managing multiple Decentralized Manufacturing Units (DMUs) via a POC Master File and serving as the primary contact for the EU regulatory system. CA: Competent Authority.

The responsibilities of the Control Site are extensive and critical for regulatory compliance, as synthesized in Table 2.

Table 2: Key Functional Responsibilities of the Control Site in a Decentralized Model

Functional Area	Key Responsibilities
Regulatory Interface	Single point of contact for EMA/National Competent Authorities; holds the marketing authorization [28].
Quality Management System (QMS)	Establishes and maintains an overarching QMS applicable to all DMUs; manages quality agreements and conducts audits [28].
POC Master File (POC-MF) Management	Creates, maintains, and updates the detailed technical and quality file that governs operations at each DMU [28].
Qualified Person (QP)	Ensures a QP is available for certification of each batch before release, even when final production occurs at a DMU [28].
Training	Develops and implements standardized training programs for personnel across all DMUs to ensure consistent operations [28].
Supply Chain Management	Manages the sourcing and qualification of raw materials and components supplied to the DMUs [28].
Process Validation & Comparability	Generates data to demonstrate that the manufacturing process is robust and comparable across all DMUs [28].

Application Notes: Implementing EU Guidelines in Decentralized Scenarios

Establishing a Compliant Quality Management System (QMS)

The QMS for a decentralized network must be integrated and robust, ensuring uniform standards across all locations. The Control Site's QMS must extend to cover all DMUs, treating them as an extension of its own manufacturing operations [28]. Key elements include:

• Standardized Procedures: All critical processes, from apheresis material receipt to final product formulation, must be governed by standardized, validated SOPs distributed from the Control Site.
• Documentation Control: A centralized, electronic document management system is essential to ensure that all DMUs use the correct, up-to-date versions of manufacturing formulae, specifications, and SOPs.
• Change Management: A single, rigorous change control system managed by the Control Site must evaluate and approve any changes to processes, equipment, or the POC-MF before implementation at any DMU.
• Supplier and Material Qualification: The Control Site is responsible for qualifying all critical raw material suppliers and ensuring that materials meet pre-defined specifications before distribution to DMUs.

Process Validation and Demonstrating Comparability

A fundamental regulatory requirement is demonstrating that the ATMP produced at any DMU is comparable in quality, safety, and efficacy. This is achieved through a three-stage process validation approach and ongoing comparability exercises, as detailed in the experimental protocol in Section 4.1. The EMA emphasizes that sponsors must demonstrate a comparable product is manufactured at each location, which includes showing that analytical methods are comparable across sites [28].

Integrating Digital Tools and Advanced Sensors

The EU's Horizon HLTH-2025-01-IND-01 topic actively encourages the integration of digital tools and advanced sensors to optimize ATMP manufacturing [47]. In a decentralized context, these technologies are indispensable for maintaining real-time control and oversight.

• Digital Twins: Computational models of the manufacturing process can predict outcomes and identify potential deviations, allowing for preemptive corrective actions.
• Process Analytical Technology (PAT): Implementing advanced sensors for parameters like pH, dissolved oxygen, and cell density enables real-time monitoring and facilitates Real-Time Release Testing (RTRT), which is highly advantageous for products with short shelf-lives [20].
• Data Integrity and AI: A centralized data hub managed by the Control Site can aggregate process data from all DMUs. AI and machine learning algorithms can analyze this data to refine the process, enhance process control, and support continuous process verification.

Experimental Protocols for Decentralized Manufacturing

Protocol: Process Performance Qualification (PPQ) and Comparability Study Across Multiple DMUs

This protocol provides a methodology to validate a decentralized manufacturing process and demonstrate comparability across three independent DMUs.

1. Objective: To generate validated data proving the manufacturing process consistently produces ATMPs meeting pre-defined quality attributes across three different DMUs, and to establish comparability between the sites.

2. Research Reagent Solutions and Essential Materials

Table 3: Key Reagents and Materials for Process Validation

Item	Function / Rationale	Quality Control Requirements
Cell Culture Media	Provides nutrients for cell growth and expansion.	Must be identical across all sites; sourced from a single, qualified vendor; tested for endotoxin and sterility.
Growth Factors/Cytokines	Directs cell differentiation or expansion.	Defined, recombinant grades; concentration and activity standardized; stability profile established.
Activation Reagents (e.g., Transduction Enhancers)	Facilitates genetic modification in gene therapies.	Critical reagent; requires rigorous qualification for identity, purity, and potency.
Closed-System Bioreactors	Provides a controlled, sterile environment for cell culture.	Equipment qualification (IQ/OQ) required at each DMU; process parameters (e.g., agitation, gas flow) must be standardized.
Flow Cytometry Antibody Panels	For characterization of cell phenotype and purity.	Panels must be identical across sites; antibodies should be from the same clone and conjugate, titrated for optimal signal.

3. Methodology:

• 3.1. Study Design: A bracketing approach will be used. The Control Site process will be compared to processes at three DMUs. For autologous processes, a panel of donor starting materials with varying initial qualities (e.g., different cell viabilities) will be split and processed in parallel at the Control Site and the three DMUs (n=5 per site).
• 3.2. Experimental Workflow: The experimental workflow for the PPQ and Comparability study is a multi-stage process designed to ensure robust validation. Figure 2 outlines the key stages from preparation through to data analysis.

Figure 2: Process Performance Qualification and Comparability Study Workflow. The diagram outlines the multi-stage experimental protocol for validating a decentralized manufacturing process. IQ/OQ/PQ: Installation/Operational/Performance Qualification.

• 3.3. Data Analysis:
  • Process Parameters: Compare all critical process parameters (e.g., culture duration, metabolite profiles) between sites using statistical methods (e.g., ANOVA).
  • Quality Attributes: Compare all critical quality attributes (CQAs) such as viability, phenotype purity, potency, and vector copy number (for gene therapies). Pre-specified equivalence margins must be defined for key CQAs.
  • Success Criteria: The process is considered validated and comparable if all CQAs from all DMUs fall within the pre-defined acceptance criteria and are statistically equivalent to those from the Control Site.

Protocol: Validation of a Real-Time Release Testing (RTRT) Strategy

For short-shelf-life ATMPs, RTRT is critical. This protocol validates an RTRT model that replaces traditional end-product testing for certain attributes.

1. Objective: To validate a multivariate RTRT model that ensures product quality based on in-process data, allowing for rapid release at the POC.

2. Methodology:

• 2.1. Model Training: Use historical manufacturing data (≥50 batches) from the Control Site to build a model correlating a set of in-process parameters (e.g., final cell density, glucose consumption rate, specific productivity) with the results of traditional quality control tests (e.g., potency, viability).
• 2.2. Model Validation: Prospectively test the RTRT model on a new set of validation batches (n=10) manufactured at the Control Site and at least two DMUs. The model's prediction of the product's CQAs is compared against the results from the full compendial testing.
• 2.3. Implementation: Once validated, the RTRT model is deployed to all DMUs. For each batch, the DMU collects the defined in-process data, which is fed into the model to generate a "release" or "reject" signal, overseen by the QP at the Control Site.

Regulatory Strategy and Engagement

Engaging with regulators early and strategically is paramount for the success of decentralized manufacturing programs. Proposals should "assess the process and methods developed for their regulatory validity" and engage with regulators in a timely manner [47].

• Early Scientific Advice and Classification: Seek scientific advice from both the EMA and the relevant National Competent Authorities where the DMUs will be located. For complex products, a request for ATMP classification to CAT is a critical first step [5].
• Pilot Programs and Regulatory Flexibility: Academia and SMEs are encouraged to participate in EU initiatives. The EMA's ATMP Pilot for academia and non-profit organizations provides enhanced regulatory support, including fee reductions, which can be instrumental for early-stage decentralized projects [5].
• Pre-submission Meetings: Prior to submitting a Marketing Authorisation Application (MAA), schedule a pre-submission meeting to present the decentralized manufacturing model, the control strategy, and the data package (including PPQ and comparability data) to secure regulatory buy-in.

Table 4: Quantitative Data Requirements for Regulatory Submissions Involving Decentralized Manufacturing

Data Category	Minimum Recommended Batches	Key Parameters to Report	Acceptance Criteria Justification
Process Validation	3 consecutive successful batches per DMU (per process) [28].	All Critical Process Parameters (CPPs); data from all DMUs.	Based on historical data and process capability; must ensure patient safety.
Product Comparability	5-10 paired batches (split starting material) per DMU vs. Control Site.	All Critical Quality Attributes (CQAs); statistical analysis (e.g., 95% CI).	Equivalence margins justified by clinical relevance and analytical variability.
RTRT Model Validation	≥50 batches for training; ≥10 for prospective validation.	Model accuracy, precision, robustness.	Prediction error for CQAs must be within pre-defined, justified limits.
Container Closure Stability	3 batches, minimum.	Stability-indicating CQAs under simulated transport conditions.	Must demonstrate product quality is maintained until administration.

The successful application of existing EU ATMP guidelines to decentralized manufacturing scenarios is not only feasible but is actively encouraged to advance patient-centric healthcare. The key to success lies in a robust, science-driven approach centered on a strong Control Site, a comprehensive POC Master File, and a thorough process validation and comparability package. By leveraging digital tools, implementing rigorous protocols like those outlined, and engaging proactively with regulators, developers can navigate this evolving landscape. This will accelerate the delivery of transformative, personalized ATMPs to patients across Europe, fulfilling the promise of these innovative therapies.

The advent of advanced therapies, particularly cell and gene therapies (CGTs), has challenged traditional pharmaceutical manufacturing and regulatory paradigms. These "living medicines," especially autologous products with very short shelf-lives, require production models that are fundamentally different from centralized factory-based manufacturing. Point-of-care (POC) manufacturing has emerged as a solution, enabling production of therapies at or near the patient's treatment location [18] [32].

The regulatory approach to this decentralized model is evolving at different paces across the globe. The United Kingdom has established the world's first comprehensive regulatory framework for POC manufacturing, which took effect in July 2025 [18] [48]. Meanwhile, the United States Food and Drug Administration (FDA) is still formulating policy for these distributed manufacturing approaches, creating a significant divergence in regulatory pathways [32].

This analysis provides a comparative examination of the UK's implemented POC framework against the FDA's evolving stance, offering strategic insights for researchers, scientists, and drug development professionals navigating this emerging landscape.

Regulatory Framework Comparison

UK POC Framework: Implemented Legislation

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has established a comprehensive regulatory system for point-of-care and modular manufacture through The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025, which amended the Human Medicines Regulations 2012 [18] [20].

Table: Key Definitions in UK POC Legislation [18]

Term	Definition
POC Medicinal Product	A medicinal product that, for reasons relating to method of manufacture, shelf life, constituents or method/route of administration, can only be manufactured at or near the place of use/administration.
POC Site	A site at which the manufacture or assembly of a POC medicinal product takes place.
POC Control Site	The premises at which the holder of a manufacturer's licence (POC) supervises and controls the manufacture of POC medicinal products.
POC Master File	A detailed description of the arrangements for the manufacture or assembly of a POC medicinal product.
Modular Manufacture (MM)	A medicinal product that, for reasons related to deployment, the licensing authority determines it necessary/expedient to be manufactured in a relocatable manufacturing unit.

The framework introduces specific manufacturer's licence types for POC and MM products and requires corresponding master files that detail manufacturing arrangements [18]. The MHRA oversees a control site that maintains responsibility for supervising all distributed manufacturing locations, rather than requiring individual inspections of potentially hundreds of POC sites [32] [20].

US FDA Stance: Ongoing Evaluation

In contrast to the UK's implemented framework, the FDA has not yet established formal guidance for POC or distributed manufacturing models. The agency is actively evaluating these approaches but faces significant regulatory challenges in their implementation [32].

• Current Status: The FDA's Center for Biologics Evaluation and Research (CBER) is "in the process of trying to understand all of these different approaches and formulate policy accordingly" [32]. Key concerns include maintaining comparability between manufacturing sites, ensuring adequate staff training, and preserving aseptic environments across distributed locations [32].
• Manufacturing Focus: Recent FDA complete response letters (CRLs) for CGT products emphasize increased scrutiny on Chemistry, Manufacturing, and Controls (CMC) issues. Data shows that 74% of CRLs issued between 2020-2024 were driven by quality or manufacturing deficiencies [49].
• Emerging Guidance: The FDA has released draft guidance on innovative clinical trial designs for CGTs in small populations, recognizing the unique challenges of rare disease trials [50] [46]. However, this does not specifically address the POC manufacturing model.

Table: Comparative Analysis of UK vs. US Regulatory Approaches to POC Manufacturing

Aspect	UK MHRA Approach	US FDA Approach
Regulatory Status	Implemented framework (July 2025) [18]	Policy development phase [32]
Oversight Model	Control site responsibility for decentralized sites [32] [20]	Traditional facility-specific licensing
GMP Application	Adapted GMP with POC-specific guidance [20]	Standard GMP requirements apply
Clinical Trial Support	Specific CTA guidance for decentralized manufacturing [20]	General CGT trial guidance [50]
Key Emphasis	Flexibility with maintained quality standards [18]	Manufacturing consistency and control [49]

Experimental Protocols for POC Manufacturing

Protocol 1: UK POC Designation Application Process

Purpose: To obtain MHRA designation for a medicinal product as suitable for point-of-care or modular manufacturing.

Methodology:

• Early Engagement: Initiate designation process early in development cycle through scientific advice procedures [20].
• Justification Dossier Preparation:
  • Present data supporting POC classification based on product characteristics (shelf-life, manufacturing method, constituents, administration route)
  • Demonstrate that convenience and cost are not primary justification factors [20]
  • For modular manufacturing, justify based on public health requirement and/or significant clinical advantage [20]
• Submission: File designation application concurrently with or prior to Clinical Trial Authorization (CTA) or Marketing Authorization (MA) applications [20].
• Review Timeline: Preliminary decision within 30 days; full approval within 60 days (assuming complete information) [20].

Critical Success Factors:

• Robust justification based on product characteristics rather than operational convenience
• Comprehensive data package demonstrating equivalence between centralized and decentralized manufacturing approaches
• Clear risk management strategy for distributed manufacturing

Protocol 2: Control Site Oversight of Distributed Manufacturing

Purpose: To establish and maintain effective quality oversight of multiple POC manufacturing sites from a central control site.

Methodology:

• Control Site Establishment:
  • Designate a physical control site located in the UK with appropriate manufacturing license [20]
  • Implement comprehensive Quality Management System (QMS) capable of managing distributed manufacturing network [20]
• POC Master File Development:
  • Create detailed instructions for manufacturing at remote sites [18] [20]
  • Establish procedures for onboarding, suspending, and pausing remote sites [20]
  • Develop training programs and materials for all POC sites [20]
• Ongoing Oversight Operations:
  • Implement audit schedule for remote sites
  • Establish data integrity monitoring procedures
  • Maintain equipment calibration and maintenance programs across all sites [20]
  • Coordinate supply of materials and components to POC sites [20]
• Product Release:
  • Designate Qualified Person (QP) responsible for product release [20]
  • Implement real-time release testing (RTRT) strategies where appropriate [20]

Critical Success Factors:

• Robust quality agreement framework between control site and POC locations
• Standardized training and certification programs
• Comprehensive change control procedures across distributed network
• Integrated data management systems for manufacturing data

UK POC Regulatory Oversight Model

This diagram illustrates the UK's control site model for POC oversight, where a central licensed facility maintains responsibility for quality management and provides manufacturing instructions to multiple point-of-care sites.

The Scientist's Toolkit: Research Reagent Solutions

Table: Essential Materials and Technologies for POC Manufacturing Implementation

Tool/Technology	Function	Application in POC Context
Isolator-Based Systems [29]	Sealed containment providing physical separation from manufacturing environment; maintains aseptic conditions	Enables GMP-compliant manufacturing in non-classified hospital environments; essential for sterility assurance
Closed-System Automated Instruments [27]	Automated, closed processing systems for cell therapy production	Reduces cleanroom space requirements; standardizes manufacturing across multiple sites
Rapid Transfer Ports [29]	Enable material ingress/egress while maintaining sterile barrier	Facilitates material transfer in isolator systems without compromising aseptic conditions
Integrated Decontamination Systems [29]	Automated sporicidal decontamination (e.g., vaporized hydrogen peroxide)	Ensures sterility of isolator interiors between manufacturing runs
Real-Time Release Testing (RTRT) Platforms [20]	Analytical methods enabling product release without extended testing	Critical for products with very short shelf-lives; allows immediate administration
GMP-Grade Reagents [27]	Qualified materials meeting regulatory standards for therapeutic manufacturing	Ensures product safety and consistency; available as "off-the-shelf" solutions

Analytical Methods and Data Interpretation

Comparative Regulatory Pathway Analysis

The divergent approaches between UK and US regulators create distinct development pathways for POC therapies:

POC Development Pathways: UK vs US

Manufacturing Comparability Assessment

For both regulatory environments, demonstrating comparability between manufacturing sites is paramount. The following analytical approach is recommended:

Methodology:

• Process Performance Qualification: Execute identical manufacturing runs at multiple proposed POC sites using standardized protocols [20]
• Critical Quality Attribute (CQA) Monitoring: Measure key product attributes across sites using validated analytical methods [49]
• Statistical Analysis: Implement statistical models to assess inter-site variability and establish equivalence ranges [20]

Acceptance Criteria:

• No statistically significant differences in CQAs between manufacturing sites
• All product batches meet pre-defined specification limits
• Process performance indicators (e.g., viability, yield) within established ranges across sites

Discussion and Future Perspectives

Strategic Implications for Drug Developers

The regulatory divergence between UK and US approaches creates both challenges and opportunities for therapy developers:

• First-Mover Advantage: The UK's implemented framework offers a clear regulatory pathway for therapies requiring POC manufacturing, potentially accelerating UK patient access and establishing the country as a leader in advanced therapy innovation [48]. Companies may consider pursuing UK approval first for products with very short shelf-lives or those requiring significant personalization.

• Development Strategy Considerations: The FDA's increased focus on CMC issues necessitates early investment in manufacturing strategy [49]. Companies should engage with FDA through pre-IND meetings specifically addressing distributed manufacturing approaches, even in the absence of formal guidance.

• Technology Selection: The emphasis on manufacturing control in both jurisdictions makes closed-system automated instruments and isolator technologies essential investments for POC implementation [27] [29]. These technologies reduce variability and maintain sterility across distributed manufacturing networks.

Emerging Trends and Future Directions

Several emerging trends will shape the future of POC manufacturing regulation:

• AI Integration: Regulatory agencies are increasingly exploring artificial intelligence for reviewing manufacturing data and monitoring product quality across distributed networks [46]. The FDA has released draft guidance on AI in regulatory decision-making [46].

• International Harmonization: Initiatives like the FDA's Gene Therapies Global Pilot Program (CoGenT) aim to increase regulatory collaboration and potentially harmonize approaches to novel manufacturing models [46].

• Advanced Analytics: Implementation of real-time release testing and process analytical technology will be critical for maintaining quality control across distributed manufacturing sites without introducing treatment delays [20].

The regulatory landscape for point-of-care cell therapy manufacturing represents a study in contrasts between the UK's implemented framework and the FDA's evolving stance. The MHRA has established a world-first comprehensive system that enables decentralized manufacturing while maintaining oversight through a control site model. Meanwhile, the FDA maintains a more cautious approach, focusing on manufacturing consistency and CMC rigor while developing policy for distributed models.

For researchers and therapy developers, this divergence necessitates strategic planning. The UK framework offers a viable pathway for therapies requiring immediate administration or significant personalization. In the US, early engagement with regulators and robust CMC planning are essential, even in the absence of specific POC guidance. As both regulatory environments continue to evolve, the integration of advanced technologies like closed-system automation, isolator platforms, and AI-driven quality control will be critical for successful POC implementation across jurisdictions.

The Role of AI, Automation, and Data Analytics in Enabling Robust Distributed Manufacturing

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), such as cell and gene therapies, the traditional centralized manufacturing model presents significant challenges. These include complex logistics for patient-specific starting materials, short shelf lives, and difficulties in scaling production [16]. Distributed manufacturing, which moves production closer to the patient at Point-of-Care (POC) or within modular units, offers a promising alternative. This application note explores how the integration of AI, automation, and data analytics is creating robust, scalable, and compliant frameworks for distributed manufacturing, with specific consideration of the evolving regulatory landscape in the EU and UK.

The Regulatory Framework for Distributed Manufacturing

Understanding the regulatory environment is critical for the successful implementation of distributed models. Both European and UK authorities have introduced specific pathways for these innovative manufacturing approaches.

The UK's MHRA Framework for Modular and POC Manufacturing

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has established a pioneering regulatory framework for the decentralised manufacture of innovative medicines, which became effective on July 23, 2025 [16] [6]. This framework introduces two key concepts:

• Point of Care (POC) Manufacturing: Activities performed at or near the patient, typically in a clinical setting, for reasons related to the method of manufacture, short shelf life, or personalized nature of the treatment [16].
• Modular Manufacturing (MM): Manufacturing activities conducted away from the primary licensed site, potentially in a relocatable unit, to address logistical challenges [16].

Under this framework, the control site holds the manufacturer's license (POC or MM) and is responsible for creating a Master File (MF) that details the operations to be performed at the satellite POC or MM units. The control site retains ultimate responsibility for product quality and release, enabling final product release to occur at the central facility rather than the bedside [16].

The EU Context: Data Act and Regulatory Considerations

Within the European Union, while a specific POC framework like the UK's is still emerging, the EU Data Act introduces crucial requirements for connected devices and related services, which took effect in September 2025 [51]. This legislation has profound implications for distributed manufacturing networks:

• Data Access and Portability: The Data Act grants users (which could include hospitals or manufacturing sites) the right to access data generated by connected products and related services, and to share that data with third parties [51].
• Product Design Obligations: Manufacturers must design products and services from the outset to enable secure and interoperable data sharing, facilitating portability and competition [51].

For ATMPs, which often rely on connected devices and generate vast amounts of process data, compliance with the Data Act is essential. This is particularly relevant when aligning with the upcoming European Health Data Space (EHDS), which will create a unified framework for the exchange of electronic health data across the EU [51].

Technological Enablers for Distributed Manufacturing

The practical implementation of distributed manufacturing relies on a suite of interconnected technologies that ensure consistency, quality, and control across multiple geographically dispersed sites.

Automation and Robotics

Automation provides the foundational layer for executing complex manufacturing processes with minimal human intervention, ensuring consistency and compliance across different sites.

• Flexible Robotic Platforms: Systems like the ESSERT Advanced Robotic Workstation offer modular, configurable automation for tasks such as pipetting, mixing, dispensing, and medical device assembly. Multiple workstations can be assembled into a MicroFactory configuration, creating an entire High-Mix Low-Volume (HMLV) production workflow that can be adapted to changing production requirements [52].
• End-to-End Process Automation: In the context of ATMPs, this encompasses everything from patient cell isolation and genetic modification to final formulation and fill-finish operations. Automated systems maintain sterile conditions, track chain of identity and custody, and ensure process parameter control throughout [52] [53].

Artificial Intelligence and Machine Learning

AI and ML algorithms transform raw data into predictive insights and adaptive control strategies, which is crucial for managing the inherent variability in patient-specific raw materials.

• Predictive Maintenance: AI algorithms process vast amounts of data from equipment sensors to forecast maintenance needs, reducing downtime in critical manufacturing processes. This is especially valuable in POC settings where specialized technical support may not be immediately available [54] [55].
• Process Optimization and Control: Machine learning models can analyze historical process data to identify optimal parameter setpoints and predict product quality attributes. This enables real-time release testing (RTRT) and adaptive process control, which are essential for managing the variability of biological starting materials [54] [55].
• Computer Vision for Quality Control: AI-powered vision systems can perform rapid, high-accuracy inspections of products, detecting minute defects or contaminants that might be missed by human inspectors. This is critical for ensuring patient safety in automated, high-throughput environments [54].

Data Analytics and Interoperability

Robust data management systems ensure that information flows seamlessly and securely across the distributed manufacturing network, supporting both operational and regulatory requirements.

• Real-Time Process Analytics: Advanced analytics platforms monitor Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) in real-time, enabling immediate intervention when processes deviate from their validated ranges [56] [53].
• Interoperable Data Systems: The EU Data Act emphasizes the importance of data interoperability. In a distributed network, this means implementing standardized data formats and interfaces to ensure that equipment and software from different vendors can communicate effectively [51].
• Comprehensive Audit Trails: Automated systems log every action with user information and timestamps, creating an inspection-ready record of the complete product lifecycle. This is a fundamental requirement for regulatory compliance in GMP environments [56].

Table 1: Quantitative Benefits of Automation in Pharmaceutical Manufacturing

Benefit Area	Key Metric	Impact
Production Efficiency	Reduction in Downtime	Predictive maintenance can significantly reduce unplanned equipment downtime [54].
Quality Control	Defect Detection Accuracy	AI-powered vision systems inspect products in milliseconds with high accuracy and consistency [54].
Process Speed	Review and Approval Cycles	Automated workflow systems with parallel review capabilities dramatically accelerate these cycles [56].
Data Management	Error Reduction	Automated data management reduces errors associated with manual entry and processing [56] [53].

Implementation Protocols and Workflows

This section provides detailed methodologies for establishing and operating a distributed manufacturing node, from initial setup through to product release.

Protocol: Establishing a POC Manufacturing Unit

This protocol outlines the steps for qualifying a new POC manufacturing site within an existing distributed network, based on the MHRA's Master File model [16].

Objective: To establish a fully qualified and licensed POC manufacturing unit capable of producing ATMPs under the supervision of a central control site.

Materials and Reagents:

• POC Manufacturing Device/Workstation: A closed, automated system for cell processing, expansion, or formulation (e.g., ESSERT Advanced Robotic Workstation or equivalent) [52].
• Single-Use, Pre-Sterilized Bioprocess Containers: For cell culture media, buffers, and intermediate product handling.
• Patient-Specific Starting Material (Apheresis Unit).
• QC Assay Kits: For in-process testing and potency assays (e.g., flow cytometry panels, PCR kits).
• Electronic Batch Record (EBR) System: Integrated with the central data platform.

Methodology:

• Site Qualification and Licensing:
  • The Control Site submits a variation to its existing Manufacturer's License (POC), including a new Master File (MF) specific to the proposed POC unit, to the relevant regulatory authority (e.g., MHRA) [16].
  • The MF must contain a detailed description of the POC unit's location, equipment, and the specific manufacturing/assembly activities to be performed.
  • The POC unit itself is listed as a licensed site on the Control Site's manufacturing license.

• Technology Transfer and Process Validation:

  • The manufacturing process, detailed in the MF, is transferred from the Control Site to the POC unit.
  • Process Performance Qualification (PPQ) runs are executed at the POC unit to demonstrate that the process, when run with the local equipment and personnel, consistently produces a product meeting its predefined CQAs.

• Operational Workflow:

  • The patient's apheresis unit is shipped to the POC unit under controlled conditions.
  • Upon receipt, the unit's identity is verified against the EBR system using barcode or RFID scanning.
  • The automated POC workstation executes the manufacturing process as per the locked MF. In-process data (e.g., temperature, gas levels, cell density) is automatically recorded and streamed to the central data platform.
  • Upon completion, the final product is quality-controlled as specified. The data is transmitted to the Qualified Person (QP) at the Control Site.
  • The QP at the Control Site reviews all data (from both the POC unit and the central site) and performs the batch release for the product.

The logical flow of responsibility and data in this decentralized model is illustrated below.

Protocol: AI-Driven Predictive Maintenance for POC Equipment

Objective: To implement a proactive maintenance schedule for critical POC equipment using AI-driven analytics, minimizing unplanned downtime.

Materials:

• Vibration, Temperature, and Power Quality Sensors (IIoT devices) attached to critical equipment.
• Cloud-Based Data Analytics Platform with machine learning capabilities.
• Maintenance Management Software.

Methodology:

• Data Acquisition:
  • Install IIoT sensors on key components (e.g., motors, pumps, compressors) of the POC manufacturing workstation.
  • Stream sensor data (vibration spectra, temperature trends, power draw) to the cloud platform in real-time. Historical maintenance records are also uploaded.

• Model Training and Deployment:

  • The ML platform is trained on the historical data to recognize patterns that precede equipment failures.
  • The model learns the normal operational "fingerprint" of the equipment and is calibrated to alert when real-time data deviates significantly from this baseline.

• Proactive Maintenance Execution:

  • The system generates alerts and work orders in the maintenance management software when a potential failure is predicted.
  • Maintenance is scheduled at the POC unit during non-production hours, based on the AI-generated recommendations, preventing unplanned downtime during critical manufacturing runs [54].

The workflow for this predictive maintenance system is as follows.

The Scientist's Toolkit: Essential Research Reagents and Solutions

For scientists developing and optimizing processes for distributed ATMP manufacturing, the following reagents, systems, and platforms are critical.

Table 2: Essential Tools for Distributed ATMP Manufacturing Research & Development

Item	Function/Application
Closed-System Automated Bioreactors	Scalable expansion of patient-specific cells in a functionally closed, automated format, reducing operator intervention and contamination risk.
Single-Use Bioprocess Assemblies	Pre-sterilized, closed fluid pathway assemblies for media, buffers, and product transfer; essential for maintaining sterility in a POC environment.
Automated Cell Counters & Viability Analyzers	Integrated, inline or at-line systems for real-time monitoring of cell growth and health during the manufacturing process.
qPCR/dPCR Kits for Vector Copy Number (VCN)	Quality control testing for gene-modified products to ensure safety and potency.
Flow Cytometry Panels for Identity/Potency	Multicolor panels for characterizing cell phenotypes and critical quality attributes of the final product.
Electronic Batch Record (EBR) System	Digital system for recording all production data, ensuring data integrity and facilitating remote QP review.
Cloud-Based Data Analytics Platform	Centralized platform for aggregating and analyzing process data from all distributed sites, enabling continuous process verification and trend analysis.
Process Analytical Technology (PAT)	In-line sensors (e.g., for pH, dissolved oxygen, metabolites) for real-time monitoring and control of CPPs.

The convergence of advanced automation, AI, and robust data analytics is making robust distributed manufacturing of ATMPs a tangible reality. These technologies are the key to overcoming the historical challenges of scalability, consistency, and compliance in decentralized models. By enabling real-time control, predictive insights, and seamless data flow across a network, they ensure that product quality and patient safety are maintained regardless of the physical location of manufacture. The emergence of clear regulatory pathways, such as the MHRA's framework for POC and modular manufacturing, provides the necessary structure for implementation. For researchers and drug developers, embracing this integrated technological and regulatory framework is essential for advancing the field of personalized cell and gene therapies and bringing their benefits to patients more efficiently.

The EASYGEN (Easy workflow integration for gene therapy) consortium represents a pioneering European Union-backed initiative aimed at revolutionizing the manufacturing landscape for Chimeric Antigen Receptor T-cell (CAR-T) therapies. This ambitious project seeks to address critical limitations in the current centralized manufacturing model, which involves a complex, multi-week process that must occur in specialized facilities often far from the patient's treatment center [57]. This traditional approach creates significant barriers to patient access, with treatment rates for eligible patients with diffuse large B-cell lymphoma ranging from just 11% in Italy to approximately 30% in France across Europe [58]. As a publicly funded research consortium, EASYGEN exemplifies the strategic push toward decentralized manufacturing models that align with emerging regulatory frameworks for Advanced Therapy Medicinal Products (ATMPs) across Europe.

The consortium's vision centers on developing an automated, modular, point-of-care cell and gene therapy manufacturing platform that would enable hospitals to generate CAR-T cells on-site, dramatically reducing manufacturing time from 4-6 weeks to under 24 hours while cutting treatment costs by an estimated 50% [57] [58]. This case study examines the EASYGEN initiative's technical approaches, regulatory context, and implementation framework to extract valuable insights for researchers, scientists, and drug development professionals working at the intersection of regulatory science and cell therapy production innovation.

Consortium Composition and Strategic Alignment

The EASYGEN consortium operates as a public-private partnership funded with €8 million from the EU's Innovative Health Initiative (IHI) [59]. The project brings together 18 organizations across 8 countries, creating a multidisciplinary ecosystem spanning industry, academia, clinical medicine, and regulatory expertise. This collaborative structure enables comprehensive addressing of the technical, clinical, and regulatory challenges inherent in decentralizing complex biological manufacturing processes.

The consortium is strategically coordinated by Fresenius, a global healthcare company with established capabilities in cell and gene therapy technologies, including its Lovo and Cue automated cell processing systems [60]. Academic co-leadership is provided by the Fraunhofer Institute, one of Europe's foremost immunotherapy research centers, in collaboration with Prof. Dr. Michael Hudecek, a recognized leader in CAR-T cell engineering, and Prof. Dr. Ulrike Köhl, a pioneer in translational cellular immunotherapies [59]. This industry-academia synergy ensures both practical implementability and scientific innovation throughout the development process.

Table: EASYGEN Consortium Participant Categories and Roles

Participant Category	Representative Organizations	Primary Role
Industry & Clinical Leaders	Fresenius (Coordinator), Helios Hospital Berlin-Buch, Quirónsalud, Cellix Ltd., Charles River [59]	Platform development, clinical validation, technology transfer
Academic & Research Institutions	Fraunhofer IZI/IESE, Technical University of Denmark, University of Glasgow, Bar-Ilan University [57]	Basic research, process optimization, safety/efficacy screening
Professional Societies & Regulatory Bodies	European Society for Blood & Marrow Transplantation, Frankfurt School of Finance & Management [57]	Standards development, workflow integration, regulatory guidance

Quantitative Project Dimensions

Table: EASYGEN Project Metrics and Financial Allocation

Project Dimension	Central Metric	Strategic Significance
Duration	5-year research project [59]	Allows for comprehensive development from concept to regulatory readiness
EU Funding	€8 million [58]	Substantial backing from EU's Innovative Health Initiative (IHI JU)
Cost Reduction Target	50% reduction in treatment cost [57]	Addresses major accessibility barrier for CAR-T therapies
Time Reduction Target	From 4-6 weeks to 24 hours [57]	Eliminates critical delay for deteriorating patients
Participant Scope	18 organizations across 8 countries [58]	Unprecedented European collaboration on decentralized manufacturing

Regulatory Context: The Evolving Framework for Point-of-Care Manufacturing

MHRA's Progressive Regulatory Framework

The EASYGEN initiative aligns with a significant regulatory evolution for decentralized manufacturing of cell and gene therapies. In 2025, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) introduced a comprehensive regulatory framework specifically addressing point-of-care and modular manufacturing of Advanced Therapy Medicinal Products (ATMPs) [20]. This framework establishes two distinct but complementary pathways:

• Point of Care (POC) Designation: For medicinal products that, due to method of manufacture, shelf life, constituents, or administration route, can only be manufactured at or near the place of use. The guidance explicitly states that convenience and cost are not valid criteria for POC designation [20].

• Modular Manufacturing (MM) Designation: For medicinal products where deployment necessities make it expedient to manufacture or assemble in modular units, justified by public health requirements and/or significant clinical advantages [20].

The regulatory process involves a designation step where sponsors petition the MHRA for evaluation of their product's suitability for decentralized manufacturing, ideally early in the development cycle. This designation process aims for a preliminary decision within 30 days and full approval within 60 days, assuming complete information submission [20].

Regulatory Workflow and Documentation Requirements

The successful implementation of decentralized manufacturing requires meticulous attention to regulatory workflows and documentation strategies. The diagram below illustrates the interrelationship between key regulatory components based on the MHRA's 2025 guidance:

For both Clinical Trial Authorization (CTA) and Marketing Authorization Application (MAA), sponsors must submit a Decentralized Manufacturing Master File (DMMF) that provides comprehensive instructions for completing manufacturing at decentralized sites [20]. The control site (where primary manufacturing occurs) must maintain robust quality management systems and procedures for onboarding, training, auditing, and overseeing remote manufacturing sites, treating them similarly to Contract Manufacturing Organizations (CMOs) with appropriate quality agreements [20].

Technical Approach: Automated Point-of-Care Manufacturing Platform

EASYGEN's Integrated Manufacturing Workflow

The EASYGEN platform aims to automate all manual steps between blood cell collection and administration of modified CAR-T cells, creating a seamless, closed-system workflow suitable for hospital environments. The technical approach leverages modular design principles and automation technologies originally developed by Fresenius Kabi's Cell and Gene Therapy team, enhanced through consortium collaboration [59]. The complete experimental and manufacturing workflow integrates multiple technology systems across the patient journey:

Key Technology Systems and Research Reagent Solutions

The EASYGEN platform integrates multiple proprietary and novel technology systems to achieve its ambitious manufacturing timeline. The consortium leverages specialized instrumentation and reagent systems from partner organizations to create a comprehensive point-of-care manufacturing solution.

Table: Essential Research Reagent Solutions and Technology Platforms in EASYGEN

Technology/Reagent	Provider	Function in Workflow
Lovo/Cue Cell Processing Systems	Fresenius Kabi [60]	Automated cell separation, concentration, and formulation
3D Screening Technologies	Charles River [58]	Early safety and efficacy screening of CAR-T cell candidates
Inish Analyzer	Cellix Ltd. [58]	Cell viability and counting for safety and dose monitoring
CAR Gene Transfer Vectors	TQ Therapeutics [57]	Genetic modification of T-cells for tumor targeting
Modular Manufacturing Platform	Fresenius (based on initial Kabi tech) [59]	Integrated closed-system automation of full manufacturing process

Quality Control and Analytical Methods

Comprehensive Quality Control Strategy

The EASYGEN consortium implements a multi-layered quality control strategy that addresses the unique challenges of decentralized manufacturing. The approach emphasizes real-time release testing (RTRT) methodologies where possible, recognizing the extremely short shelf-life of point-of-care manufactured products [20]. Key analytical methods focus on critical quality attributes including identity, purity, potency, viability, and cell number [61].

For the EASYGEN platform, Cellix's Inish Analyser provides critical quality control functions by measuring cell viability and cell numbers to monitor safety and ensure correct dosing of T cells before patient infusion [58]. This technology enables rapid, on-site assessment of critical quality parameters without the need for external laboratory testing, which is essential for the 24-hour manufacturing timeline.

Process Validation and Comparability Protocols

A fundamental regulatory requirement for decentralized manufacturing is demonstrating process validation and comparability between products manufactured across multiple remote sites [20]. The EASYGEN validation approach likely includes:

• Process Characterization Studies: Establishing the operating parameters and acceptance criteria for each unit operation in the automated manufacturing process.
• Site-to-Site Comparability Protocols: Demonstrating equivalence of products manufactured across different installations of the EASYGEN platform at various hospital sites.
• Closed-System Validation: Verifying the integrity and aseptic conditions of the automated closed-system processing modules throughout the entire manufacturing workflow.

The consortium's academic partners, including the Technical University of Denmark and University of Glasgow, contribute specialized expertise in process analytics and quality-by-design approaches to strengthen the validation framework [57].

Implementation Framework: Hospital Integration and Workflow Optimization

Hospital Readiness and Workforce Development

Successful implementation of point-of-care CAR-T manufacturing requires careful attention to hospital workflow integration and staff training protocols. The EASYGEN project specifically addresses these implementation challenges through collaboration with clinical partners including Helios Hospital Berlin-Buch and Quirónsalud, which have established CAR-T therapy programs [59]. The implementation framework includes:

• Workflow Mapping and Optimization: Analyzing and redesigning hospital processes to accommodate point-of-care manufacturing without disrupting other clinical operations.
• Staff Training and Certification Programs: Developing comprehensive training protocols for hospital staff operating the manufacturing platform, with emphasis on aseptic processing, equipment operation, and quality control procedures.
• Service Level Agreements: Establishing clear agreements between hospital departments (housekeeping, engineering, IT) and the manufacturing unit to ensure regulatory compliance [61].

Regulatory Documentation and Compliance Systems

The EASYGEN implementation model requires robust documentation systems to maintain regulatory compliance across decentralized manufacturing sites. Based on MHRA guidance, key documentation elements include:

• Decentralized Manufacturing Master File (DMMF): Comprehensive instructions for completing manufacturing at decentralized sites, submitted as part of Marketing Authorization Applications [20].
• Pharmacovigilance System Master File: Updated safety monitoring protocols that account for multi-site manufacturing variations and ensure rapid detection of product-quality-related safety signals [20].
• Quality Management System Documentation: Comprehensive standard operating procedures (SOPs) for the control site's oversight of remote manufacturing locations, including audit protocols, training records, and quality agreements [20].

The EASYGEN consortium represents a groundbreaking initiative that bridges technological innovation with evolving regulatory frameworks for decentralized manufacturing of advanced cell therapies. Its modular, automated platform approach addresses fundamental limitations in current CAR-T therapy models, potentially expanding access to these transformative treatments while reducing costs and manufacturing timelines. The project demonstrates the critical importance of cross-sector collaboration between industry, academia, clinicians, and regulators in advancing complex biomedical innovations.

For researchers and drug development professionals, EASYGEN offers valuable insights into the technical and regulatory requirements for successful point-of-care therapy implementation. The consortium's approach to process automation, quality control integration, and regulatory documentation provides a template for future developments in the decentralized manufacturing landscape. As regulatory frameworks continue to evolve in Europe and globally, initiatives like EASYGEN will play a crucial role in defining standards and best practices for making advanced cell and gene therapies more accessible to patients worldwide.

Conclusion

The regulatory landscape for point-of-care cell therapy manufacturing is at a pivotal juncture, with the UK's MHRA establishing a world-first, concrete framework and other regions, including the EU, actively developing their approaches. Success in this decentralized model hinges on robust quality systems, masterful tech transfer, and a highly skilled workforce. For researchers and developers, engaging early with regulators, leveraging modern technologies like AI for process control, and designing therapies with distribution in mind will be critical. The future promises greater regulatory harmonization and more sophisticated, automated platforms, ultimately accelerating the delivery of transformative, patient-specific therapies. Proactive adaptation to this evolving paradigm is no longer optional but essential for leading the next wave of advanced therapy innovation.

References

• 1. The Cell and Gene Therapy Dilemma Centralized Vs ... [https://www.cellandgene.com/doc/the-cell-and-gene-therapy-dilemma-centralized-vs-decentralized-manufacturing-0001]
• 2. Centralized vs. Point-of-Care Manufacturing [https://www.roslinct.com/insights/centralized-vs-point-of-care-manufacturing/]
• 3. Regulatory Round-up - July 2025 - Cell and Gene Therapy [https://ct.catapult.org.uk/news/regulatory-round-up-july-2025]
• 4. UK Introduces World-First Framework for Point-of-Care ... [https://www.aabb.org/news-resources/news/article/2025/07/23/uk-introduces-world-first-framework-for-point-of-care-advanced-therapies-manufacturing]
• 5. Advanced therapy medicinal products: Overview [https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview]
• 6. Regulatory Round-up - September 2025 [https://ct.catapult.org.uk/news/regulatory-round-up-september-2025]
• 7. Cell and Gene Therapy Infrastructure Market Rising ... [https://finance.yahoo.com/news/cell-gene-therapy-infrastructure-market-160000518.html]
• 8. Manufacturing Solutions for Cell and Gene Therapies [https://www.valicare.com/en/cell-and-gene-therapy/production-solutions/]
• 9. Smart cell manufacturing for therapeutic applications - CORDIS [https://cordis.europa.eu/article/id/430106-smart-cell-manufacturing-for-therapeutic-applications]
• 10. ATMPs: Authorization and Access [https://www.ppd.com/blog/present-future-advanced-therapy-medicinal-products-atmps-market-access/]
• 11. ATMPs: Chemistry, Manufacturing, and Controls [https://www.bioprocessintl.com/cell-therapies/manufacture-and-regulation-of-cell-gene-and-tissue-therapies-part-1-chemistry-manufacturing-and-control-challenges]
• 12. Navigating through Advanced Therapy Medicinal Products ... [https://ispe.org/pharmaceutical-engineering/ispeak/navigating-through-advanced-therapy-medicinal-products-atmps]
• 13. Current challenges and future directions of ATMPs in ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12274769/]
• 14. ATMP Development in 2025: Promise, Pressure, and the ... [https://www.cryoport.com/bio-blog-atmp-development-in-2025-promise-pressure-and-the-push-to-scale/]
• 15. Point-of-Care Production of CAR-T Cells - NCBI - NIH [https://www.ncbi.nlm.nih.gov/books/NBK584163/]
• 16. MHRA Issues New Regulation On Modular And Point Of ... [https://www.cellandgene.com/doc/mhra-issues-new-regulation-on-modular-and-point-of-care-manufacture-of-atmps-0001]
• 17. Unregulated advanced therapy medicinal products pose ... [https://www.ema.europa.eu/en/news/unregulated-advanced-therapy-medicinal-products-pose-serious-risks-health]
• 18. Human medicines Modular Manufacture and Point of Care ... [https://www.gov.uk/government/publications/human-medicines-modular-manufacture-and-point-of-care-regulations-2025-overview/human-medicines-modular-manufacture-and-point-of-care-regulations-2025-overview]
• 19. Decentralised Manufacturing: emerging considerations [https://mhrainspectorate.blog.gov.uk/2025/09/15/decentralised-manufacturing-emerging-considerations/]
• 20. 7 New MHRA Guidances To Help You With Decentralized ... [https://www.cellandgene.com/doc/new-mhra-guidances-to-help-you-with-decentralized-manufacturing-for-cell-and-gene-therapies-0001]
• 21. MHRA - Human medicines Modular Manufacture and Point ... [https://www.isctglobal.org/telegrafthub/blogs/fajar-dumadi/2025/07/24/uk-mhra]
• 22. CRISPR Cell and Gene Therapies: Key Challenges in ... [https://www.synthego.com/blog/crispr-cell-gene-therapy-obstacles/]
• 23. Manufacturing Authorisation of ATMPs [https://www.eurogct.org/research-pathways/manufacturing/manufacturing-authorisation-atmps]
• 24. Guidance on good manufacturing practice and good ... [https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice/guidance-good-manufacturing-practice-good-distribution-practice-questions-answers]
• 25. MHRA's Decentralized Manufacturing Regulation Set to ... [https://www.pda.org/pda-letter-portal/home/full-article/mhra-s-decentralized-manufacturing-regulation-set-to-take-effect]
• 26. Decentralised Manufacturing: New UK Framework in ... [https://www.gmp-compliance.org/gmp-news/decentralised-manufacturing-new-uk-framework-in-operation]
• 27. Point-of-care cell therapy manufacturing; it's not for everyone [https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03238-5]
• 28. Implementation of a quality management system for ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12361990/]
• 29. Isolator-based point-of-care manufacturing - PubMed Central [https://pmc.ncbi.nlm.nih.gov/articles/PMC12440961/]
• 30. EudraLex - Volume 4 - Public Health - European Commission [https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en]
• 31. Good Manufacturing Practice for ATMPs [https://www.eurogct.org/research-pathways/manufacturing/good-manufacturing-practice-atmps]
• 32. UK point-of-care production of cell therapies could arrive in ... [https://www.pharmaceutical-technology.com/analyst-comment/uk-point-of-care-production-cell-therapies/]
• 33. New legislation supports quicker and cheaper ... [https://www.anthonynolan.org/blog/2025/07/28/new-legislation-supports-quicker-and-cheaper-manufacturing-car-t-therapies]
• 34. Regulatory Round-up - May 2025 [https://ct.catapult.org.uk/news/regulatory-round-up-may-2025]
• 35. Umbrella Architectural Pattern in Telco [https://softwaremind.com/blog/leveraging-the-power-of-umbrella-architectural-pattern-in-telecom-it-systems/]
• 36. The Regulatory Framework for CAR-T Cells in Europe - NCBI [https://www.ncbi.nlm.nih.gov/books/NBK584158/]
• 37. Unified Namespace: What is UNS? (Examples and Tips) [https://www.clarify.io/learn/unified-namespace-uns]
• 38. Implementing a quality management system: best practice [https://www.ideagen.com/thought-leadership/blog/implementing-a-quality-management-system-best-practice]
• 39. Guidelines relevant for advanced therapy medicinal products [https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview/guidelines-relevant-advanced-therapy-medicinal-products]
• 40. Gibco Cell Therapy Scale Up Solutions [https://www.thermofisher.com/us/en/home/life-science/bioproduction/gibco-bioprocessing/cell-therapy.html]
• 41. Guide to Cell Therapy GMP Manufacturing for Autologous ... [https://www.thermofisher.com/blog/behindthebench/guide-to-cell-therapy-gmp-manufacturing-for-autologous-car-t-and-beyond/]
• 42. In-process Microbial Control During Aseptic Processing [https://www.pda.org/pda-letter-portal/home/full-article/in-process-microbial-control-during-aseptic-processing-medium-risk]
• 43. Regulation of Cell-Based Therapies in Europe - PubMed Central [https://pmc.ncbi.nlm.nih.gov/articles/PMC3883134/]
• 44. EMA Guideline On Clinical-Stage ATMPs Comes Into Effect [https://www.cellandgene.com/doc/ema-guideline-on-clinical-stage-atmps-comes-into-effect-on-the-verge-of-convergence-0001]
• 45. Current challenges in cell and gene therapy: a joint view ... [https://www.sciencedirect.com/science/article/pii/S1465324924000549]
• 46. From the Editors — Cell Therapy Regulation in 2025 [https://www.isctglobal.org/telegrafthub/blogs/isct-head-office1/2025/10/07/from-the-editors-cell-therapy-regulation-in-2025-a]
• 47. Optimising the manufacturing of Advanced Therapy Medicinal ... [https://cordis.europa.eu/programme/id/HORIZON_HORIZON-HLTH-2025-01-IND-01]
• 48. MHRA publishes 'world first' decentralised manufacturing ... [https://pharmaceutical-journal.com/article/news/mhra-publishes-world-first-decentralised-manufacturing-guidance]
• 49. Why gene and cell therapies are stalling at the FDA [https://www.drugdiscoverynews.com/why-gene-and-cell-therapies-are-stalling-at-the-fda-16527]
• 50. Innovative Designs for Clinical Trials of Cellular and Gene ... [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/innovative-designs-clinical-trials-cellular-and-gene-therapy-products-small-populations]
• 51. EU Data Act: Unlocking data in healthcare, life sciences ... [https://www.whitecase.com/insight-alert/eu-data-act-unlocking-data-healthcare-life-sciences-and-beyond]
• 52. Pharmaceutical Automation: Innovations Shaping an Industry [https://www.essert.com/blog/process-automation/automation-pharmaceutical-industry/]
• 53. The Benefits of Automation in Pharmaceutical Manufacturing [https://www.mrlcg.com/resources/blog/the-benefits-of-automation-in-pharmaceutical-manufacturing/]
• 54. Top Manufacturing Tech Applications in 2025 [https://www.linkedin.com/pulse/top-manufacturing-tech-applications-2025-grnpalmetto-487re]
• 55. Automation Trends to Watch in AI - IMT Solutions 2025 [https://imt-soft.com/en/2024/10/23/ai-automation-trends-to-watch-in-2025/]
• 56. Automating pharmaceutical protocol management for speed ... [https://www.nutrient.io/blog/pharmaceutical-workflow-automation/]
• 57. EASYGEN | IHI Innovative Health Initiative - European Union [https://www.ihi.europa.eu/projects-results/project-factsheets/easygen]
• 58. European decentralised CAR T manufacturing consortium ... [https://www.europeanpharmaceuticalreview.com/news/265008/european-decentralised-car-t-manufacturing-easygen-launch/]
• 59. Fresenius leads new EASYGEN consortium aimed at ... [https://www.fresenius.com/pressrelease-easygen]
• 60. Christian Hauer's Post [https://www.linkedin.com/posts/christian-hauer-a4138a31_futurefresenius-teamfresenius-committedtolife-activity-7366052019654037506-2s_q]
• 61. Cell therapy: cGMP facilities and manufacturing - PMC [https://pmc.ncbi.nlm.nih.gov/articles/PMC3666518/]