Navigating EU Regulations for Decentralized Manufacturing of ATMPs: A Strategic Guide for Drug Developers

Abstract

This article provides a comprehensive analysis of the evolving regulatory landscape for decentralized manufacturing of Advanced Therapy Medicinal Products (ATMPs) in the European Union and the United Kingdom. Tailored for researchers, scientists, and drug development professionals, it explores the foundational principles of point-of-care and modular manufacturing, details the implementation of a compliant Quality Management System with a central Control Site, and addresses critical challenges in demonstrating product comparability and managing complex supply chains. It further offers strategic guidance on regulatory engagement, process validation, and leveraging new funding opportunities, synthesizing key takeaways to support the successful development and deployment of these innovative, patient-centric production models.

Understanding Decentralized ATMP Manufacturing and the Evolving EU Regulatory Landscape

Defining Decentralized, Point-of-Care, and Modular Manufacturing for ATMPs

The development of Advanced Therapy Medicinal Products (ATMPs), including cell and gene therapies, represents a paradigm shift in medicine, offering potential one-time curative treatments for a range of diseases [1]. However, their traditional centralized manufacturing model faces significant challenges, including complex logistics, lengthy production times, and high costs, which can compromise product potency and patient access [2] [3]. Decentralized manufacturing has emerged as a transformative strategy to address these limitations by moving production closer to the patient.

This technical guide defines and differentiates three core concepts within this new paradigm: Decentralized Manufacturing, Point-of-Care (POC) Manufacturing, and Modular Manufacturing. For researchers and drug development professionals, understanding these models is critical for designing efficient, scalable, and compliant production strategies for ATMPs, particularly within the evolving European regulatory landscape [4] [5]. These approaches are particularly vital for autologous therapies, where a patient's own cells are harvested, manipulated, and reintroduced, creating a highly personalized and time-sensitive supply chain [2].

Defining the Core Concepts

The terms decentralized, point-of-care, and modular manufacturing are often used interchangeably, but they describe distinct concepts with specific applications in the ATMP field. The table below provides a structured comparison of these three core manufacturing models.

Table 1: Core Concepts in ATMP Manufacturing Modernization

Concept	Definition	Primary Application & Scale	Key Regulatory Consideration
Decentralized Manufacturing (DCM)	An umbrella term for any manufacturing model where production activities occur away from a single central facility. It encompasses both regional manufacturing hubs and hospital-based production [2] [5].	Broad; can include multiple regional sites or hospital networks serving a wider geographic area than a single hospital.	Requires a robust regulatory framework for multi-site manufacturing, ensuring product comparability across different locations [4] [5].
Point-of-Care (POC) Manufacturing	A form of decentralized manufacturing where the ATMP is produced at or very near the location where it will be administered to the patient, typically within a hospital or clinical center [2] [6].	Specific; individual hospitals or specialized units within a hospital, focusing on immediate treatment of their patient population.	The MHRA's "manufacturer's license (POC)" is a pioneering regulatory pathway for this model, with product release occurring at the central control site [4].
Modular Manufacturing	A approach to facility design and construction using prefabricated, pre-engineered units (modules) that can be assembled on-site. It can be applied to both centralized and decentralized facilities [7] [8].	Flexible; can range from small-scale POC units to large-scale centralized production facilities, emphasizing speed of deployment and flexibility.	The MHRA's "manufacturer's license (MM)" provides a pathway for licensure of relocatable modular units, which are specified in a Master File [4].

Regulatory Frameworks and Guidelines

The regulatory landscape for decentralized ATMP manufacturing is evolving rapidly, with new guidelines providing much-needed clarity for industry and academic developers.

EU Regulatory Context and Horizon Europe

Within the European Union, the overarching framework for ATMPs is established by Regulation (EC) No 1394/2007 [7] [2]. While specific EU-wide guidelines for decentralization are still developing, the Horizon Europe funding program actively encourages innovation in this area. The 2025 "Optimising the manufacturing of Advanced Therapy Medicinal Products (ATMPs" topic explicitly calls for proposals that demonstrate "the translatability, scalability, and robustness of the process suitable for flexible manufacturing (centralised or decentralised)" [1] [9]. This signals a strong regulatory and policy push towards enabling more adaptable manufacturing models to improve patient access.

The Pioneering MHRA Framework

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has established the world's first comprehensive regulatory pathway specifically for modular and point-of-care manufacture of ATMPs, effective July 2025 [4]. This framework introduces two new license types:

• Manufacturer’s License (Modular Manufacture): For activities performed in potentially relocatable modular units away from the main control site.
• Manufacturer’s License (Point of Care): For manufacturing at or near the place of product administration.

A critical feature of this model is the use of a Master File (MF). The license holder (the "control site") creates and maintains this MF, which contains full instructions for manufacturing and/or assembling the product at the satellite MM or POC locations [4]. This structure ensures that the control site retains ultimate responsibility for the quality of the product released, even when final manufacturing steps occur remotely. The diagram below illustrates the regulatory and operational relationships in this new framework.

Technical Implementation and Workflows

Implementing decentralized models requires specific technologies and workflows to ensure GMP compliance and product quality in a non-traditional setting.

Enabling Technologies: Isolators and Modular Cleanrooms

Isolator-based systems are core enabling technologies for POC manufacturing. These sealed containment devices provide a physical barrier between the operator and the manufacturing environment, maintaining an ISO Class 5 aseptic workspace within a non-classified hospital room [6]. They utilize integrated decontamination systems (e.g., vaporized hydrogen peroxide) and rapid transfer ports, making them ideal for hospital settings where full GMP cleanroom infrastructure is unavailable [6].

Modular cleanrooms offer a prefabricated, pre-engineered alternative to traditional "stick-built" cleanrooms. They are constructed from standardized sections built off-site and assembled on location, dramatically reducing deployment time from 12-18 months to just 3-6 months [7] [8]. This agility is critical for rapidly scaling ATMP production capacity and establishing decentralized facilities. Their inherent flexibility also allows for reconfiguration or expansion as processes evolve, providing long-term value [8].

Experimental Protocol: Isolator-Based POC Manufacturing of a Cell Therapy

The following detailed methodology outlines a typical workflow for producing an autologous cell therapy at the point of care using an isolator system.

Table 2: Research Reagent Solutions for POC Cell Therapy Manufacturing

Reagent / Material	Function in the Protocol	Key Quality Consideration
Cell Culture Media	Provides essential nutrients for cell survival and expansion.	Must be GMP-grade, supplemented with xeno-free or human-derived growth factors to ensure patient safety and compliance [10].
Trypsin/EDTA Solution	Enzymatically detaches adherent cells from the culture surface for sub-culturing.	GMP-grade; concentration and exposure time must be validated to maintain cell viability and phenotype [3].
Vaporized Hydrogen Peroxide (VHP)	Sporicidal agent for decontaminating the isolator chamber and all materials introduced via rapid transfer ports (RTPs) [6].	Validation of the VHP cycle (concentration, dwell time) is critical for sterility assurance. Must be compatible with materials being sterilized.
Sterile Single-Use Bioreactor	Provides a closed, controlled environment for 3D cell expansion, improving scalability and consistency over planar culture [3].	Pre-sterilized and validated for compatibility with the specific cell type; integrates with the isolator's RTPs to maintain a closed system.

Workflow Steps:

• Isolator System Decontamination: Initiate a validated automated VHP decontamination cycle for the isolator chamber and all internal equipment prior to initiating the manufacturing process. This step is critical for establishing the initial aseptic environment [6].
• Aseptic Introduction of Materials: Transfer all pre-sterilized raw materials, including GMP-grade media, cytokines, and the patient's apheresis material, into the isolator via sealed containers attached to RTPs. This maintains the integrity of the closed system [6].
• Cell Processing and Culture:
  • Within the isolator, manipulate cells using integrated glove ports.
  • For immune cell therapies (e.g., CIK, NK cells), activate the patient's cells using GMP-grade cytokines and antibodies.
  • Transfer cells to a sterile single-use bioreactor within the isolator for expansion. This automated, closed-system bioreactor reduces human handling and variability [3].
  • Monitor key process parameters like pH, dissolved oxygen, and glucose concentration using integrated, automated sensors.
• In-process Quality Control (IPC):
  • At defined intervals, withdraw small samples for in-process testing.
  • Automated cell counters and analyzers within or adjacent to the isolator can assess cell count, viability, and potentially phenotype.
  • For more complex assays (e.g., potency, sterility), samples are transferred out of the isolator but are considered destructive testing.
• Final Formulation and Harvesting: Once the target cell number or phenotype is achieved, harvest the cells from the bioreactor. The final product is aseptically formulated into the infusion bag within the isolator.
• Final Product Release: The filled product bag is transferred out of the isolator. While the POC site performs the physical assembly, the legal batch release is conducted by the Qualified Person (QP) at the central control site, based on review of all manufacturing and QC data transmitted electronically, as per the MHRA's POC model [4].

The following diagram visualizes this end-to-end workflow and the critical control points.

Decentralized, point-of-care, and modular manufacturing are not merely synonyms but represent a cohesive and innovative strategy to overcome the primary barriers in the ATMP sector. Decentralization provides the overarching business and regulatory model, point-of-care manufacturing enables radical supply chain compression for faster patient treatment, and modular approaches offer the physical infrastructure to deploy these facilities with unprecedented speed and flexibility [7] [4] [2].

For researchers and developers in the EU, this evolving landscape, supported by initiatives like Horizon Europe and clarified by pioneering regulations from the MHRA, presents a clear path forward. Success will depend on the strategic integration of advanced technologies like isolator systems and process automation with robust quality management systems designed for multi-site control. By adopting these models, the field can advance beyond overcoming manufacturing hurdles to truly fulfilling the promise of ATMPs: providing transformative, curative treatments to patients in a timely and accessible manner.

Autologous cell therapies represent a paradigm shift in personalized medicine, using a patient's own cells to treat conditions like cancer and autoimmune diseases. Unlike conventional drugs, these Advanced Therapy Medicinal Products (ATMPs) require a complex, patient-specific journey from cell collection to reinfusion. This process faces significant hurdles in manufacturing capacity, stringent logistics, and timely delivery. Decentralized manufacturing models, supported by evolving regulatory frameworks like the European Medicines Agency (EMA) and the UK's Medicines and Healthcare products Regulatory Agency (MHRA), are emerging as a critical solution. These models, which include modular and point-of-care manufacturing, aim to enhance patient access, reduce transit times, and alleviate capacity constraints, thereby ensuring these transformative therapies can fulfill their potential.

Autologous cell therapies are highly personalized treatments where a patient's own cells are harvested, processed, and reintroduced. This approach minimizes risks of immune rejection and enables long-term remission for various severe conditions [11] [12]. The global autologous cell therapy market is projected to grow from an estimated $6.37 billion in 2025 to $29.96 billion by 2033, reflecting a compound annual growth rate (CAGR) of 21.35% [11]. Another analysis estimates the market will grow from $5 billion in 2025 at a CAGR of 25% through 2033 [13]. In North America alone, the market was valued at $5.41 billion in 2024 and is expected to reach $11.69 billion by 2031 [14].

This remarkable growth is driven by the clinical success of these therapies, particularly in oncology. However, their personalized nature creates a fundamental manufacturing and logistical challenge: each treatment is a unique batch produced for a single patient [15]. Scaling up does not mean producing larger batches, but rather managing an exponentially growing number of individual, patient-specific batches [16] [15]. This, coupled with a severe shortage in manufacturing capacity—estimated at 500% for cell and gene therapies—creates a critical bottleneck that threatens patient access [17].

Core Challenges: A Detailed Analysis

The development and delivery of autologous therapies are fraught with interconnected challenges that span manufacturing, logistics, and regulation.

The Manufacturing and Capacity Crunch

The centralized manufacturing model, where a single facility serves a wide geographic area, is struggling to support the scale-up of autologous therapies.

• High Costs and Complex Processes: Manufacturing approved CAR-T treatments can cost between $200,000 and $800,000 per dose [15]. The process is resource-intensive, requiring expensive raw materials and significant labor inputs [16].
• Extended Turnaround Times: The vein-to-vein time—from cell collection from the patient to reinfusion of the finished therapy—can span several weeks [12]. For patients with rapidly progressing diseases, this delay can render the treatment ineffective.
• Lack of Scalability: The "service-based" model of autologous therapies means that increasing patient volume requires a proportional increase in manufacturing suites and staff, which is neither economically sustainable nor practically feasible with current technologies [12]. Lead times for contracting manufacturing organizations (CMOs) to begin new projects can exceed 18 months, further stifling development [17].
• Product and Process Variability: Starting material from different patients exhibits significant variability in quality, potency, and stability [10]. This donor-to-donor variability makes it challenging to establish standardized, reproducible manufacturing processes that consistently yield a safe and effective product [16] [12].

The Logistical and Supply Chain Labyrinth

The living nature of the therapeutic product necessitates a supply chain that is fundamentally different from and more complex than that of traditional pharmaceuticals.

• Stringent Temperature and Time Constraints: Cellular starting material and the final drug product have very short shelf lives, sometimes as little as a few hours ex vivo [12]. They must be transported under strict temperature-controlled conditions, typically in liquid nitrogen (cryogenic conditions) or at refrigerated temperatures, within extremely tight door-to-door transport windows of 40-50 hours or less [15].
• Chain of Identity and Custody: Given that each therapy is personalized to a specific patient, maintaining an unbreakable chain of identity (COI) and chain of custody throughout the entire journey is paramount. Any error can lead to a patient receiving the wrong therapy, with devastating consequences [12] [15].
• Coordination Complexity: The process requires flawless coordination between the clinical site (for cell collection and patient conditioning), the manufacturing site, and logistics providers. This includes aligning apheresis schedules, manufacturing capacity, and transport logistics, a task often managed manually in early stages but requiring sophisticated IT solutions at commercial scale [15].

Regulatory and Standardization Hurdles

The unique nature of autologous ATMPs presents novel challenges for regulators and developers alike.

• Demonstrating Comparability: For decentralized manufacturing, a major regulatory hurdle is demonstrating that the product manufactured at multiple sites is comparable in quality, safety, and efficacy [17]. Process changes or different facility environments can contribute to product variability [10].
• Lack of Standardization: A significant bottleneck lies in the lack of standardization at clinical sites. The processes for onboarding sites for clinical trials or commercial treatments can take months or even years, particularly for smaller institutions lacking internal expertise [16].
• Evolving Regulatory Landscape: While regulators like the MHRA have introduced pioneering frameworks for point-of-care manufacturing [4] [17], the field is still evolving. Navigating these new and sometimes differing regulatory pathways across regions adds complexity to global development.

Table 1: Quantitative Overview of Autologous Cell Therapy Market and Challenges

Aspect	Metric	Source
Global Market (2025)	$6.37 Billion (Est.)	[11]
Projected Global Market (2033)	$29.96 Billion	[11]
Projected CAGR (2025-2033)	21.35% - 25%	[11] [13]
North America Market (2024)	$5.41 Billion	[14]
Manufacturing Capacity Shortfall	~500%	[17]
Typical Transport Time	40-50 hours	[15]
Manufacturing Cost per Dose (CAR-T)	$200,000 - $800,000	[15]

The Paradigm Shift: Decentralized Manufacturing as a Solution

Decentralized manufacturing is a promising strategy to overcome the challenges of capacity, logistics, and timeliness. It involves manufacturing products at multiple sites under central management, often at or near the point of patient care (POCare) [17].

Regulatory Frameworks Enabling Decentralization

Regulatory agencies are actively creating pathways to facilitate decentralized manufacturing.

• The MHRA's Pioneering Framework: The UK's MHRA has introduced two new licenses: the "manufacturer’s license (modular manufacturing, MM)" and the "manufacturer’s license (Point of Care, POC)" [4] [17]. This model relies on a Control Site that holds the license and maintains a Master File with full manufacturing instructions. The Control Site is responsible for supervising and ensuring compliance at all satellite manufacturing units, which follow the Master File. Crucially, product release occurs at the main Control Site, simplifying the regulatory process at the point-of-care [4].
• FDA and EMA Perspectives: The FDA's Center for Drug Evaluation and Research (CDER) has initiated the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), which includes distributed manufacturing as a platform for POCare production [17]. The EMA has also acknowledged that decentralized manufacturing could help address supply chain challenges and improve medicine accessibility [17].

Technological and Operational Enablers

The practical implementation of decentralized models relies on technological innovations.

• Automated Closed-System Technologies: To minimize process variability and human error, automated, closed-system bioreactors and processing platforms are essential. These systems reduce the infrastructure requirements at treatment facilities, allowing them to operate in lower-grade cleanrooms while maintaining GMP compliance [17].
• Deployable Manufacturing Units: Concepts like "GMP-in-a-box"—prefabricated, modular units that can be quickly deployed—enable rapid and flexible expansion of manufacturing capacity to regional hubs or large hospital networks [17].
• Advanced Digital Infrastructure: Robust IT systems are required for scheduling, tracking, and maintaining chain of identity. This includes real-time monitoring of shipments and seamless data integration between clinical sites, the Control Site, and satellite manufacturing units [15].

The following workflow diagram illustrates the material and information flow within a decentralized manufacturing model for autologous therapies, highlighting the central role of the Control Site.

The Scientist's Toolkit: Key Reagents and Technologies

Implementing robust and scalable autologous therapy processes requires a suite of specialized reagents and technologies. The following table details critical components for research, development, and manufacturing.

Table 2: Essential Research Reagent Solutions and Technologies

Category	Specific Examples / Functions	Critical Role in Autologous Therapy
Cell Culture Media	Serum-free, xeno-free media; Activation/expansion cytokines (e.g., IL-2)	Provides defined, GMP-compliant environment for cell growth and genetic modification; critical for maintaining cell viability and potency [16].
Genetic Modification Tools	Viral vectors (Lentivirus, Retrovirus); CRISPR-Cas9 reagents; mRNA for transient expression	Enables engineering of patient cells (e.g., CAR-T cells) to target specific diseases; key to therapeutic mechanism of action [13].
Cell Separation & Activation Reagents	Antibody-coated beads (e.g., for T-cell activation); Magnetic cell separation kits	Isulates and activates target cell populations (e.g., T-cells) from apheresis material, initiating the manufacturing process [16].
Cryopreservation Solutions	GMP-grade DMSO; Cryopreservation media	Protects cell viability during long-term storage and transport, essential for managing logistics and scheduling [18] [15].
Analytical Quality Control Kits	Flow cytometry panels; PCR for vector copy number; Sterility, endotoxin, and mycoplasma tests	Ensures final product meets release specifications for identity, purity, potency, and safety; required for batch release [10] [16].
Automated Bioreactors	Closed-system, scalable bioreactors	Enables scalable cell expansion in a controlled, sterile environment, reducing manual labor and variability; key for decentralization [10] [17].

Detailed Experimental Protocol: A Model for Process Validation

To ensure that a decentralized manufacturing process consistently produces a therapy that meets pre-defined quality attributes, a rigorous comparability study must be conducted. The following protocol outlines the key steps for validating a process across multiple manufacturing sites.

Objective: To demonstrate that an autologous cell therapy product manufactured at a proposed Point-of-Care (POC) site is comparable to the product manufactured at the established Centralized (Control) site.

Methodology:

• Study Design:

  • A paired sample design is recommended. A single donor's apheresis material will be split into two equal aliquots.
  • One aliquot will be processed at the Centralized (Control) manufacturing site using the validated process.
  • The second aliquot will be processed at the POC (Test) manufacturing site using the identical, Master File-defined process and the same batch of critical reagents.

• Critical Quality Attributes (CQA) Assessment: Both the Control and Test final drug products must be characterized against a comprehensive panel of CQAs. Analytical methods must be qualified and consistent across sites. Testing should include:

  • Identity and Phenotype: Flow cytometry to confirm the presence of target cells (e.g., CD3+ for T-cells) and expression of the therapeutic transgene (e.g., CAR).
  • Potency: Functional assays such as in vitro cytotoxic activity against target tumor cells and cytokine secretion profiles.
  • Purity and Viability: Measures of cell viability (e.g., by trypan blue exclusion) and composition of impurities (e.g., residual non-target cells).
  • Safety: Sterility (bacteria/fungi), mycoplasma, and endotoxin testing. For iPSC-derived products, in vivo teratoma formation assays are used to detect residual undifferentiated cells. For somatic cells, more sensitive in vitro assays like digital soft agar colony formation are recommended over traditional methods [10].

• Process Parameter Monitoring: Key process parameters such as cell growth kinetics, metabolic profiles (e.g., glucose consumption), and transduction efficiency should be monitored and shown to be equivalent between the two sites.

• Data Analysis and Acceptance Criteria:

  • Results for CQAs from the POC site must fall within pre-specified acceptance ranges, which are often based on the historical data and variability of the Control site's process.
  • Statistical analysis (e.g., equivalence testing) should be applied where appropriate to conclusively demonstrate comparability.

This rigorous experimental approach provides the necessary data to support regulatory submissions for decentralized manufacturing, ensuring that product quality and patient safety are maintained regardless of the manufacturing location.

The critical challenges of logistics, capacity, and timeliness in autologous therapies are not insurmountable. The convergence of innovative regulatory frameworks, advanced automated technologies, and fit-for-purpose quality management systems paves the way for decentralized manufacturing models. By moving production closer to the patient, the field can overcome the crippling bottlenecks of centralized production, significantly reduce vein-to-vein times, and ultimately make these life-changing therapies accessible to a broader patient population. Continued collaboration between industry, regulators, and healthcare providers is essential to fully realize the promise of decentralized manufacturing and deliver on the transformative potential of autologous cell therapies.

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, tissue-engineered products, and combined ATMPs, represent a paradigm shift in therapeutic interventions for conditions with limited treatment options [19]. These innovative treatments are subject to a complex regulatory framework within the European Union (EU), balancing centralized authorization procedures with specific national provisions [20]. The framework is designed to ensure patient safety and product quality while fostering innovation in this rapidly evolving field. For developers and manufacturers of ATMPs, particularly those exploring decentralized manufacturing models, navigating this regulatory landscape requires thorough understanding of both EU-wide guidelines and Member State implementations [21] [22].

The core EU legislation for ATMPs is established in Regulation (EC) No 1394/2007, which classifies these products and sets specific requirements for their authorization, supervision, and pharmacovigilance [20]. This regulation works in conjunction with the general pharmaceutical legislation (Directive 2001/83/EC and Regulation (EC) No 726/2004) while addressing the distinctive nature of ATMPs [20]. A fundamental characteristic of the EU system is the mandatory centralized authorization procedure through the European Medicines Agency (EMA), resulting in a single marketing authorization valid across all Member States [19] [20]. However, this centralized approach is complemented by the Hospital Exemption (HE) clause, which allows for the preparation and use of ATMPs under specific conditions at the national level, creating a dual-path system that is particularly relevant for decentralized manufacturing sites [21].

EU-Level Regulatory Framework

Centralized Authorization and Key Institutions

The European Medicines Agency (EMA) serves as the cornerstone of the EU regulatory framework for ATMPs. Within EMA, the Committee for Advanced Therapies (CAT) plays a pivotal role in the scientific assessment of ATMPs [19] [20]. The CAT is responsible for preparing draft opinions on the quality, safety, and efficacy of ATMPs, which then inform the final opinion of the Committee for Medicinal Products for Human Use (CHMP) [20]. Based on the CHMP's recommendation, the European Commission grants a marketing authorization that is valid across the entire EU [20]. This centralized procedure ensures harmonized oversight for these complex therapies, which often involve novel manufacturing processes and technologies.

Beyond the assessment of marketing authorization applications, the CAT provides recommendations on ATMP classification, evaluates applications for certification of quality and non-clinical data for small and medium-sized enterprises (SMEs), and contributes scientific advice on ATMP development [19]. This comprehensive involvement positions the CAT as a central scientific body shaping the regulatory environment for advanced therapies. The certification procedure for SMEs is particularly noteworthy as it provides a mechanism for early regulatory feedback on quality and non-clinical data, potentially de-risking development before substantial investment in clinical trials [19].

EudraLex Volume 4 and Good Manufacturing Practice (GMP) Requirements

EudraLex Volume 4 contains the Good Manufacturing Practice (GMP) guidelines governing medicinal products in the European Union [23]. Part IV of EudraLex Volume 4 specifically addresses GMP requirements for Advanced Therapy Medicinal Products [23]. These guidelines are crucial for ensuring that ATMPs are consistently produced and controlled according to quality standards appropriate for their intended use. The GMP framework for ATMPs takes into account their unique characteristics, including their biological nature, often limited shelf life, and frequently patient-specific application.

Table: Key Elements of EudraLex Volume 4, Part IV - GMP for ATMPs

Element	Description	Relevance to Decentralized Manufacturing
Pharmaceutical Quality System	Risk-based approach covering all manufacturing activities	Essential for multi-site manufacturing operations
Personnel Requirements	Specific qualifications and training for staff handling ATMPs	Critical for ensuring competency across decentralized sites
Premises and Equipment	Controlled environments for aseptic processing	Challenging to standardize across multiple locations
Documentation	Comprehensive traceability from starting materials to final product	Complex but crucial for decentralized models
Quality Control	In-process controls and final product testing	Requires robust strategy for multi-site operations

For ATMP manufacturers, compliance with GMP requirements is mandatory regardless of the authorization pathway (centralized or hospital exemption) [21]. The guidelines address the entire manufacturing process, from the qualification of starting materials of human origin (which themselves are subject to quality and safety standards under the Substances of Human Origin (SoHO) Regulation) through to the finished product [20] [22]. Recent regulatory developments include new guidelines on "quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials," applicable from July 1, 2025, which further refine expectations for ATMP development [20].

Ongoing Regulatory Evolution

The regulatory framework for ATMPs continues to evolve rapidly, reflecting scientific advancements and practical experience gained since the implementation of the ATMP Regulation. Several key developments are particularly relevant for decentralized manufacturing:

The Health Technology Assessment (HTA) Regulation ((EU) 2021/2282), which became applicable in January 2025, introduces joint clinical assessments for ATMPs at the EU level [24]. This regulation aims to align evidence requirements between regulators and HTA bodies, potentially streamlining market access decisions across Member States [24]. For ATMP developers, this means that evidence generation strategies must consider both regulatory and HTA requirements from early development stages.

The SoHO Regulation ((EU) 2024/1938), published in July 2024 and applicable from 2027, will replace existing directives on blood, cells, and tissues [20] [22]. This regulation establishes more stringent standards for substances of human origin intended for human application and introduces new oversight mechanisms, including the establishment of SoHO national authorities and authorization systems for SoHO preparations [20]. The relationship between the ATMP and SoHO frameworks is particularly important for cell-based therapies, and the new regulation may influence the classification of certain lower-risk cell-based ATMPs [22].

Recent updates to EudraLex Volume 4 also include draft revisions to Annex 11 (Computerised Systems) and the introduction of a new Annex 22 (Artificial Intelligence), published for consultation in July 2025 [25]. These updates reflect the increasing digitalization of manufacturing processes and the adoption of advanced technologies in ATMP production, which have implications for decentralized manufacturing models utilizing innovative technologies.

National Provisions and Hospital Exemption

The Hospital Exemption Pathway

The Hospital Exemption (HE) constitutes a critical exception to the centralized authorization requirement for ATMPs. Article 3(7) of Directive 2001/83/EC, as modified by the ATMP Regulation, excludes from the scope of EU pharmaceutical legislation those "advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient" [21]. This pathway enables hospitals to prepare and use ATMPs without obtaining a centralized marketing authorization, subject to specific conditions and national oversight.

The HE pathway is particularly relevant for decentralized manufacturing models as it inherently operates at the hospital or local level. However, EU law mandates that Member States implement certain requirements for exempted ATMPs, including authorization of the manufacturing by the national competent authority, and the establishment of national traceability, pharmacovigilance, and specific quality standards equivalent to those applicable to centrally authorized ATMPs [21]. Despite these harmonizing requirements, significant heterogeneity exists in how Member States interpret and implement the HE clause [21] [22].

Table: Key Concepts and Interpretations in Hospital Exemption

Concept	EU Definition	National Interpretation Variations
Non-routine basis	Not expressly defined in EU binding law	Based on scale/frequency; some states set patient number limits while others require treatment "one by one"
Custom-made product	Not expressly defined in EU binding law	Ranges from strictly patient-specific to small batch production for defined patient groups
Specific quality standards	Must be equivalent to centrally authorized ATMPs	Differences in specific GMP implementation and clinical evidence requirements
Hospital setting	Not comprehensively defined	Varies from public hospitals only to inclusion of private entities; different supervision models

National Implementation and Challenges

The implementation of the Hospital Exemption across EU Member States reveals significant fragmentation, creating a complex landscape for developers and healthcare providers [21] [22]. National differences extend to multiple aspects of the HE pathway, including:

• Eligible approval holders: Some Member States limit HE to public hospitals, while others allow private entities to obtain authorization [21].
• Clinical evidence requirements: The level of evidence required for HE authorization varies between states, impacting development timelines and costs [21].
• Interpretation of "non-routine basis": Approaches range from strict numerical limits on patient numbers to more flexible interpretations based on the product and clinical context [21].
• Duration of approval: Authorization periods range from one year to several years, with varying requirements for renewal [21].
• Intended purpose of HE: Differences exist regarding whether HE should be used for early development, treatment outside clinical trials, compassionate use, or as an alternative to marketing authorization [21].

A particularly challenging aspect concerns the interplay between HE and centralized authorization. The European Commission has emphasized that HE should not undermine the centralized authorization system, but practical questions remain regarding the use of data generated through HE pathways to support marketing authorization applications [21]. This creates uncertainty for developers considering a progression from hospital-based development to broader commercialization.

The European Commission has initiated studies and proposed legislative changes to address these challenges. A study on hospital exemption launched in September 2023 aims to map HE pathways across Member States and analyze their interplay with other regulatory frameworks [21]. Additionally, the 2023 proposal for a revision of the general pharmaceutical legislation includes new provisions for improved data collection and reporting on ATMPs produced under HE [21] [22].

Regulatory Framework for Decentralized Manufacturing

Quality System and Documentation Requirements

Decentralized manufacturing of ATMPs presents unique regulatory challenges, particularly in maintaining consistent quality across multiple manufacturing sites. The Pharmaceutical Quality System required under EudraLex Volume 4, Chapter 1 provides the foundation for ensuring product quality in decentralized models [23]. This system must be comprehensive and well-documented, with clear lines of responsibility and accountability across all manufacturing sites.

Recent revisions to EU GMP guidelines emphasize data integrity and governance throughout the product lifecycle. The 2025 draft revision of Chapter 4 (Documentation) introduces significantly expanded requirements for data governance systems, incorporating the ALCOA++ principles (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Traceable) [26]. For decentralized manufacturing, this means implementing robust systems that ensure data integrity across multiple locations, with particular attention to:

• Electronic documentation systems that maintain data integrity while allowing appropriate access across sites
• Harmonized Standard Operating Procedures for all manufacturing sites
• Centralized quality oversight with defined mechanisms for escalation of issues
• Data traceability throughout the product lifecycle, from starting materials to patient administration

The draft revision also requires a risk-based approach to data management, assessing both data criticality (impact on product quality and decisions) and data risk (likelihood of alteration or deletion) [26]. This is particularly relevant for decentralized models where manufacturing processes may be adapted to local resources while maintaining overall quality standards.

Supply Chain and Starting Material Controls

Decentralized ATMP manufacturing involves complex supply chains for starting materials, particularly when utilizing substances of human origin (SoHO). The upcoming SoHO Regulation ((EU) 2024/1938), applicable from 2027, will establish comprehensive standards for quality and safety of all human-origin substances intended for human application [20] [22]. This regulation introduces:

• SoHO national authorities with authorization, oversight and control functions
• Authorization systems for SoHO preparations with specific clinical indications
• Distinction between SoHO entities (subject to registration) and SoHO centres (subject to authorization) based on the nature of activities involving substances
• Enhanced donor protection measures, including provisions on voluntary donation and informed consent [20]

For decentralized ATMP manufacturing, compliance with both the ATMP framework and SoHO regulation requires meticulous traceability systems and quality agreements with all suppliers of starting materials. The complex interface between these regulatory frameworks necessitates careful planning, particularly regarding the classification of products as either ATMPs or SoHO products, which has implications for the applicable regulatory requirements [22].

Table: Key Regulatory Instruments Impacting Decentralized ATMP Manufacturing

Regulatory Instrument	Scope/Application	Key Requirements for Decentralized Manufacturing
ATMP Regulation (EC) No 1394/2007	All ATMPs in EU	Defines ATMP categories; establishes centralized authorization procedure; creates Committee for Advanced Therapies (CAT)
EudraLex Vol 4, Part IV GMP for ATMPs	Manufacturing of ATMPs	Specific GMP requirements for ATMPs; quality system requirements; personnel qualifications
SoHO Regulation (EU) 2024/1938	Substances of human origin intended for human application (from 2027)	Quality and safety standards for starting materials; donor protection; traceability requirements
HTA Regulation (EU) 2021/2282	Joint Clinical Assessments for ATMPs (from 2025)	Evidence requirements for relative effectiveness assessments; parallel scientific consultations with regulators
Directive 2001/83/EC (as amended)	Medicinal products for human use	Hospital exemption provisions; national implementation requirements

The Scientist's Toolkit: Regulatory Compliance for ATMP Manufacturing

Successfully navigating the regulatory landscape for decentralized ATMP manufacturing requires careful attention to multiple aspects of regulatory compliance. The following table outlines key components of the "regulatory toolkit" for scientists and developers operating in this space.

Table: Essential Components for ATMP Regulatory Compliance

Component	Function/Purpose	Application in Decentralized Manufacturing
Quality Management System	Ensures consistent product quality and regulatory compliance	Must be implemented across all manufacturing sites with centralized oversight
Data Integrity Framework	Maintains ALCOA++ principles for all GMP records	Critical for ensuring data reliability across multiple locations; requires robust electronic systems
Change Control Procedures	Manages changes to processes, equipment, or materials	Essential for maintaining consistency when implementing changes across decentralized sites
Quality Risk Management	Proactive identification and control of potential quality issues	Enables risk-based approach to managing differences between manufacturing sites
Supplier Qualification	Ensures starting materials meet required quality standards	Particularly important for SoHO-based materials with complex supply chains
Stability Program	Demonstrates product quality over time	Must account for potential variations in storage conditions across sites
Container Closure System	Maintains product sterility and stability during storage and transport	Critical for products shipped between manufacturing and administration sites
Environmental Monitoring	Controls particulate and microbial contamination	Must be standardized across all manufacturing sites
Process Validation	Demonstrates manufacturing process consistency and robustness	Challenging for patient-specific products; often employs continuous verification approaches

The regulatory framework for ATMPs in the European Union represents a carefully balanced system that combines centralized oversight with national implementation flexibility, particularly through the Hospital Exemption pathway. For decentralized manufacturing models, this creates both opportunities and challenges, requiring developers to navigate EU-level requirements while accommodating national variations in implementation [21] [22].

The landscape continues to evolve rapidly, with several significant developments on the horizon:

• The ongoing revision of the general pharmaceutical legislation may introduce changes to the Hospital Exemption, including improved data collection and reporting requirements [21] [22].
• The implementation of the SoHO Regulation from 2027 will create a more harmonized framework for starting materials of human origin, potentially influencing the classification of certain lower-risk cell-based ATMPs [20] [22].
• The application of the HTA Regulation to ATMPs from 2025 introduces new evidence requirements that must be considered in development programs, potentially influencing clinical trial design and endpoint selection [24].
• Technological advances in manufacturing, including the use of artificial intelligence and advanced analytics, are driving updates to GMP guidelines, as reflected in the draft Annex 22 on AI [25].

For researchers, scientists, and drug development professionals working in the ATMP field, understanding this dynamic regulatory landscape is essential for successful development and implementation of decentralized manufacturing models. The interplay between EU guidelines and national provisions requires careful navigation, but also offers opportunities for innovative approaches to making these transformative therapies available to patients.

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has established a world-first regulatory framework for decentralized manufacturing (DM) of medicinal products, effective July 23, 2025 [27] [28]. This pioneering legislation introduces two new license types: Manufacturer's Licence (Point of Care - POC) and Manufacturer's Licence (Modular Manufacture - MM) [28] [29]. Designed to address the unique challenges of advanced therapy medicinal products (ATMPs) and other innovative medicines, this "hub and spoke" model enables manufacturing closer to patients, potentially transforming the accessibility and supply chain logistics for personalized therapies [27] [30]. This whitepaper provides an in-depth technical analysis of these new regulations, offering strategic implementation guidance for researchers and drug development professionals operating within the global ATMP landscape.

Decentralized Manufacturing (DM) refers to the production of medicinal products at multiple locations under central management, close to where patients receive care [30]. For ATMPs, particularly autologous cell therapies, this paradigm shift from traditional centralized manufacturing addresses critical challenges including complex logistics, limited shelf lives, and manufacturing capacity constraints [17] [31].

The MHRA's new framework creates a regulated pathway for innovative manufacturing approaches that were previously hampered by legislation designed for fixed-site, factory-based production [29]. The regulatory driver is clear: to ensure patients can access innovative medicines that cannot be practically delivered through traditional centralized manufacturing, without compromising quality, safety, or efficacy [27]. The UK is the first country to implement a tailored framework of this kind, positioning itself at the forefront of advanced therapy regulation [4] [30].

Analysis of the MHRA's 2025 Regulatory Framework

Legislative Foundation

The framework is established through The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025 (Statutory Instrument 2025 No. 87), which amends the Human Medicines Regulations 2012 and the Medicines for Human Use (Clinical Trials) Regulations 2004 [28]. The legislation underwent a six-month implementation period following its signing on January 23, 2025 [27] [28].

License Types and Definitions

The framework introduces two distinct manufacturing pathways with precise legal definitions, as summarized in the table below.

Table 1: Key Definitions in the MHRA's Decentralized Manufacturing Framework

Term	Legal Definition	Key Characteristics
POC Medicinal Product	A 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 the place where the product is to be used or administered" [28] [29].	- Very short shelf life (seconds/minutes) [29]- Highly personalized [27]- Manufactured at time of patient need
MM Medicinal Product	A product that "for reasons related to deployment, the licensing authority determines it necessary or expedient to be manufactured or assembled in a modular unit" [28] [29].	- Relocatable manufacturing units [29]- Faster deployment (e.g., pandemics) [27]- Scale-out rather than scale-up
Manufacturer's Licence (POC)	A manufacturer's licence that relates to the manufacture or assembly of the POC medicinal products specified in that licence [28] [29].	- "Hub and spoke" model [30]- POC Control Site maintains oversight- POC Master File required
Manufacturer's Licence (MM)	A manufacturer's licence that relates to the manufacture or assembly of the MM medicinal products specified in that licence [28] [29].	- "Hub and spoke" model [30]- MM Control Site maintains oversight- MM Master File required

The Control Site Model and Regulatory Architecture

The regulatory framework operates on a "hub and spoke" model, where a central Control Site holds the manufacturing license and supervises operations across multiple decentralized manufacturing sites [30]. The Control Site serves as the single point of regulatory contact and maintains the DM Master File (DMMF)—a detailed description of manufacturing arrangements across all sites [27] [17]. This model ensures regulatory oversight while providing the flexibility needed for distributed manufacturing.

The diagram below illustrates the fundamental regulatory structure and relationships within this new framework.

Implementation Guide for ATMP Developers and Researchers

Application Process and Designation Step

The MHRA has established a designation step where applicants must demonstrate their product meets the legal criteria for either POC or MM classification [27] [30]. This critical first step provides regulatory clarity before full application submission.

Table 2: MHRA Application Timeline and Key Requirements

Process Stage	Timeline	Key Requirements	Strategic Considerations
Designation Step	60-90 days [27]	- Justification for DM classification [27]- Background product information [27]	Early engagement is encouraged; designation provides regulatory certainty for investment [27].
Formal Application	Standard MIA timeline with specific DM assessment	- Detailed DMMF [27]- Control Site details [29]- Process validation data across sites	Application triggers inspection of systems and controls coordinated with DMMF [27].
Licence Variation	Standard variation procedure	- Updated DMMF- Additional site information	Existing MIA or MS holders can vary their licence to add POC or MM [27] [29].

Quality Management System Framework

A robust, Control Site-centric Quality Management System (QMS) is fundamental to successful DM implementation. The QMS must ensure consistent product quality across all manufacturing sites through [17]:

• Standardized Manufacturing Platforms: Use of automated, closed-system technologies to minimize process variability and operator dependency [17] [31].
• Centralized Oversight: The Control Site must demonstrate effective supervision of all decentralized sites, including audit procedures and quality assurance [17].
• Comparability Protocols: Extensive data demonstrating product comparability across different manufacturing locations is required [17].

The following diagram details the core functional relationships and workflows that a DM QMS must govern.

Operational Requirements and Technical Protocols

Qualified Person (QP) Release

The QP can nominate an individual independent of the manufacturing and clinical team to release POC products, but the license holder must demonstrate [27]:

• Consistency in the release process across all sites.
• How oversight will be maintained by the QP.
• A robust process for review of the release activities.

Pharmacovigilance and Traceability

For DM products, the pharmacovigilance system master file (PSMF) must include all control and manufacturing sites [27]. License holders must demonstrate [27]:

• How adverse events are collected, allocated, and evaluated across multiple healthcare settings.
• How the Qualified Person for Pharmacovigilance (QPPV) maintains oversight of all sites.
• Robust batch traceability systems throughout the product lifecycle.

Labeling Exemptions

A labeling exemption exists for POC medicines manufactured for immediate administration where no portion of the product is retained after administration [27]. In such cases, using "pre-applied patient identified" on primary packaging is recommended [27].

Essential Research Reagents and Technological Solutions

Successful implementation of DM for ATMPs requires specific technological solutions to ensure consistency and quality across multiple sites. The table below outlines key categories of these enabling technologies.

Table 3: Research Reagent Solutions and Essential Materials for Decentralized ATMP Manufacturing

Solution Category	Specific Examples	Function in Decentralized Manufacturing
Automated Closed-System Platforms	CliniMACS Prodigy, Lonza Cocoon [31]	Integrated, automated manufacturing within functionally closed, single-use kits; reduces operator-dependent variability and lower cleanroom requirements [17] [31].
Deployable Manufacturing Units	"GMP-in-a-box" [17], prefabricated units [29]	Relocatable, self-contained GMP environments enabling rapid establishment of manufacturing capacity in non-traditional locations (e.g., hospitals) [17] [29].
Process Analytical Technologies (PAT)	In-line and at-line monitoring systems	Provide real-time data on critical process parameters (CPPs) to ensure process consistency and product quality across different sites; enables real-time release [30].
Single-Use Bioreactors & Disposables	Functionally closed bioreactors, sterile tube welders [31]	Maintain aseptic processing in decentralized environments; eliminate cross-contamination risks and reduce validation burden between batches [31].

Strategic Implications for the ATMP Sector

The MHRA's pioneering framework presents significant opportunities for the ATMP sector:

• Improved Accessibility: DM can dramatically improve patient access to autologous ATMPs by reducing complex logistics and enabling fresh product administration [17] [31].
• Supply Chain Resilience: Distributed manufacturing networks mitigate risks associated with centralized production and complex global supply chains [32].
• Economic Sustainability: Reduced transportation costs, inventory holding, and product losses may improve the economic model for personalized therapies [4] [31].

However, challenges remain in implementing robust comparability protocols and standardized automated platforms across multiple sites [17]. The "hub and spoke" model, while innovative, places significant responsibility on the Control Site to maintain consistent quality and oversight [27] [17].

The MHRA's 2025 POC and Modular Manufacturing licenses represent a fundamental shift in pharmaceutical regulation, creating a tailored pathway for the next generation of medicines. This world-first framework positions the UK as a regulatory pioneer in advanced therapy manufacturing. For researchers and drug development professionals, understanding and leveraging this framework is crucial for advancing ATMPs and other innovative medicines through decentralized models. As experience with DM grows, this regulatory approach will likely evolve and potentially influence international standards through organizations like the International Coalition of Medicines Regulatory Authorities (ICMRA) [30]. The successful implementation of this framework could accelerate the global availability of transformative, personalized therapies.

The European regulatory and funding landscape is undergoing a significant transformation to foster innovation in Advanced Therapy Medicinal Products (ATMPs), particularly those manufactured at decentralized sites. The European Medicines Agency's (EMA) Network Strategy to 2028 and the European Union's Horizon Europe 2025 Work Programme represent two pivotal, interconnected drivers. For researchers, scientists, and drug development professionals, understanding the synergy between these initiatives is crucial for navigating the regulatory framework and securing necessary funding. This whitepaper provides an in-depth technical analysis of these key drivers, framed within the context of advancing decentralized manufacturing for ATMPs.

EMA Network Strategy to 2028: A Focus on Agility and Innovation

The European medicines regulatory network, comprising the EMA and the national competent authorities (NCAs) of EU Member States, has adopted a strategic plan extending to 2028. This strategy is designed to equip the network to respond effectively to change and emerging health threats while fostering a resilient ecosystem for medicinal products [33].

Strategic Pillars and Relevance to ATMPs

The strategy is built around six core focus areas, each with specific implications for ATMP development and decentralized manufacturing:

• Leveraging Data, Digitalisation and Artificial Intelligence: This pillar aims to improve regulatory decision-making and increase efficiency by harnessing new data sources and digital tools [33]. For decentralized ATMP manufacturing, this could facilitate the real-time monitoring of critical quality attributes at point-of-care sites and enable more robust comparability assessments between batches produced across different locations.
• Regulatory Science, Innovation and Competitiveness: A primary goal is to help improve innovation and competitiveness within the EU healthcare sector [33]. The strategy explicitly aims to support the development of novel manufacturing platforms, which directly encompasses the advanced technologies required for decentralized ATMP production.
• Accessibility and Availability: The network seeks to facilitate access to medicines across the EU and strengthen the supply chain to protect public health [33]. Decentralized manufacturing models can directly address these goals by improving patient access to bespoke ATMPs, particularly those with short shelf-lives, and by mitigating risks associated with centralized supply chains.

Table 1: Key Strategic Pillars of the EMA Network Strategy to 2028 and Their Impact on ATMPs

Strategic Pillar	Key Objectives	Relevance to ATMP Decentralized Manufacturing
Leveraging Data & AI	Improve decision-making, optimise processes	Enables real-time quality monitoring and batch comparability across sites.
Regulatory Science & Innovation	Boost EU competitiveness and innovation	Supports development of novel, scalable manufacturing platforms.
Accessibility & Availability	Facilitate access to medicines, strengthen supply chains	Improves patient access to bespoke therapies and enhances supply resilience.
Antimicrobial Resistance & Health Threats	Prepare for potential health threats	Provides a flexible framework for rapid response with novel biological therapies.
Network Sustainability	Ensure available resources for regulatory decisions	Builds capacity to evaluate complex, decentralized production models.

The Regulatory Pathway for ATMPs

ATMPs, which include gene therapies, somatic-cell therapies, and tissue-engineered products, are subject to a centralized marketing authorization procedure coordinated by the EMA's Committee for Advanced Therapies (CAT) [19]. The regulatory pathway is stringent, emphasizing robust quality, safety, and efficacy data. The Network Strategy's focus on regulatory science is particularly vital for navigating the complexities of ATMPs, where small batch sizes, use of biological materials, and complex manufacturing processes present unique challenges [34]. The strategy’s alignment with the One Health approach further underscores the interconnectedness of human, animal, and environmental health, which is relevant for ATMPs derived from biological sources [33].

Horizon Europe 2025: Funding Innovation and Research Careers

The Horizon Europe programme is the EU's key financial instrument for research and innovation, with an indicative budget of €93.5 billion for 2021-2027 [35]. The 2025 Work Programme specifically allocates €7.3 billion to support a more competitive, fair, and resilient Europe, with a substantial part dedicated to green and digital transitions [36].

Key Funding Opportunities for ATMP Research

The 2025 Work Programme presents several targeted funding avenues relevant to ATMP development:

• Marie Skłodowska-Curie Actions (MSCA): With a budget of €1.25 billion, the MSCA supports researchers' careers through doctoral networks, postdoctoral fellowships, and staff exchanges [36]. These actions are critical for building the specialized scientific and technical expertise required to advance ATMP manufacturing technologies.
• Food, Bioeconomy, Natural Resources, Agriculture and Environment: This cluster, with a budget of €948.9 million, funds research into sustainable use of natural resources and bioeconomy [36]. This can support upstream innovation in sourcing and processing biological materials for ATMPs.
• Research Infrastructures: An allocation of €400.5 million aims to strengthen the capacities of research infrastructures and develop advanced digital solutions [36]. This funding can be leveraged to establish and validate the specialized, GMP-compliant infrastructure necessary for decentralized manufacturing nodes.

Table 2: Selected Horizon Europe 2025 Funding Areas Relevant to ATMP Development

Programme Area	2025 Indicative Budget	Relevant Funding Topics
Marie Skłodowska-Curie Actions (MSCA)	€1.25 billion	Doctoral networks, postdoctoral fellowships, staff exchanges to build research capacity.
Food & Bioeconomy	€948.9 million	Sustainable use of natural resources, advanced bioprocessing.
Research Infrastructures	€400.5 million	Strengthening research capacities, developing advanced digital tools.
Widening Participation	€128 million	Spreading excellence, supporting research institutions in widening countries.
Culture & Creative Society	€275.10 million	Addressing challenges related to health, incl. mental health and disabilities.

Synergy in Action: Driving Decentralized ATMP Manufacturing

The true potential for innovation in decentralized ATMP manufacturing lies at the intersection of the EMA's regulatory strategy and Horizon Europe's funding power. The Network Strategy creates a regulatory environment that is increasingly adaptable to novel manufacturing concepts, while Horizon Europe provides the financial resources to generate the necessary technical and scientific evidence.

A Conceptual Workflow for Regulatory and Funding Strategy

The following diagram visualizes the integrated workflow for navigating the regulatory and funding landscape to advance decentralized ATMP manufacturing, from foundational research to market access.

The Scientist's Toolkit: Essential Research Reagent Solutions for ATMP Process Development

The development and validation of a decentralized ATMP manufacturing process require a suite of specialized reagents and materials. The table below details key solutions and their functions in critical experiments.

Table 3: Key Research Reagent Solutions for ATMP Process Development

Research Reagent / Material	Function in Experimental Protocols
Cell Separation Kits (e.g., Ficoll, CDx+ magnetic beads)	Isolate and enrich specific cell populations (e.g., T-cells, stem cells) from starting material (apheresis, tissue biopsy) for subsequent manipulation. Critical for process reproducibility.
Cell Culture Media (Serum-free & Xeno-free)	Support the expansion and maintenance of cells during the manufacturing process. Defined, xeno-free formulations are essential for regulatory compliance and minimizing variability.
Activation/Transduction Reagents (e.g., Retro/Lentiviral vectors, mRNA)	Introduce genetic material into cells (e.g., for CAR-T therapies) or activate them for expansion. The quality and consistency of these reagents are vital for product efficacy and safety.
Critical Quality Attribute (CQA) Assay Kits (e.g., flow cytometry, ELISA)	Quantify identity (phenotype), potency (functional activity), and purity (e.g., residual contaminants) of the final ATMP product and in-process samples.
Cryopreservation Media	Maintain cell viability and functionality during transport and storage between centralized and decentralized manufacturing sites or before patient infusion.

Navigating the Hospital Exemption and Regulatory Flexibilities

A critical aspect of the ATMP regulation is the Hospital Exemption (HE) clause, which allows for the use of non-centrally authorized ATMPs manufactured on a non-routine basis within a specific member state [37]. However, the application of HE varies significantly across member states, creating a fragmented landscape [37]. The EMA Network Strategy's emphasis on regulatory agility and harmonization is pertinent here, as it could lead to more consistent interpretation of the HE, facilitating managed access to ATMPs from decentralized hospital sites while ensuring patient safety. Furthermore, the ATMP pilot for academia and non-profit organisations launched by the EMA provides dedicated regulatory support, including fee reductions, to help these entities navigate the complex regulatory pathway [19].

The concurrent implementation of the EMA Network Strategy to 2028 and the Horizon Europe 2025 Work Programme creates a powerful, synergistic framework for advancing the field of ATMPs in the EU. For researchers and drug development professionals, the path forward involves a proactive, integrated approach: designing research projects that not only seek Horizon Europe funding but also actively generate the robust data required to satisfy the evolving regulatory expectations of the EMA network. By aligning scientific innovation with strategic regulatory and funding priorities, the vision of making decentralized, patient-specific advanced therapies more accessible and available across Europe can become a tangible reality.

Implementing a Compliant Decentralized Manufacturing Model: The Control Site and QMS Framework

Decentralized manufacturing has emerged as a transformative approach for Advanced Therapy Medicinal Products (ATMPs), particularly for autologous therapies where patient-specific cells are manipulated and returned to the same patient [17]. This model, which involves manufacturing at multiple sites including regional facilities or certified treatment centers close to the patient, addresses critical challenges of scalability, accessibility, and logistical complexity associated with centralized manufacturing [17]. The intrinsic variability of starting materials, complex logistics, and limited shelf-life of these living therapies necessitate manufacturing solutions that are both geographically distributed and rigorously controlled [17] [34].

Within this decentralized framework, the Central Control Site serves as the pivotal regulatory and quality nexus, ensuring consistency, compliance, and product quality across multiple manufacturing locations [17]. As defined in emerging regulatory frameworks, the Control Site is the holder of the manufacturing license for modular or point-of-care manufacturing and maintains ultimate responsibility for supervising decentralized manufacturing activities [4]. This whitepaper examines the core functions, regulatory responsibilities, and operational frameworks of the Central Control Site, providing a technical guide for researchers and drug development professionals navigating the evolving landscape of ATMP regulations in the EU and UK.

Regulatory Foundation: The Control Site in Evolving ATMP Frameworks

The regulatory recognition of Central Control Sites represents a significant evolution in ATMP governance. The European medicines regulatory network has identified decentralized manufacturing as a priority area, acknowledging that closed, easy-to-operate systems could be used in hospital pharmacies or operating theaters to provide customized products for individual patients [17]. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has established a pioneering regulatory framework that explicitly defines and licenses Control Sites for modular and point-of-care manufacture [4].

Table 1: Regulatory Framework Evolution for Control Sites

Regulatory Body	Initiative/Framework	Key Control Site Provisions	Status/Timeline
MHRA (UK)	Manufacturer's License (Point of Care) & Manufacturer's License (Modular Manufacture)	Control Site holds manufacturing license, creates and maintains Master File, supervises satellite sites [4]	Effective July 2025 [4]
European Commission	EU Pharmaceutical Legislation Revision	Proposed derogation allowing decentralized sites to operate under qualified person of a central site [34]	Under negotiation
EMA/HMA Network	Network Strategy 2025	Recognition of decentralized manufacturing potential for improving accessibility [17]	Ongoing implementation

The MHRA's framework creates two new license categories: the "manufacturer's license (MM)" for modular manufacturing and the "manufacturer's license (POC)" for point-of-care manufacturing [4]. The holders of these licenses are designated as Control Sites, creating a regulatory architecture where a single entity maintains oversight of distributed manufacturing activities. This model employs a Master File (MF) process, similar to the Drug Master File system, where the Control Site creates detailed manufacturing instructions that satellite sites must follow [4].

Core Functions of the Central Control Site

Regulatory Nexus and Oversight Functions

The Control Site serves as the primary interface between the decentralized manufacturing network and regulatory authorities, consolidating regulatory accountability that would otherwise be fragmented across multiple sites. According to current regulatory developments, the Control Site acts as the "primary focus point for interaction with regulatory agencies" [17]. This centralized regulatory interface streamlines communications, submissions, and inspections for complex manufacturing networks that might span numerous clinical sites, hospitals, or even countries.

Key regulatory responsibilities include:

• License Maintenance: Holding the manufacturer's license for modular or point-of-care production [4]
• Master File Management: Creating, maintaining, and updating the Master File that specifies manufacturing processes for all satellite sites [4]
• Regulatory Submissions: Serving as the single point of contact for all regulatory submissions and communications [17]
• Inspection Coordination: Coordinating and hosting regulatory inspections for the entire decentralized network [17]

Quality Management and Assurance

The Control Site establishes and maintains an integrated Quality Management System that spans all decentralized manufacturing locations. This system must ensure that products manufactured across different sites maintain consistent quality attributes, despite geographical distribution [17]. The QMS integrates current Good Manufacturing Practice principles with specific adaptations for decentralized operations [17].

Table 2: Quality Management System Components for Decentralized Manufacturing

System Component	Control Site Responsibility	Implementation Mechanism
Quality Assurance	Provision of overarching quality assurance systems [17]	Standardized SOPs, training platforms, audit systems
Qualified Person (QP)	Provision of Qualified Person oversight [17]	Centralized batch certification and release
Documentation Control	Maintenance of POCare Master Files [17]	Master File defining processes for all sites
Process Validation	Ensuring process comparability across sites [17]	Validation protocols, hardware standardization
Change Control	Managing process changes across network [17]	Centralized change management system

Technical Operations and Process Control

A critical technical function of the Control Site is establishing and maintaining process comparability across all manufacturing sites. As noted in regulatory guidance, "differences between manufacturing facilities may contribute to product variability" and sponsors must "demonstrate that a comparable product is manufactured at each location" [17]. The Control Site addresses this challenge through several technical mechanisms:

• Platform Standardization: Implementing standardized, automated, closed-system manufacturing platforms across all sites to minimize process variability [17]
• Process Characterization: Defining critical process parameters and quality attributes that are consistently monitored and controlled [38]
• Analytical Comparability: Ensuring analytical methods are comparable across different sites through method validation and technology transfer protocols [17]
• Data Management: Implementing centralized data collection and analysis systems to monitor process performance across the network [17]

Operational Framework and Implementation

Control Site Architecture and Organizational Structure

The operational framework of a Control Site requires specialized organizational capabilities and clear delineation of responsibilities across the manufacturing network. The structure must facilitate oversight while enabling operational flexibility at distributed locations.

Diagram 1: Control Site Operational Architecture

Master File Structure and Content

The Master File serves as the technical foundation for decentralized manufacturing operations, containing comprehensive information that enables consistent production across multiple sites. While specific requirements may vary by jurisdiction, the core components typically include:

• Manufacturing Process Description: Detailed, step-by-step manufacturing instructions with defined critical process parameters [4]
• Facility and Equipment Specifications: Standardized requirements for manufacturing environments, equipment, and systems [17]
• Quality Control Testing: Defined analytical methods, specifications, and testing protocols for in-process, release, and stability testing [38]
• Raw Material Specifications: Qualified materials and components with approved suppliers and testing requirements [38]
• Training and Qualification: Standardized training programs and personnel qualification requirements [17]

The Master File is a living document maintained by the Control Site, with updates managed through a centralized change control process. Under the MHRA framework, "updating will be as simple as that for a DMF and will not require the manufacturing license to be resubmitted or a variation written for it" [4], providing important regulatory flexibility for process improvements.

The Scientist's Toolkit: Essential Components for Control Site Implementation

Table 3: Research and Implementation Toolkit for Control Site Establishment

Tool/Component	Function/Purpose	Technical Considerations
Automated Closed Systems	Minimizes process variability and operator dependence; enables deployment in lower-grade cleanrooms [17]	Must be validated for consistent performance across multiple units; integration with central data systems
Master File Template	Regulatory document defining manufacturing process for all sites [4]	Should accommodate platform processes while allowing product-specific parameters
Centralized Data System	Collects and analyzes process data from all manufacturing sites for continuous monitoring [17]	Must enable real-time data access while maintaining data integrity and security
Standardized Training Platform	Ensures consistent operator training and qualification across all sites [17]	Should include competency assessment and requalification protocols
Quality Attribute Framework	Defines Critical Quality Attributes (CQAs) and target ranges for product quality assessment [38]	Must demonstrate correlation with safety and efficacy; establishes release specifications

Technical Protocols and Methodologies

Process Comparability Protocol

Demonstrating comparability across decentralized manufacturing sites requires a systematic, data-driven approach. The following protocol provides a methodology for establishing and maintaining process comparability:

Objective: To demonstrate that the ATMP manufactured at multiple decentralized sites exhibits comparable critical quality attributes, ensuring consistent safety and efficacy profiles regardless of manufacturing location.

Experimental Design:

• Define Critical Quality Attributes: Identify product-specific CQAs that potentially impact safety, purity, potency, or efficacy based on mechanism of action and previous studies [38]
• Establish Acceptance Ranges: Define statistically based acceptance ranges for each CQA using data from manufacturing experience and clinical batches
• Execute Parallel Manufacturing: Manufacture multiple batches across different sites using the same Master File and standardized materials
• Comprehensive Testing: Perform analytical testing on all batches using validated, standardized methods across sites
• Statistical Analysis: Apply statistical models (e.g., equivalence testing, multivariate analysis) to compare CQA data across sites

Key Parameters and Acceptance Criteria:

• Potency Measures: Biological activity should fall within predefined equivalence margins (typically 80-125% of reference)
• Identity and Purity: Should meet identical specifications across all sites
• Process-Related Impurities: Should demonstrate comparable profiles and fall within safety-based limits
• Product Variants: Should show comparable profiles and ratios

Site Qualification Methodology

Qualifying new manufacturing sites within a decentralized network requires a rigorous assessment protocol:

Protocol:

• Infrastructure Assessment: Verify facility design, environmental controls, and equipment qualification
• Technology Transfer: Execute predefined technology transfer protocol with knowledge transfer from Control Site
• Performance Qualification: Manufacture a minimum of three consecutive batches meeting all predefined specifications
• Comparative Analysis: Demonstrate statistical equivalence of CQAs with established manufacturing sites
• Quality System Audit: Conduct comprehensive audit of local quality systems and their integration with Control Site systems

The establishment of Central Control Sites represents a paradigm shift in ATMP manufacturing, enabling the scalability and accessibility required to bring these transformative therapies to broader patient populations while maintaining rigorous quality standards. The regulatory framework for these entities is rapidly evolving, with the UK's MHRA establishing a comprehensive pathway and EU authorities considering similar approaches.

For researchers and drug development professionals, understanding the roles, responsibilities, and technical requirements of Control Sites is essential for navigating the future of decentralized ATMP manufacturing. Successful implementation will depend on robust quality systems, standardized platform technologies, and sophisticated data management capabilities that enable centralized oversight of distributed operations. As regulatory frameworks mature and operational experience accumulates, Control Sites will play an increasingly critical role in realizing the full potential of advanced therapies for patients worldwide.

The Decentralized Manufacturing Master File (DMMF) is emerging as a critical regulatory document for implementing decentralized production strategies for Advanced Therapy Medicinal Products (ATMPs) within the European Union. Decentralized manufacturing describes production at multiple sites under central management, while point-of-care (POC) manufacturing occurs at or near the patient's treatment location [17]. This approach addresses significant challenges in ATMP production, particularly for autologous therapies with limited shelf lives and complex logistics [34] [17]. The European medicines regulatory network has recognized that traditional centralized manufacturing models create capacity constraints and accessibility barriers for these innovative treatments [17].

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has established the first comprehensive regulatory framework for this innovative manufacturing approach, creating two new license types: the manufacturer's license (Modular Manufacture - MM) and the manufacturer's license (Point of Care - POC) [27] [4]. The DMMF serves as the cornerstone document under this framework, providing the detailed information necessary to ensure consistent quality and GMP compliance across all manufacturing locations [27]. The control site—the central regulatory nexus—maintains responsibility for the DMMF and supervises all decentralized manufacturing operations [17]. This technical guide examines the content requirements and lifecycle management strategies for developing a comprehensive DMMF that meets EU regulatory expectations for ATMPs.

DMMF Content Requirements and Structure

Core Components and Regulatory Specifications

The DMMF must provide a complete description of the decentralized manufacturing model and demonstrate robust control over all production sites. Based on the MHRA's new framework, the DMMF should contain the following essential components [27] [4]:

• Location and Status of Manufacturing Sites: A comprehensive list of all authorized sites, including the control site and all modular units or POC locations, with their current operational status.
• Contact Details: Specific contact information for quality management personnel at each site, including the Qualified Person (QP) responsible for batch certification.
• Product and Process Details: Complete descriptions of the ATMP(s) manufactured under the framework and their detailed manufacturing processes.
• Procedures and Protocols: Standardized procedures that ensure consistent operations across all sites, covering manufacturing, quality control, and handling of deviations.

The control site holds ultimate responsibility for creating and maintaining the DMMF, serving as the single point of contact for regulatory agencies [17]. This centralized oversight model ensures that any process carried out at decentralized locations meets mandatory EU GMP standards, despite the geographical distribution of manufacturing activities [34].

Quantitative Data Requirements for DMMF Sections

Table 1: Key Documentation Requirements for DMMF Submission

DMMF Section	Required Information	Regulatory Reference
Site Information	List of all manufacturing locations (control site + secondary sites); Contact details; Site status	[27]
Product Description	Comprehensive details on ATMP type (GTMP, sCTMP, TEP); Specific characteristics; Starting materials	[27] [19]
Manufacturing Process	Detailed, step-by-step production instructions; Process parameters; In-process controls	[4] [17]
Quality Control	Testing methods and specifications; Release criteria; Analytical method validation	[27] [34]
Personnel	Organizational structure; QP details; Staff qualifications and training records	[34] [17]

Process Comparability and Quality Control

For ATMPs manufactured across multiple decentralized sites, demonstrating process comparability is a fundamental requirement [17]. The DMMF must contain comprehensive validation data showing that different manufacturing locations produce equivalent products. This includes:

• Process Validation Data: Evidence that the same critical process parameters and quality attributes are maintained across all sites.
• Analytical Method Comparability: Demonstration that testing methods produce equivalent results when performed at different locations.
• Product Characterization: Extensive data showing consistent critical quality attributes (CQAs) in products manufactured across the decentralized network.

A robust Contamination Control Strategy must be documented within the DMMF, aligned with PIC/S Annex 2A and EMA's GMP specific to ATMPs [39]. For cell-based ATMPs that cannot be sterile filtered due to cell size, the DMMF must detail alternative aseptic processing controls and monitoring procedures [39]. The DMMF should reference ICH Q5A (R2) guidance on viral safety, particularly for processes like lentiviral vector production where conventional viral clearance may not be feasible [39].

Lifecycle Management of the DMMF

Change Management and Regulatory Reporting

Effective lifecycle management of the DMMF requires a systematic approach to managing changes while maintaining regulatory compliance. The MHRA's framework establishes specific obligations for DMMF maintenance [27]:

• Annual Reporting: License holders must submit annual reports documenting all updates and changes to the DMMF.
• Material Alteration Notification: Any material changes to the control site or modular units must be promptly notified to the regulatory authority.
• Change Classification: Modifications must be classified based on risk (Type IA, IB, or II) according to the EU Variations Guidelines [40] [41].

The European Commission's new Variations Guidelines, effective January 2025, provide a streamlined framework for managing post-approval changes through a risk-based classification system [40] [41]. When managing DMMF changes, manufacturers should utilize tools like Post-Approval Change Management Protocols (PACMPs) to pre-plan for anticipated changes and Product Lifecycle Management (PLCM) documents to track changes throughout the product lifecycle [40] [41].

Diagram: DMMF Lifecycle Management Workflow

DMMF Lifecycle Management Workflow: This diagram illustrates the continuous process of maintaining regulatory compliance for the Decentralized Manufacturing Master File, from initial development through routine maintenance and change management.

Pharmacovigilance and Batch Traceability

Throughout the product lifecycle, the DMMF must support robust pharmacovigilance and complete batch traceability [27]. The license holder must demonstrate:

• Adverse Event Management: Processes for collecting, allocating, and evaluating adverse events across all manufacturing sites.
• Qualified Person for Pharmacovigilance (QPPV) Oversight: Clear documentation of how the QPPV maintains oversight of pharmacovigilance activities across the decentralized network.
• Batch Tracking: Systems to track products and batches throughout the manufacturing and distribution chain, integrating multiple healthcare settings.

The decentralized manufacturing framework requires that all control and manufacturing sites be included in the Pharmacovigilance System Master File (PSMF) [27]. The license holder must also demonstrate how they will identify whether issues at one site represent isolated incidents or affect multiple locations within the network [27].

Implementation Strategies and Technical Requirements

Experimental Protocols for Process Validation

Implementing a successful decentralized manufacturing model requires rigorous validation protocols to ensure consistent product quality across sites. The following methodologies are essential for DMMF development:

• Protocol 1: Multi-Site Process Comparability Study

  • Objective: To demonstrate that different manufacturing sites produce ATMPs with equivalent critical quality attributes.
  • Methodology: Manufacture multiple batches of the ATMP at three different sites using identical starting materials, processes, and equipment. Test critical quality attributes using validated analytical methods at a central quality control laboratory.
  • Acceptance Criteria: No statistically significant differences (p < 0.05) in potency, identity, purity, or safety attributes between sites. All batches must meet pre-defined specifications.

• Protocol 2: Closed System Validation for POC Manufacturing

  • Objective: To validate that automated closed-system technologies can maintain sterility and product quality in lower-grade cleanrooms.
  • Methodology: Perform media fills and process simulations using the closed system technology in a representative POC environment. Challenge the system with worst-case scenarios and monitor for contamination.
  • Acceptance Criteria: Zero growth in media fill units. Consistent product quality attributes meeting pre-defined specifications across all runs.

Essential Research Reagent Solutions

Table 2: Key Reagents and Materials for Decentralized ATMP Manufacturing

Reagent/Material	Function in Decentralized Manufacturing	Application Example
Closed System Automated	Enables manufacturing in lower-grade cleanrooms by	Automated CAR-T cell processing
Bioreactors	reducing contamination risk and operator dependency	systems [17]
Cell Separation	Isolation and purification of specific cell populations	Magnetic bead-based separation
Reagents	from heterogeneous starting materials	of T-cells for CAR-T therapy
Cryopreservation	Maintains cell viability during storage and	Dimethyl sulfoxide (DMSO) based
Media	transportation between centralized and decentralized sites	cryoprotectant solutions
Vector Production	Genetic modification of cells for gene therapy	Lentiviral or retroviral vectors
Systems	products or genetically-modified cell therapies	for CAR-T cell engineering
Sterility Testing	Ensures microbial safety of final ATMP products	BacT/ALERT culture system
Kits	through rapid and sensitive detection methods	for rapid sterility testing

Regulatory Pathway and Submission Strategy

The regulatory pathway for DMMF approval follows a structured designation process [27]:

• Early Application: Sponsors are encouraged to apply early once data indicate their product meets DM designation criteria.
• Designation Process: The regulatory authority issues a decision on DM designation within 60-90 days, depending on whether additional information or meetings are required.
• Documentation Requirements: The application must provide comprehensive background information and justification for why the product meets the legal basis for decentralized manufacturing.

Manufacturers holding existing licenses can submit a variation to add POC or MM licenses to their authorization [27]. According to the MHRA, such applications will trigger an inspection that assesses systems and controls in coordination with the DMMF [27].

The Decentralized Manufacturing Master File represents a paradigm shift in how ATMPs are regulated and manufactured in the European Union. By providing a comprehensive framework for controlling quality across multiple manufacturing sites, the DMMF enables the scale-out of ATMP production while maintaining the high quality standards required for patient safety. The successful implementation of a DMMF requires meticulous attention to content details, robust change management processes, and rigorous validation protocols to ensure comparability across sites. As the EU continues to refine its regulatory approach to decentralized manufacturing, the DMMF will play an increasingly important role in making ATMPs more accessible to patients while ensuring consistent quality, safety, and efficacy.

Designing the Overarching Quality Management System (QMS) for Multi-Site Oversight

The field of Advanced Therapy Medicinal Products (ATMPs), encompassing cell and gene therapies, is undergoing a pivotal transformation in its manufacturing paradigm. Decentralized manufacturing has emerged as a critical solution to overcome the significant challenges posed by traditional centralized production, particularly for autologous therapies which are patient-specific [17]. This model involves manufacturing at multiple sites, including Point of Care (POC) locations near the patient or Modular Manufacturing (MM) units, under a central management system [42] [17].

The drivers for this shift are compelling. The cell and gene therapy sector is experiencing an estimated 500% shortage in manufacturing capacity, with contract manufacturing organization (CMO) lead times exceeding 18 months [17]. For autologous therapies with very short shelf-lives, decentralized manufacturing mitigates complex logistics and time constraints, enabling faster and more cost-effective patient treatment [17]. Regulatory bodies, including the EMA, FDA, and MHRA, have recognized this need and are developing frameworks to facilitate decentralized production while ensuring rigorous quality, safety, and efficacy standards [42] [17]. This whitepaper provides a technical guide for designing a robust, overarching Quality Management System (QMS) essential for successful multi-site oversight in this novel manufacturing environment.

Regulatory Framework for Decentralized ATMPs

A comprehensive understanding of the evolving regulatory landscape is fundamental to QMS design. Key regulatory concepts and specific regional requirements are summarized in the table below.

Table 1: Key Regulatory Concepts in Decentralized Manufacturing

Concept/Term	Definition	Regulatory Source
Control Site	The central, licensed manufacturing site acting as the regulatory hub responsible for supervising all decentralized manufacturing sites.	MHRA, EU Pharmaceutical Package Reform [17] [43]
Point of Care (POC)	A medicinal product that, due to its method of manufacture, short shelf-life, or nature, can only be manufactured at or near its place of use/administration.	MHRA [42]
Modular Manufacturing (MM)	A medicinal product determined by the licensing authority as necessary or expedient to be manufactured or assembled in a modular unit for public health or significant clinical advantage.	MHRA [42]
Master File (DMMF/POCare MF)	The central manufacturing dossier (e.g., Decentralized Manufacturing Master File) containing all critical regulatory and process documents for a product, maintained by the Control Site.	MHRA, EU Framework [42] [17] [43]

Regional Regulatory Perspectives

• MHRA (UK): The UK has pioneered a tailored framework, operational from July 2025, introducing two new license types: the "manufacturer’s license (modular manufacturing)" and the "manufacturer’s license (Point of Care)" [42] [43]. This framework establishes the "Control Site" model, which holds the primary manufacturing license and supervises satellite sites, which do not need their own separate approvals [43]. The MHRA has released seven supporting guidances covering designation, Marketing Authorization Applications (MAA), Clinical Trial Authorization (CTA), GMP, Pharmacovigilance, and Labeling [42].

• EMA (EU): The EU's regulatory network strategy acknowledges decentralized manufacturing as a future model to enhance medicine accessibility [17]. The 2025 EMA Guideline on clinical-stage ATMPs serves as a multidisciplinary reference, with a significant portion dedicated to Chemistry, Manufacturing, and Controls (CMC), providing a roadmap for organizing information in clinical trial applications [44]. While the new EU Pharmaceutical Package includes a proposed Directive for decentralized manufacturing, the UK's framework is the first to be implemented [43].

• FDA (US): The FDA's Emerging Technology Program includes the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), which proposes Distributed Manufacturing as a platform for POCare manufacturing [17]. In its draft guidance on CAR-T cell products, the FDA acknowledges multi-site manufacturing but emphasizes that sponsors must demonstrate comparability of the product across all locations [17].

Core Architecture of an Overarching QMS for Multi-Site Oversight

The transition to decentralized manufacturing requires a QMS that is both robust and adaptable. The proposed architecture is built on a "Control Site" model, which acts as the regulatory and operational nexus.

The Control Site Model and Centralized QMS

The Control Site is the single point of contact for regulatory agencies and holds ultimate responsibility for the quality of products manufactured across the entire network [17]. Its functions, enabled by a centralized QMS, include:

• Maintaining the Master File: Housing and controlling the Decentralized Manufacturing Master File (DMMF) or POCare Master File for each product [42] [17].
• Oversight and Governance: Implementing a robust system for onboarding, auditing, suspending, and pausing remote manufacturing sites [42].
• Quality Assurance (QA) and Qualified Person (QP): Providing central QA oversight and a designated QP responsible for certifying product releases, where applicable [17].
• Training Platform: Establishing and managing a standardized, overarching training program to ensure consistent personnel competency across all sites [17].

The following diagram illustrates the logical structure and information flow within this model.

Essential QMS Components and Features for 2025

A modern QMS must integrate specific features to manage the complexity of multi-site operations effectively. The following table summarizes the priorities for a decentralized manufacturing context.

Table 2: Priority QMS Features for Multi-Site ATMP Oversight

QMS Feature	Application in Decentralized Manufacturing	Reference
Cloud-Based Architecture	Enables real-time access for global teams across all sites without VPNs; supports seamless updates and continuous validation.	[45]
End-to-End Process Integration	Unifies document control, training, CAPA, and change management across the network, creating a single source of truth.	[45]
Real-Time Analytics & Dashboards	Provides Control Site with live visibility into performance, compliance metrics, and overdue tasks at all remote sites.	[45] [46]
AI-Enabled Insights	Uses risk prediction and trend analysis to flag anomalies in deviations, CAPAs, and complaints across the network.	[45]
Interoperability (APIs)	Allows the QMS to connect with other critical systems at remote sites (e.g., EHR, LIMS) for consistent data flow.	[45]
Built-In Validation Support	Provides pre-configured documentation for FDA 21 CFR Part 11, EU Annex 11, and ISO 13485 compliance, easing multi-site validation.	[45]

Methodologies for Validation and Ensuring Comparability

A cornerstone of regulatory success in decentralized manufacturing is the ability to validate processes and demonstrate product comparability across all manufacturing sites.

Process Validation and Comparability Protocols

Regulators require evidence that a comparable product is manufactured at each location within the network [17]. The methodology for demonstrating this involves:

• Defining Critical Quality Attributes (CQAs): Identify the product's physicochemical, biological, and functional characteristics that must be within an appropriate range to ensure product quality.
• Establishing a Standardized Platform: Implement a standardized, closed-system, automated manufacturing platform across all sites to minimize process variability and human error [17]. This is often described as a "GMP-in-a-box" approach [17].
• Executing a Comparability Study: Conduct a pre-defined study comparing products manufactured at the Control Site with those manufactured at each remote site. The study should use validated, comparable analytical methods across all locations [17].
• Utilizing Real-Time Release Testing (RTRT): For many autologous products with short shelf-lives, RTRT is essential. The QMS must contain the data to support this strategy, ensuring release is based on in-process data rather than end-product testing alone [42].

The Risk-Based QMS and Monitoring

The new quality management standards require a proactive, risk-based approach, shifting from "quality by tradition" to "quality by design" [47]. The operational workflow for this is outlined below.

The risk assessment process is continuous [48] [47]:

• Establish Quality Objectives: Define desired outcomes for governance, resources, and engagement performance across the network.
• Identify and Assess Quality Risks: Brainstorm potential failures (e.g., site-specific deviations, training inconsistencies) that could prevent achieving quality objectives.
• Design and Implement Responses: Deploy policies, procedures, and technological controls (e.g., automated monitoring) to mitigate identified risks.
• Monitoring and Remediation: Continuously monitor the system's performance, evaluate findings, identify root causes of deficiencies, and implement effective remediation [48].

Implementation Toolkit for Researchers and Scientists

Successful implementation of a multi-site QMS requires a combination of strategic planning, specific technical tools, and robust contractual governance.

Research Reagent Solutions and Essential Materials

Table 3: Essential "Reagents" for Multi-Site QMS Implementation

Tool / Material	Function in QMS Implementation
Centralized Cloud QMS Platform	Serves as the technological backbone for document control, data sharing, and real-time dashboards across all sites [45] [46].
Automated, Closed-System Bioreactors	The core manufacturing platform at remote sites; minimizes human intervention and process variability, ensuring consistency [17].
Standardized Audit & Compliance Templates	Customizable checklists within the QMS to ensure all sites meet standardized and site-specific regulatory requirements [46].
Automated Roll-Up Reporting Software	Transforms raw data from multiple sites into actionable intelligence and executive-level reports for the Control Site [46].
Digital Training Platform	Delivers and tracks standardized training modules to ensure personnel competency and consistent procedures across the network [17].

Implementation and Governance Strategies

• Phased Implementation: A structured, phased approach is recommended. Begin by assigning core roles (e.g., Ultimate Responsible Individual), then conduct the risk assessment, design responses, and finally prepare for ongoing monitoring [47].
• Contractual and Governance Frameworks: The Control Site must have robust contracts with all satellite sites. These must mandate compliance with the master file, permit audits and inspections, define intellectual property ownership for process improvements, and establish clear liability and safety reporting protocols [43].
• Role of the Qualified Person (QP): The QP's role is multiplied in a decentralized model. The business must ensure QPs have the necessary support and resources to oversee the entire network effectively, a role sometimes conceptualized as a "Super QP" [43].

Designing an overarching QMS for multi-site oversight is no longer a theoretical exercise but a practical necessity for the future of ATMPs. The Control Site model, supported by a risk-based, technologically-enabled QMS, provides a viable framework to meet this need. By leveraging cloud platforms, automated manufacturing, and robust comparability protocols, sponsors can navigate the complex regulatory expectations from the MHRA, EMA, and FDA. This approach transforms the significant challenge of decentralized manufacturing into a strategic opportunity, ultimately enabling more scalable, accessible, and cost-effective advanced therapies for patients.

Integrating Automated, Closed-System Technologies to Minimize Process Variability

The field of Advanced Therapy Medicinal Products (ATMPs), which includes cell and gene therapies, is transitioning from laboratory-scale production to industrialized manufacturing. This shift is critical for meeting rising clinical demand; over 2,000 cell and gene therapy candidates are currently under investigation [49]. However, the conventional manufacturing process for these therapies is inherently labor-intensive and time-consuming, often resulting in significant batch-to-batch variation [49]. Automated and closed-cell processing systems have emerged as a pivotal technological solution to these challenges. These systems are designed to perform aseptic cell manipulations—such as washing, expansion, and cryopreservation—within a sealed, sterile environment, thereby streamlining clinical-grade manufacturing while drastically mitigating contamination risks and operational variability [50].

The drive toward automation is further amplified within the context of decentralized manufacturing, a model where production activities occur away from a central factory, potentially at a clinic or hospital bedside [4]. This model is particularly relevant for autologous therapies (personalized to individual patients) and products with very short shelf lives. The European Union's evolving regulatory landscape now explicitly supports this paradigm, recognizing that the traditional, wholly centralized model is not always fit-for-purpose for these innovative treatments [4] [51]. Integrating automated closed systems is a fundamental enabler for decentralized manufacturing, as it ensures that complex processes can be executed reliably and consistently across multiple, geographically dispersed sites without compromising quality [50].

The EU Regulatory Framework for Decentralized ATMP Manufacturing

The regulatory environment in the European Union is rapidly adapting to accommodate the unique challenges posed by ATMPs and their manufacturing. A key development is the new regulation from the UK's Medicines and Healthcare products Regulatory Agency (MHRA), which came into effect on July 23, 2025 [4]. Although from the UK, this regulation is influential across Europe and was penned in consultation with 16 regulatory bodies via the International Coalition of Medicines Regulatory Authorities (ICMRA). It introduces two critical pathways for non-centralized production: Modular Manufacturing (MM) and Point-of-Care (POC) Manufacturing [4].

In both models, a central "control site" holds the manufacturer's license and creates a detailed Master File (MF) that contains the full instructions for the final manufacturing or assembly steps at the satellite locations. The product is released at this central site, not at the bedside, which is a significant departure from previous approaches and crucial for ensuring quality [4]. This regulatory structure places the onus on the license holder to supervise and control all decentralized units, similar to the relationship with a Contract Manufacturing Organization (CMO).

Concurrently, the European Medicines Agency (EMA) is undertaking its own modernization efforts. A concept paper released in May 2025 proposes a revision to Part IV of the EU Good Manufacturing Practice (GMP) guidelines specific to ATMPs [52] [53]. This revision aims to harmonize ATMP GMP with recently updated standards, notably the revised Annex 1 for sterile medicinal products, and to incorporate modern quality principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) [52]. Furthermore, the revision explicitly acknowledges the emergence of new technologies, including automated systems and closed single-use systems, and will provide clarifications on their qualification and control [52]. These regulatory updates collectively create a more predictable pathway for deploying automated, closed systems in a decentralized network, ensuring that quality and patient safety remain paramount.

Regulatory Pathway Diagram

The following diagram illustrates the relationship between the central control site and the point-of-care manufacturing units under the new regulatory models.

Market and Technology Landscape of Automated Systems

The market for automated and closed-cell processing systems is experiencing robust growth, reflecting the industry's rapid adoption of this technology. The global market, valued between $1.32 billion and $220 million in 2024/2025, is projected to grow at a compound annual growth rate of 16% to 19.8%, reaching approximately $3.7 billion by 2030-2033 [49] [54] [50]. This expansion is fueled by the increasing number of cell therapy candidates and the pressing need to reduce the high cost of goods (COGs) associated with manual, labor-intensive processes [49] [50].

The technology landscape is characterized by a variety of systems tailored to different stages of the cell therapy workflow. Key players include established companies like Miltenyi Biotec, Terumo BCT, Cytiva, and Lonza [50]. The market is moderately concentrated, with a few major players holding a significant share, but it remains dynamic with active competition and innovation [54]. The prevailing trend is toward integrated modular platforms—such as the CliniMACS Prodigy and Cocoon—which combine multiple processing steps (e.g., expansion, formulation, and fill-finish) into a single, closed-loop system [50]. These platforms are particularly advantageous for decentralized manufacturing, as they reduce the facility footprint and simplify the technology transfer to hospital-based or POC sites.

Market Data and System Segmentation

Table 1: Global Market Forecast for Automated and Closed Cell Therapy Processing Systems

Region	2024/2025 Market Value (USD Billion)	Projected CAGR (2024-2030)	Primary Growth Drivers
North America	$0.54 - $1.32 Bn [50] [54]	17.5% - 18.7% [50]	FDA CMC push, CDMO scale-up, digital twin adoption [50]
Europe	$0.44 Bn [50]	16.2% [50]	EMA Annex 1 compliance, Horizon Europe funding [50]
Asia-Pacific	$0.31 Bn [50]	20.5% [50]	PMDA fast-track (Japan), ATMP parks (China) [50]

Table 2: Automated System Segmentation by Workflow and Type

Segment	Key Categories	Market Share & Notes
By Workflow Stage	Upstream Processing, Cell Expansion, Downstream Processing, Cryopreservation & Fill-Finish	Cell Expansion is the largest application segment (36% share) [50]
By Product Type	Integrated Modular Platforms, Closed-System Bioreactors, Automated Washers/Separators, Cryopreservation Systems	Integrated Modular Platforms are the fastest-growing sub-segment (CAGR >21%) [50]
By End User	CDMOs, Biopharma & CGT Firms, Academic/Research Centers, Hospitals/POC Units	CDMOs are the largest end-user segment (42% share) [50]

Implementation and Integration Strategies

Successfully integrating automated closed systems into a decentralized manufacturing network requires a strategic approach that encompasses technology selection, process validation, and data management. The primary objective is to create a robust, reproducible process that minimizes human intervention and maximizes product quality.

A critical first step is the selection of appropriate technology based on the specific ATMP and its intended commercial model. For autologous therapies destined for POC manufacture, small-footprint, easy-to-use platforms like the Cocoon are designed for operation within a hospital setting [50]. For allogeneic therapies, larger-scale systems such as Terumo BCT's Quantum Plus enable the simultaneous expansion of multiple batches [50]. A core strategy is the implementation of single-use technologies. Disposable flow paths and bioreactor bags eliminate the need for cleaning and sterilization validation between batches, which is a significant advantage in a multi-product decentralized network [50]. Furthermore, the integration of advanced Process Analytical Technologies (PAT) is essential. Embedded sensors for metrics like metabolite and lactate levels allow for real-time monitoring and adaptive feed control, moving the process from a fixed recipe to a dynamic, quality-by-design (QbD) approach [50].

From a regulatory and quality standpoint, implementation must be guided by a robust Quality Risk Management process, as per ICH Q9 [52]. This involves conducting a Failure Mode and Effects Analysis to identify and mitigate potential risks in the automated process [55]. A comprehensive Contamination Control Strategy, aligned with EU GMP Annex 1, must be developed and validated, proving the closed nature of the system and the efficacy of its aseptic connections [52]. Finally, the implementation of a Pharmaceutical Quality System that spans the entire network is mandatory. The central control site is responsible for ensuring that all POC units operate in compliance with the registered process in the Master File, requiring rigorous training, standardized procedures, and synchronized data management [4] [52].

Process Integration Workflow

The following diagram outlines the key stages for integrating an automated closed-system into a GMP-compliant, decentralized workflow.

Experimental Protocols for Process Validation

Validating an automated closed-system is crucial to demonstrating that it consistently produces a product meeting its pre-determined quality attributes. The following protocols provide a framework for this essential activity.

Protocol for Closed-System Integrity and Aseptic Processing Validation

Objective: To validate the integrity of the closed system and the efficacy of its aseptic processing capabilities, in alignment with EU GMP Annex 1 requirements for sterile products [52].

Materials:

• Automated closed-system platform
• Culture media
• Environmental monitoring equipment (settle plates, active air samplers)
• Sterility testing kits
• Bioburden and endotoxin testing kits

Methodology:

• System Setup: Assemble the closed system, including all single-use sets, within a Controlled Non-Classified (CNC) area, leveraging barrier systems like isolators where appropriate [52].
• Media Fill Simulation: Perform a minimum of three consecutive successful media fill runs using culture media instead of patient cells. The process must simulate the entire manufacturing sequence, including all aseptic manipulations like connections, additions, and sampling.
• Environmental Monitoring: Conduct thorough environmental monitoring throughout the process using settle plates and active air samplers to demonstrate the absence of microbial contamination in the immediate operating environment.
• Post-Process Testing: Incubate the final media-filled container and all in-process samples for sterility (14 days). Test for bioburden and endotoxin levels at critical process steps.
• Acceptance Criteria: All media fill units must show no microbial growth after incubation. Bioburden and endotoxin levels must remain within specified limits. Environmental monitoring results must meet the classification requirements for the surrounding area.

Protocol for Automated Process Performance Qualification (PPQ)

Objective: To demonstrate and document that the automated process, when deployed at a designated POC unit, is capable of consistently producing ATMPs that meet all critical quality attributes (CQAs).

Materials:

• Automated closed-system platform at the POC unit
• Representative starting materials
• Analytical methods for measuring CQAs
• Electronic Batch Record (EBR) system

Methodology:

• Protocol Definition: Define a PPQ protocol that specifies the manufacturing process, CQAs, sampling plan, and statistical criteria for success.
• Consecutive Batches: Execute a minimum of three consecutive successful batches at the POC unit using the automated system.
• In-Process Data Collection: Utilize the system's integrated sensors and PAT tools to collect real-time data on process parameters.
• CQA Verification: Test in-process and final product samples against all defined CQAs (e.g., cell viability, identity, potency, purity).
• Data Analysis & Reporting: Analyze the data using statistical process control methods. The process is considered validated if all batches meet all pre-defined CQAs and demonstrate minimal batch-to-batch variability.

The Scientist's Toolkit: Key Research Reagent Solutions

Table 3: Essential Reagents and Materials for Automated Cell Therapy Processing

Reagent/Material	Function in Automated Processing	Application Example
Chemically Defined Media	Provides a consistent, serum-free nutrient base for cell growth and differentiation, crucial for process reproducibility and reducing raw material variability.	Expansion of CAR-T cells or iPSCs in closed-system bioreactors [50].
Recombinant Growth Factors & Cytokines	Directs cell differentiation, expansion, and activation. Using GMP-grade, recombinant factors is essential for controlling process outcomes and ensuring patient safety.	Activation of T-cells for CAR-T therapy; differentiation of iPSCs into target cell types [50].
Single-Use, Sterile Fluid Path Assemblies	Forms the closed pathway for media, cells, and buffers within the automated system. Eliminates cross-contamination and cleaning validation between batches.	All processing steps in systems like the CliniMACS Prodigy or Quantum Plus [50].
GMP-Grade Transfection Reagents	Enables the introduction of genetic material into cells (e.g., for CARs or gene editing) in a closed, automated format.	Viral transduction or non-viral transfection in CAR-T and gene therapy manufacturing [50].
Cryopreservation Solutions	Protects cell viability and function during freeze-thaw in an automated fill-finish process. Formulated for consistency in automated dispensing.	Final formulation and cryopreservation of the finished ATMP product [50].

The integration of automated, closed-system technologies is no longer a mere option but a cornerstone for the successful and scalable commercialization of ATMPs, particularly within the emerging decentralized manufacturing paradigm. These systems directly address the core challenge of process variability by minimizing human intervention, standardizing complex unit operations, and enabling real-time quality monitoring. The regulatory framework in Europe is evolving in lockstep with this technological shift, with the MHRA's new POC/MM regulations and the EMA's ongoing revision of GMP guidelines for ATMPs providing a more predictable pathway for implementation. For researchers and drug development professionals, mastering these technologies—from selection and validation to integration within a quality risk management system—is critical. As the market continues its rapid growth, the synergy between robust automation, intelligent data management, and agile regulatory frameworks will be the key driver in delivering transformative advanced therapies to patients in a consistent, safe, and efficient manner.

The field of Advanced Therapy Medicinal Products (ATMPs) is undergoing a paradigm shift from centralized to decentralized manufacturing models to overcome critical challenges in logistics, scalability, and patient access. Decentralized manufacturing involves producing ATMPs at multiple sites under central management, often at or near the point of care (POCare) where patients receive treatment [17]. This approach is particularly vital for autologous cell therapies with short shelf lives, where traditional centralized manufacturing poses significant hurdles related to manufacturing capacity and timely delivery of patient-specific products [17]. The European Union's regulatory framework, particularly Regulation (EC) No 1394/2007, establishes ATMPs as medicinal products subject to full regulatory oversight, requiring adherence to Good Manufacturing Practice (GMP) principles regardless of manufacturing location [56] [57].

Within this evolving landscape, the Qualified Person (QP) assumes critical responsibilities for ensuring product quality, safety, and efficacy across distributed manufacturing networks. The QP's role encompasses oversight of quality management systems, batch certification, and regulatory compliance across multiple manufacturing sites, presenting unique challenges in maintaining consistency and control [17] [58]. This technical guide examines the regulatory frameworks, practical strategies, and technological solutions enabling effective QP oversight in decentralized ATMP manufacturing networks, with particular focus on the control site model and emerging digital tools that facilitate robust quality assurance across distributed production facilities.

Regulatory Framework for Decentralized Manufacturing

EU Regulatory Foundations and the Control Site Model

The European regulatory framework for ATMPs establishes rigorous standards for decentralized manufacturing, emphasizing the necessity of a centralized control site to maintain oversight across distributed production locations. The control site serves as the regulatory nexus, maintaining responsibility for quality assurance, regulatory interactions, and overall supervision of decentralized manufacturing operations [17]. This model requires the control site to hold the manufacturing license and maintain essential documentation, including the POCare Master File (or Decentralized Manufacturing Master File, DMMF), which comprehensively describes the manufacturing process, quality controls, and oversight mechanisms for all decentralized sites [17] [42].

Under the UK's MHRA framework – one of the most developed regulatory models for decentralized manufacturing – two distinct license types exist for decentralized production: the Manufacturer's License (Point of Care, POC) for medicines manufactured close to the patient for immediate administration, and the Manufacturer's License (Modular Manufacturing, MM) for activities performed away from traditional sites to enable deployment to other locations [27]. The control site must be located within the UK and maintain a comprehensive quality management system with procedures for managing the decentralized manufacturing control strategy, onboarding and overseeing remote sites, maintaining equipment, implementing training programs, and conducting product release [42]. Regulatory agencies typically inspect the control site's oversight systems and may select individual remote sites for inspection rather than auditing every location [42].

Emerging Regulatory Perspectives Across Jurisdictions

Global regulatory authorities are developing frameworks to accommodate decentralized manufacturing while maintaining product quality and patient safety:

• MHRA (UK): Has implemented a comprehensive framework effective July 2025 that introduces specific licenses for POC and modular manufacturing, requiring a DMMF and emphasizing the control site's overarching responsibilities [42] [27].
• FDA (USA): Through initiatives like the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), has recognized distributed manufacturing as enabling POCare manufacturing near healthcare facilities [17]. The FDA's Emerging Technology Program encourages early engagement to explore novel control strategies compatible with decentralized models [58].
• EMA (EU): Has identified decentralized manufacturing as a priority in its network strategy, acknowledging its potential to improve availability and accessibility of medicines [17]. The EU's regulatory framework requires that Marketing Authorisation Holders must be established within the European Economic Area, maintaining responsibility for all manufacturing activities regardless of location [59].

Table 1: Regulatory Framework Comparison for Decentralized ATMP Manufacturing

Regulatory Authority	Key Regulatory Mechanisms	QP/Control Site Requirements	Documentation Framework
MHRA (UK)	Manufacturer's License (POC/MM), Designation Step	Control site in UK, QP oversight, annual reporting	Decentralized Manufacturing Master File (DMMF)
EMA (EU)	ATMP Regulation (EC) 1394/2007, Centralized Procedure	Control site as regulatory nexus, QP release	POCare Master File, Pharmacovigilance System Master File
FDA (USA)	FRAME Initiative, Emerging Technology Program	Centralized quality oversight, comparability data	Master File, Real-time quality monitoring

QP Oversight Responsibilities and Challenges in Distributed Networks

Core QP Responsibilities in Decentralized Environments

The Qualified Person in a decentralized manufacturing network assumes expanded responsibilities that transcend traditional batch release functions. The QP must ensure that every batch manufactured across all sites complies with the marketing authorization and GMP standards, despite geographical distribution [42] [58]. This requires establishing and maintaining a robust quality management system that treats remote manufacturing sites like contracted organizations, with clear quality agreements, audit schedules, and performance monitoring mechanisms [42] [58].

A critical QP responsibility involves maintaining the Decentralized Manufacturing Master File, which must comprehensively document all manufacturing locations, their status, contact details, products, processes, and procedures [42] [27]. The QP must ensure this living document is continuously updated as new sites are added or decommissioned, with annual reporting of changes to regulatory authorities [27]. Additionally, the QP holds responsibility for pharmacovigilance oversight, ensuring robust processes for adverse event collection, evaluation, and reporting across all manufacturing sites, with clear integration between the quality system and pharmacovigilance processes [42] [27].

Technical and Operational Challenges

Decentralized ATMP manufacturing presents unique challenges for QP oversight, primarily centered on maintaining consistency and comparability across multiple manufacturing sites. The inherent variability of autologous starting materials combines with potential site-to-site processing differences, creating significant challenges in ensuring product uniformity [17] [58]. QPs must implement strategies to demonstrate that comparable products are manufactured at each location, with analytical methods that provide equivalent results across sites [17].

Personnel variability represents another substantial challenge, as decentralized sites may be staffed by individuals with diverse backgrounds and expertise levels [58]. Without consistent, standardized training protocols and competency assessments, this variability can directly impact product quality. The QP must ensure comprehensive training programs and ongoing performance monitoring across all sites [42] [58]. Additionally, batch traceability becomes exponentially more complex in decentralized networks, requiring sophisticated systems to track products from manufacturing through administration and to link adverse events to specific production sites and conditions [42] [27].

Strategic Framework for Certification and Batch Release

Control Strategy Implementation

Implementing an effective control strategy for decentralized networks requires a comprehensive, multi-layered approach centered on standardization and real-time monitoring. The foundation of this strategy involves standardized manufacturing platforms utilizing automated, closed-system technologies to minimize process variability and hardware deviations across sites [17] [60]. These platforms should incorporate inline analytics measuring critical process parameters (CPPs) such as dissolved oxygen, pH, lactate, glucose, temperature, gas mix, and pump activity, enabling real-time process monitoring and intervention [60].

A robust control strategy must also include harmonized standard operating procedures across all manufacturing sites, ensuring consistent execution of critical process steps regardless of location [42] [58]. These procedures should be supported by a centralized training platform with competency assessment and certification programs to guarantee uniform operator readiness and performance [17] [58]. Additionally, interoperable digital systems that enable seamless data flow from apheresis to final disposition are essential for maintaining oversight and facilitating rapid batch release decisions [60].

Batch Release Mechanisms and Real-Time Monitoring

Batch release in decentralized ATMP manufacturing requires innovative approaches to accommodate the short shelf lives of many autologous products while maintaining rigorous quality standards. A two-phase release strategy has emerged as an effective model, incorporating rapid, data-rich checks for immediate disposition decisions followed by confirmatory assays [60]. This approach enables fresh products to be administered within clinically viable timeframes while maintaining comprehensive quality documentation.

Advanced digital batch records with automated data ingestion from manufacturing equipment create a foundation for real-time release capabilities by ensuring information accuracy and accessibility throughout the production process [60]. These systems should be supported by AI-powered predictive quality tools that analyze process parameters (e.g., dissolved oxygen slope after activation, lactate trend breaks, and pump-rate recovery) to predict product quality and identify potential deviations before they impact final product quality [60]. The QP must establish clear rapid-release criteria documenting who can release products, what real-time data is required, and how to respond if later results disagree with initial quality assessments [60].

Table 2: Batch Release Strategy Components for Decentralized ATMP Manufacturing

Release Component	Traditional Centralized Model	Decentralized Network Model	Key Technologies
Batch Documentation	Paper-based batch records	Electronic batch records (EBR) with automated data ingestion	Digital EBR platforms, IoT integration
Quality Verification	End-product testing, QP certification after complete review	Real-time monitoring, parametric release, two-phase approach	Inline analytics, AI prediction algorithms
QP Oversight	Direct involvement in each release	Oversight of release system, exception-based review	Centralized QA dashboards, risk-based analytics
Regulatory Compliance	GMP certification at single site	Control site with DMMF, site auditing program	Digital audit trails, remote inspection readiness

Technological Enablers for Effective QP Oversight

Digital Quality Management Systems

Advanced digital platforms are revolutionizing QP oversight in decentralized networks by enabling real-time monitoring and data-driven decision making across distributed manufacturing sites. Electronic batch records with automated data capture transform previously manual documentation processes, reducing transcription errors and providing immediate access to manufacturing data [60]. These systems significantly reduce QA effort – with reports indicating approximately two-thirds reduction in QA resources and reclamation of 100 days per month for QA teams – while dramatically cutting documentation errors [60].

Centralized remote QA dashboards enable QPs to monitor multiple manufacturing sites simultaneously, providing comprehensive oversight without requiring physical presence at each location [58] [60]. These dashboards aggregate data from all manufacturing sites, applying machine learning algorithms to identify patterns, predict potential quality issues, and optimize manufacturing processes based on cumulative data from across the network [58] [60]. When integrated with predictive maintenance systems, these platforms can anticipate equipment failures before they occur, preventing disruptions in manufacturing capacity and ensuring consistent process performance across all sites [58].

Data Integrity and Interoperability Solutions

Maintaining data integrity across decentralized manufacturing networks requires sophisticated solutions for secure data collection, transmission, and storage. Automated data ingestion directly from manufacturing instruments ensures information accuracy from the point of generation, eliminating manual transcription errors and providing reliable data for release decisions [60]. These systems must incorporate robust audit trails that track all data modifications, providing regulatory compliance documentation and facilitating investigations when deviations occur.

Interoperability between systems is crucial for efficient tech transfer and consistent execution across manufacturing sites [60]. Platforms that "talk" to each other enable seamless transfer of processes between locations, with standardized data structures making tech transfer resemble configuration rather than reimplementation [60]. A single orchestration workflow consolidating logins and standardizing interfaces across manufacturing, filling, and QC systems simplifies operations while reducing training requirements and implementation errors [60]. These technological solutions collectively create a connected quality ecosystem capable of maintaining rigorous standards across distributed manufacturing networks.

Implementation Protocols and Research Methodologies

Experimental Protocol for Process Comparability

Demonstrating process comparability across decentralized manufacturing sites requires a structured experimental approach. The following protocol provides a methodology for establishing and validating equivalence between manufacturing locations:

• Experimental Design: Define sample size using statistical power analysis, with minimum of 10 parallel runs per site for autologous processes or 20 runs for allogeneic products. Include intentional operational variations within predefined acceptable ranges to demonstrate robustness.

• Critical Quality Attribute (CQA) Assessment: Monitor CQAs throughout the process, including cell viability, identity, potency, purity, and microbiological safety. Employ standardized analytical methods across all sites with demonstrated method comparability.

• Process Parameter Monitoring: Track CPPs in real-time using inline analytics, including dissolved oxygen, pH, lactate, glucose, temperature, and gas mix. Establish acceptable ranges for each parameter based on development data.

• Statistical Analysis: Apply multivariate analysis to identify potential site-specific effects on CQAs. Utilize principle component analysis (PCA) to visualize clustering of data by manufacturing site. Employ equivalence testing with pre-defined equivalence margins (generally ±1.5 standard deviations) for key quality attributes.

• Long-term Monitoring: Implement continuous verification through statistical process control (SPC) charts tracking CQAs and CPPs across all sites, with alert and action limits derived from initial validation data.

Research Reagent Solutions for Decentralized Manufacturing

Standardized reagent systems are essential for maintaining consistency across decentralized ATMP manufacturing networks. The following table details critical reagent categories and their functions in ensuring product quality:

Table 3: Essential Research Reagent Solutions for Decentralized ATMP Manufacturing

Reagent Category	Specific Examples	Function in Manufacturing Process	Quality Control Requirements
Cell Activation Reagents	Anti-CD3/CD28 antibodies, Recombinant cytokines	T-cell activation and expansion	Identity, purity, potency, endotoxin testing, functional activity validation
Cell Culture Media	Serum-free media formulations, Supplement cocktails	Support cell growth and maintenance	Composition verification, performance testing, endotoxin and mycoplasma testing
Gene Delivery Vectors	Lentiviral vectors, Retroviral vectors, mRNA	Genetic modification of patient cells	Titer determination, identity, purity, sterility, replication-competent virus testing
Cryopreservation Solutions	DMSO-containing solutions, Serum-free cryomedias	Cell product storage and transport	Composition verification, sterility, endotoxin testing, performance validation
Analytical Reagents	Flow cytometry antibodies, ELISA kits, PCR reagents	Product quality assessment and release testing	Specificity, sensitivity, accuracy, precision validation

The evolution of decentralized manufacturing for ATMPs represents a fundamental shift in pharmaceutical production, requiring equally innovative approaches to QP oversight and batch release strategies. The control site model with comprehensive DMMF documentation provides a regulatory-compliant framework for managing distributed manufacturing networks, while emerging digital technologies enable unprecedented levels of oversight and control. As regulatory frameworks continue to evolve in response to these new manufacturing paradigms, QPs must embrace technological solutions that enhance rather than replace their expert judgment. The successful implementation of decentralized ATMP manufacturing will depend on robust quality systems, standardized processes, and sophisticated digital infrastructure that together ensure patient safety and product efficacy while expanding access to these transformative therapies.

Standardizing Training Platforms and Procedures Across All Manufacturing Sites

The advent of decentralized manufacturing for Advanced Therapy Medicinal Products (ATMPs) represents a paradigm shift in biopharmaceutical production, particularly for autologous cell and gene therapies. This model brings manufacturing closer to patients, overcoming critical logistical and market access challenges that have previously hindered life-saving treatments [61]. However, this distribution of manufacturing activities across multiple geographically dispersed sites introduces significant complexities in maintaining consistent product quality and regulatory compliance. Within this context, the standardization of training platforms and procedures emerges not merely as an operational objective, but as a fundamental prerequisite for patient safety and regulatory viability.

Regulatory agencies have identified inadequate personnel training as a persistent and critical deficiency. The U.S. FDA's 2025 warning letters repeatedly cite violations of 21 CFR 211.25(a), which mandates that personnel must have "education, training, and experience... to perform assigned functions" [62]. These findings underscore a global regulatory consensus: without standardized, documented, and effective training, the entire quality framework supporting decentralized manufacturing is compromised. The human element becomes the most significant variable in systems where manufacturing occurs at or near the point of care, often staffed by individuals with varied backgrounds and expertise levels [61]. Standardized training transforms this variable into a controlled parameter, ensuring uniform execution of critical processes regardless of physical location.

Regulatory Framework and Requirements

Evolving Regulatory Expectations for Distributed Manufacturing

The regulatory landscape for decentralized manufacturing is rapidly evolving to address the unique challenges of distributed ATMP production. The MHRA (Medicines and Healthcare products Regulatory Agency) has established a pioneering framework with its 2025 regulations specifically addressing modular and point-of-care manufacturing [42]. This framework introduces two distinct license types: the Manufacturer's License (MM) for modular manufacture and the Manufacturer's License (POC) for point-of-care manufacture [61]. Both require maintenance of a dedicated master file detailing manufacturing processes, quality controls, and crucially, the training and oversight protocols that ensure personnel competency across all sites.

Similarly, the U.S. Food and Drug Administration (FDA) has advanced its thinking through the 2022 discussion paper on "Distributed Manufacturing and Point-of-Care Manufacturing of Drugs" and the 2025 guidance "Considerations for Complying With 21 CFR 211.110" [61]. These documents collectively emphasize a science- and risk-based approach to in-process controls, which inherently depends on personnel having standardized training to properly execute and monitor these controls. The FDA explicitly encourages early engagement with its Emerging Technology and Advanced Technologies Teams to explore novel control strategies, including those related to personnel training and qualification [61].

Specific Training-Related Regulatory Requirements

Table 1: Key Regulatory Requirements for Training in Decentralized Manufacturing

Regulatory Source	Training Requirement	Documentation Needed	Application to Decentralized Sites
21 CFR 211.25(a) (FDA)	"Each person shall have education, training, and experience... to perform assigned functions" [62]	Training records, curricula vitae, competency assessments	Applies equally to all personnel at centralized and decentralized sites
MHRA POC/MM Regulations (2025)	Central control site must implement "a training program for the sites" [42]	Training protocols, certification records, DMMF inclusions	Training must be standardized across all remote manufacturing locations
EU GMP Guidelines	Training on specific operations and GMP principles	Training plans, records, assessments of effectiveness	Requires equivalent training rigor at all manufacturing sites regardless of location

The foundational regulatory principle across all jurisdictions is that training must be adequate, documented, and regularly assessed. The 2025 FDA warning letters reveal that deficiencies often cluster around insufficient documentation of training, lack of regular retraining, and failure to demonstrate training effectiveness [62]. For decentralized models, regulators expect a unified training framework managed by the central control site, with mechanisms to ensure consistent implementation across all manufacturing locations. The control site must maintain comprehensive records demonstrating that personnel at all sites, regardless of location, possess equivalent competencies to perform their assigned functions [42] [61].

Core Components of Standardized Training Systems

Training Program Architecture and Content Standardization

A robust standardized training system for decentralized ATMP manufacturing requires a modular architecture that can be consistently deployed across all sites while allowing for site-specific adaptations where necessary. The core curriculum must address both universal competencies applicable to all sites and site-specific elements tailored to local equipment, processes, and responsibilities. Critical components include:

• Good Manufacturing Practice (GMP) Fundamentals: Standardized GMP training establishing a uniform understanding of quality standards across all sites, particularly crucial for personnel who may come from clinical rather than manufacturing backgrounds [61].
• Product-Specific Technical Operations: Detailed training on the specific manufacturing processes for each ATMP, ensuring identical execution whether at central or point-of-care facilities. This includes aseptic techniques, cell processing, and quality control testing [42].
• Quality Management System (QMS) Training: Comprehensive instruction on the centralized QMS, including deviation reporting, change control, and corrective/preventive actions, ensuring uniform quality responses across the network [61].
• Emergency Response Procedures: Standardized protocols for handling equipment failures, product quality issues, or other emergencies at decentralized sites, with clear escalation paths to the central control site.

The Decentralized Manufacturing Master File (DMMF) required by MHRA regulations should comprehensively document this training architecture, including how training content is developed, maintained, and uniformly deployed [42].

Training Delivery Modalities and Technological Enablers

Effective training standardization in decentralized networks leverages digital learning platforms and blended learning approaches to ensure consistent delivery while accommodating geographical dispersion. Implementation requires integrating several technological solutions:

• Learning Management Systems (LMS): Centralized platforms hosting standardized training content, tracking completion, and managing competency records across all sites, with role-based access controls ensuring personnel receive appropriate training for their specific responsibilities [61].
• Virtual Reality (VR) and Augmented Reality (AR) Simulations: Immersive technologies enabling hands-on practice with complex manufacturing procedures in a risk-free environment, particularly valuable for training on rare or critical operations that may not be frequently performed at individual sites.
• Remote Auditing and Monitoring Tools: Digital platforms allowing the central quality unit to remotely observe and assess training execution at decentralized sites, maintaining oversight without physical presence [61].
• Real-Time Performance Support Systems: Just-in-time digital job aids, checklists, and guided procedures accessible at the point of need, reinforcing standardized approaches during actual manufacturing operations.

Table 2: Technological Solutions for Standardized Training Implementation

Technology Solution	Primary Function	Benefits for Standardization
Centralized LMS	Hosts training content, tracks completion, manages records	Ensures identical content delivery across all sites; provides centralized compliance reporting
VR/AR Simulations	Provides immersive hands-on practice without product risk	Enables standardized procedural training regardless of local equipment availability
Remote Monitoring Tools	Allows real-time observation of operations and assessments	Facilitates consistent competency evaluation across geographically dispersed sites
Electronic Performance Support	Delivers just-in-time guidance during manufacturing operations	Reinforces standardized approaches at the point of use; reduces reliance on memory

Implementation Methodology and Experimental Protocols

Training Program Development and Validation Workflow

The development and implementation of standardized training programs follows a systematic methodology that ensures both regulatory compliance and operational effectiveness. The process begins with a comprehensive training needs analysis conducted across all manufacturing sites to identify competency gaps and procedural variations. This analysis informs the development of standardized training curricula that address both universal requirements and site-specific needs while maintaining core consistency.

Training Program Development Workflow

The critical validation phase employs a rigorous assessment protocol to demonstrate training effectiveness before full deployment. This protocol incorporates both knowledge-based evaluations (written tests, quizzes) and performance-based assessments (practical demonstrations, simulations) to ensure personnel can correctly apply their training in operational contexts. For procedural training, assessment includes direct observation of technicians executing manufacturing processes using the same equipment and documentation systems employed in actual operations [61]. The validation success criteria must be predefined, quantifiable, and aligned with the quality targets for the manufacturing process itself.

Competency Assessment and Maintenance Protocols

Standardized training requires equally standardized assessment methodologies to ensure consistent competency levels across all sites. The experimental protocol for competency assessment involves:

• Baseline Assessment: Evaluation of existing personnel competency before training implementation to establish baseline performance metrics and identify specific knowledge or skill gaps.
• Post-Training Assessment: Immediate evaluation following training completion using standardized written examinations (with predetermined passing scores) and practical demonstrations assessed against validated checklists.
• Retention Testing: Periodic unannounced assessments conducted at defined intervals (e.g., 3, 6, and 12 months post-training) to evaluate knowledge and skill retention over time.
• Performance Correlation Analysis: Statistical comparison of training assessment results with actual manufacturing performance metrics (e.g., deviation rates, batch success rates) to validate the training program's effectiveness in preparing personnel for their responsibilities.

The MHRA's guidance emphasizes that the central control site must maintain comprehensive records of all competency assessments conducted across the network, with clear documentation of any required remedial training [42]. This creates an audit trail demonstrating consistent competency standards throughout the decentralized manufacturing network.

Table 3: Key Research Reagent Solutions for Training Program Development

Tool/Resource	Function	Application in Training
Standardized Training Modules	Pre-developed content covering GMP, technical procedures, quality systems	Ensures consistent foundational knowledge across all sites; reduces development burden
Competency Assessment Platforms	Digital tools for creating, administering, and scoring knowledge and practical assessments	Provides objective, standardized evaluation of training effectiveness across sites
Simulation Materials	Non-product materials mimicking actual production inputs (e.g., culture media, buffers)	Enables realistic hands-on practice without consuming expensive production materials
Document Management Systems	Centralized platforms for managing SOPs, batch records, and training materials	Ensures all sites use current versions of controlled documents
Remote Auditing Tools	Digital systems for real-time observation and documentation of operations	Allows central quality unit to verify compliance with standardized procedures across all sites

Data Integrity and Documentation Standards

In decentralized manufacturing environments, standardized documentation practices form the backbone of effective training and quality oversight. The central control site must implement a unified document control system that ensures all sites utilize identical versions of standard operating procedures (SOPs), batch records, and training materials [61]. This documentation system must provide:

• Version Control: Automated management of document revisions with clear implementation timelines across all sites.
• Access Controls: Role-based permissions ensuring personnel can only access documents relevant to their responsibilities.
• Audit Trails: Comprehensive tracking of document changes, training completions, and competency assessments.
• Cross-Platform Compatibility: Accessibility across different hardware and operating systems that may be in use at various sites.

Training records specifically must demonstrate complete traceability of each employee's qualifications, including initial training, recurrent training, and any specialized certifications. The FDA's 2025 warning letters specifically cite inadequate training documentation as a recurring deficiency, emphasizing that records must clearly show "who was trained, on what, when, and by whom" [62]. In decentralized models, these records must be accessible to both the central quality unit and regulatory investigators during inspections of any manufacturing site.

Case Study: Successful Implementation in Mobile Cleanroom Deployment

A recent pilot program demonstrating standardized training in practice involved the deployment of a mobile modular cleanroom stationed outside a hospital for compounding essential medications [61]. Over a six-month period, this initiative manufactured more than 12,000 doses while maintaining strict quality standards through a comprehensive training approach. Key elements of this successful implementation included:

• Centralized Training Development: All training content was developed at a central facility with input from subject matter experts across multiple disciplines, ensuring comprehensive coverage of both technical and quality requirements.
• Standardized Trainer Certification: Personnel responsible for delivering training at the point of care underwent a rigorous certification process to ensure consistent messaging and evaluation standards.
• Digital Performance Support: Technicians at the mobile cleanroom accessed standardized electronic work instructions and decision aids through tablets, providing immediate guidance during operations.
• Remote Quality Oversight: The central quality unit conducted real-time monitoring of operations through integrated cameras and data feeds, allowing immediate intervention when deviations from standardized procedures were observed.

This case study demonstrates that with proper training standardization and technological support, decentralized manufacturing can achieve quality standards equivalent to traditional centralized facilities while providing the benefits of proximity to patients [61]. The success of this model is particularly relevant for ATMPs with limited stability profiles that benefit from manufacturing near the patient bedside.

Standardizing training platforms and procedures across all manufacturing sites represents both a regulatory imperative and an operational necessity for the successful implementation of decentralized ATMP manufacturing. The evolving regulatory landscape, exemplified by the MHRA's 2025 framework and FDA's ongoing guidance development, increasingly recognizes that personnel competency is the critical link ensuring product quality in distributed manufacturing models [42] [61]. The recurrence of training-related deficiencies in regulatory inspections underscores that traditional, site-specific training approaches are insufficient for the unique challenges of decentralized production [62].

The future of training standardization in pharmaceutical manufacturing will increasingly leverage Industry 4.0 technologies to enhance effectiveness and efficiency. Emerging approaches include:

• AI-Powered Personalized Learning Paths: Adaptive training systems that customize content and pacing based on individual learner performance and knowledge gaps.
• Predictive Competency Analytics: Machine learning algorithms analyzing training and performance data to predict which personnel may need additional support or retraining before issues occur in manufacturing.
• Extended Reality (XR) Integration: Combined virtual, augmented, and mixed reality environments creating increasingly sophisticated simulations of complex manufacturing processes.
• Blockchain-Verified Credentialing: Immutable records of training completion and competency certification accessible across organizational boundaries.

As decentralized manufacturing continues to evolve, the standardization of training will remain foundational to ensuring that regardless of where production occurs, the personnel conducting manufacturing operations possess the consistent knowledge, skills, and competencies required to produce safe, effective, and high-quality advanced therapies for patients.

Overcoming Key Challenges in Decentralized ATMP Production: Comparability, Logistics, and GMP

Strategies for Demonstrating Product Comparability and Process Consistency Across Multiple Sites

For developers of Advanced Therapy Medicinal Products (ATMPs) in the European Union, the ability to demonstrate product comparability and process consistency across multiple manufacturing sites is not merely a technical challenge—it is a critical regulatory requirement for the successful implementation of decentralized manufacturing models. Decentralized manufacturing, which includes point-of-care (POC) and modular manufacturing (MM) concepts, is increasingly vital for autologous ATMPs with limited shelf-lives and those requiring customization near the patient's bedside [42]. The inherent complexity of these living therapies, combined with the use of substances of human origin and their biological variability, creates significant hurdles for manufacturers who must prove that their products remain equivalent regardless of where they are manufactured [34] [63].

The EU regulatory framework mandates that any legal entity manufacturing medicinal products must hold a manufacturing authorisation from the national competent authority of the Member State where the activities occur [34]. Historically, biological products have been partially defined by their manufacturing process, meaning that changes in the process, equipment, or facilities could potentially alter the product itself, necessitating additional clinical studies to demonstrate ongoing safety and efficacy [64]. The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions for decentralised production sites, potentially allowing manufacturing authorisation exemptions for decentralised sites operating under the responsibility of a qualified person at a central site [34]. This evolving regulatory landscape underscores the importance of robust, scientifically sound strategies for demonstrating comparability across sites—a capability that can significantly impact both regulatory approval and patient access to these transformative therapies.

Regulatory Framework and Key Definitions

EU Regulatory Foundations for Multi-Site Manufacturing

The manufacture of ATMPs within the European Union is governed by a comprehensive regulatory framework that emphasizes quality standards and regulatory oversight. The European Medicines Agency (EMA) plays a pivotal role in coordinating and harmonizing Good Manufacturing Practice (GMP) activities across member states, while national competent authorities issue manufacturing authorisations and conduct regular inspections to ensure compliance [34]. For ATMPs specifically, the European Commission has published detailed GMP guidelines that acknowledge the unique challenges posed by their complex manufacturing processes and specific characteristics, particularly the use of live biological samples with limited shelf-lives [34].

The MHRA's 2025 guidances on decentralized manufacturing represent a significant evolution in this framework, specifically addressing the challenges of multi-site manufacturing for cell and gene therapies. These guidances establish two distinct pathways for decentralized production: Point of Care (POC) products, designated as those that "for reasons relating to method of manufacture, shelf life, constituents, or method or route of administration, can only be manufactured at or near the place where the product is to be used or administered," and Modular Manufacturing (MM), defined for products where "the licensing authority determines it necessary or expedient to be manufactured or assembled in a modular unit" based on public health requirements or significant clinical advantage [42]. The regulatory framework requires a formal designation step where sponsors petition the MHRA for evaluation of their proposed decentralized manufacturing process early in the development cycle [42].

Core Comparability Concepts and Terminology

Table 1: Essential Comparability and Manufacturing Terminology

Term	Definition	Regulatory Significance
Comparability	The regulatory requirement to demonstrate product equivalence (highly similar) after a process change [63].	Enables process improvements and multi-site manufacturing without repeating clinical efficacy studies [64].
Critical Quality Attributes (CQAs)	Physical, chemical, biological, or microbiological properties or characteristics that should be within appropriate limits, ranges, or distributions to ensure desired product quality [63].	Form the basis for assessing comparability; variability in CQAs may impact product safety/efficacy.
Critical Process Parameters (CPPs)	Process parameters whose variability impacts a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality [63].	Key to establishing process consistency across different manufacturing sites.
Real-Time Release Testing (RTRT)	An approach where "compliance of a product with its specification is demonstrated based on process data, which typically include a valid combination of assessed material attributes and process controls" [42].	Particularly valuable for ATMPs with limited shelf-lives; emphasized in MHRA's decentralized manufacturing guidance.
Decentralized Manufacturing Master File (DMMF)	A document that describes how to complete manufacturing at decentralized sites under the oversight of a control site [42].	Required for both Marketing Authorization Applications and Clinical Trial Authorizations involving decentralized manufacturing.
Qualified Person (QP)	An individual responsible for ensuring that products have been manufactured and controlled in accordance with regulatory requirements before release [34].	Maintains oversight responsibility for decentralized sites under the proposed EU regulatory changes.

The concept of comparability is fundamental to manufacturing process changes. As stated in FDA guidance, "FDA may determine that two products are comparable if the results of the comparability testing demonstrate that the manufacturing change does not affect safety, identity, purity, or potency" [64]. A well-managed change process is required which needs access to good science and regulatory advice, and developers are encouraged to seek help early [63]. The goal of the comparability exercise is to ensure the quality, safety, and efficacy of the drug product produced by a changed manufacturing process through collection and evaluation of relevant data [63].

Strategic Framework for Multi-Site Comparability

Establishing a Control Strategy for Decentralized Networks

A robust control strategy is the cornerstone of successful multi-site manufacturing for ATMPs. The MHRA's 2025 guidance on Good Manufacturing Practices for decentralized manufacturing mandates the establishment of a designated "control site" located in the UK (or presumably within the EU for EMA-regulated products) that holds a manufacturing license and maintains a comprehensive Quality Management System (QMS) [42]. This control site assumes responsibility for multiple critical functions:

• Management of the decentralized manufacturing control strategy across all sites
• Generation and management of Decentralized Manufacturing Master Files (DMMFs) that provide detailed instructions for remote sites
• Onboarding, suspending, and pausing remote sites with adequate communication protocols
• Ongoing oversight of these sites including data integrity assurance
• Supplier management for materials and components supplied to the sites
• Training program development and implementation for personnel at all sites
• Product release procedures for point-of-care products [42]

This control strategy should treat remote manufacturing sites similarly to Contract Manufacturing Organizations (CMOs), with formal quality agreements, regular audits, and comprehensive oversight [42]. The guidance emphasizes that during inspections, regulatory authorities will focus on these assurance systems and may inspect a selection of remote sites to verify compliance [42].

Risk-Based Approach to Process Changes

Implementing a risk-based approach to process changes is essential for managing multi-site manufacturing consistency. Prior to undertaking any comparability study, it is crucial to understand what is expected based on the nature of the change and the stage of the product's lifecycle [63]. Historical data and process development data should be used to set comparability acceptance criteria for selected CQAs, and all data gathered during comparability exercises should be thoroughly analyzed to support claims of comparability at the quality level [63].

The significance of process changes should be evaluated based on their potential impact on product CQAs, with particular attention to:

• Changes in raw materials or components that may interact directly with the product
• Modifications to equipment that alter the processing environment or parameters
• Site-to-site transfers that introduce environmental or operational variations
• Scale-out adaptations for autologous cell therapies requiring parallel processing [34]

Any differences identified during comparability assessment should be thoroughly explained in terms of their potential effect on safety and efficacy. Where the effect on safety and efficacy cannot be predicted with confidence, further nonclinical or clinical data may be required by regulators [63].

Diagram 1: Risk-based approach to process changes

Methodologies and Experimental Protocols

Analytical and Functional Characterization Methods

A comprehensive analytical comparability package forms the foundation of any multi-site comparability assessment. Manufacturers should provide extensive chemical, physical, and bioactivity comparisons with side-by-side analyses of the pre-change product and qualification lots of the post-change product [64]. The analytical strategy should incorporate a tiered testing approach that focuses on the most sensitive and relevant methods for detecting potential impacts of manufacturing changes:

• Identity and Purity Profiling: Techniques such as flow cytometry for cell surface markers, DNA fingerprinting, and high-resolution chromatography for secreted factors should demonstrate identical profiles between sites.
• Potency and Bioactivity Assays: These are often the most critical for assessing comparability and should reflect the product's mechanism of action. Both in vitro (e.g., cell-based assays) and in vivo models may be employed, with emphasis on assay precision and ability to detect clinically relevant differences.
• Process-Related Impurities: Testing should evaluate clearance of residuals from manufacturing processes (e.g., cytokines, growth factors, antibiotics) and demonstrate consistent removal across sites.
• Product-Related Variants: Assessment should characterize and quantify variant forms of the active substance (e.g., differentiated states, senescent cells, aberrant populations) [64] [63].

The assay selection strategy should prioritize methods that are validated, stability-indicating, and capable of detecting quality changes. As emphasized in regulatory guidance, "Assays which enable the detection of variation as a result of any change are useful to inform conclusions. Assays should be shown to be capable of detecting quality changes" [63].

Process Performance Qualification and Monitoring

Establishing process consistency across multiple sites requires rigorous process performance qualification and ongoing monitoring. The following protocol outlines key elements for ensuring process consistency:

• Process Characterization Studies: Prior to multi-site implementation, conduct extensive characterization to identify Critical Process Parameters (CPPs) and their proven acceptable ranges through designed experiments (DoE).

• Site Qualification Lots: Manufacture a minimum of three consecutive qualification lots at each new manufacturing site using identical processes, materials, and equipment specifications.

• Statistical Process Control: Implement control charts for CPPs and CQAs to monitor process stability and capability across sites, establishing alert and action limits based on pooled data from all qualified sites.

• Comparative Stability Studies: Conduct real-time stability studies on products manufactured at different sites using the same stability protocol and storage conditions to demonstrate comparable shelf-life.

• Raw Material Sourcing Strategy: Implement a consistent approach to raw material qualification across sites, with particular attention to critical reagents and materials of biological origin [63].

The manufacturing process for ATMPs presents unique challenges for multi-site consistency, including maintaining sterility throughout, dealing with the variability of biological starting materials, and the autologous nature of many products which limits the number of analytical tests that can be performed [34]. Process mechanization—where equipment achieves better than human performance—rather than simple automation of manual processes can provide significant gains in reducing manufacturing variability across sites [63].

Table 2: Essential Research Reagent Solutions for Comparability Studies

Reagent/Category	Function in Comparability Assessment	Critical Quality Considerations
Characterized Reference Standard	Serves as benchmark for side-by-side comparison of products from different sites; essential for assay qualification [64].	Well-characterized; representative of clinical material; sufficient quantity for all studies; stable under storage conditions.
Cell-Based Potency Assay Reagents	Measures biological activity relevant to mechanism of action; often the most critical comparability assay [63].	Relevant to clinical activity; precise and reproducible; qualified/validated; sensitive to detect meaningful differences.
Process-Related Impurity Standards	Quantifies clearance of manufacturing residuals (cytokines, growth factors, antibiotics) across sites [64].	Certified reference materials when available; demonstrate consistent removal across manufacturing sites.
Cell Phenotyping Reagents	Characterizes surface markers, intracellular proteins, and functional states critical to product identity [63].	Validated specificity; appropriate controls; lot-to-lot consistency; minimal background interference.
Molecular Characterization Kits	Assess genetic stability, identity, and potential contaminants across manufacturing sites.	High sensitivity and specificity; validated for the specific matrix; reproducible across testing sessions.

Statistical Approaches for Comparability Assessment

A robust statistical framework is essential for demonstrating comparability across multiple manufacturing sites. The following methodologies support objective assessment of product and process consistency:

• Equivalence Testing: Utilize statistical equivalence tests rather than traditional significance tests, with equivalence margins justified based on clinical relevance and process capability.
• Multivariate Analysis: Apply Principal Component Analysis (PCA) and other multivariate techniques to evaluate the overall similarity of products from different sites across multiple attributes simultaneously.
• Process Capability Analysis: Calculate Cpk and Ppk values for CQAs to quantify the ability of each manufacturing site to consistently produce product within specified limits.
• Design of Experiments (DoE): Employ structured experimental designs during process characterization to understand interactions between process parameters and product attributes across different sites [63].

The sample size strategy for comparability studies should provide sufficient statistical power to detect clinically relevant differences, while acknowledging the practical limitations of ATMP manufacturing, particularly for autologous products. The use of historical data and process understanding can help justify the approach to sample size selection [63].

Diagram 2: Experimental workflow for comparability assessment

Documentation and Regulatory Submissions

Comparability Protocol and Master File Requirements

A well-defined comparability protocol is essential for successful regulatory review of multi-site manufacturing strategies. The US FDA defines a comparability protocol as "a well-defined, detailed, written plan for assessing the effect of specific CMC changes in the identity, strength, quality, purity and potency of a specific drug product as these factors relate to the safety and effectiveness of the product" [63]. While submission of a comparability protocol is optional, it represents a proactive approach that can facilitate more efficient review of manufacturing changes.

For decentralized manufacturing applications in the EU, the MHRA requires a Decentralized Manufacturing Master File (DMMF) which describes how to complete the manufacturing at decentralized sites under the oversight of a control site [42]. This document should include:

• Detailed manufacturing instructions for all steps performed at remote sites
• Testing requirements and acceptance criteria for in-process controls and final product
• Equipment specifications and qualification requirements
• Training requirements for personnel at remote sites
• Data recording and reporting procedures
• Handling of deviations and non-conformances
• Product release procedures for point-of-care products [42]

The DMMF follows classic Drug Master File rules of designation and reporting, and variations to the POC or MM master file must be submitted to regulators for approval [42].

Regulatory Submission Strategies

Navigating the regulatory pathways for multi-site manufacturing requires careful planning and coordination with health authorities. The MHRA's 2025 guidance outlines a designation step whereby sponsors petition for evaluation of products proposed to use decentralized manufacturing processes early in the development cycle [42]. This preliminary decision can be made as soon as 30 days, with full approval in 60 days, assuming all required information is presented [42].

For Marketing Authorization Applications (MAAs) involving decentralized manufacturing, particular emphasis is placed on process validation and demonstration that there is comparability between products made at the variety of remote manufacturing sites [42]. Since many autologous products use real-time release testing (RTRT), significant data should be presented to support this strategy [42]. The submission should describe the controlling site where the majority of manufacture occurs and how it will oversee decentralized sites [42].

For Clinical Trial Authorizations (CTAs), applications should reference the decentralized manufacturing designation and include a Manufacturing Importation Authorisation Application (MIA) with supporting data [42]. For point-of-care trials, special emphasis should be placed on assuring retention of blinding given the potential for differences in manufacturing processes between active and placebo products [42].

Successfully demonstrating product comparability and process consistency across multiple manufacturing sites for ATMPs requires a systematic, science-based approach integrated throughout the product lifecycle. The strategic implementation of decentralized manufacturing models depends on several critical success factors:

• Early Regulatory Engagement: Proactively seeking regulatory advice and pursuing formal designation for decentralized manufacturing approaches during development.
• Robust Control Strategies: Establishing comprehensive quality systems with clear oversight responsibilities between control sites and remote manufacturing locations.
• Tiered Analytical Approaches: Implementing orthogonal methods focused on detecting clinically relevant differences, with potency assays representing the most critical assessment.
• Risk-Based Change Management: Systematically evaluating the impact of process changes on product quality attributes and implementing appropriate verification strategies.
• Comprehensive Documentation: Preparing detailed comparability protocols and master files that transparently present data supporting manufacturing consistency across sites.

As the regulatory landscape evolves to accommodate innovative manufacturing approaches for ATMPs, the ability to demonstrate comparability across multiple sites will remain a fundamental enabler for expanding patient access to these transformative therapies. By adopting the strategies outlined in this guide, developers can navigate the complex technical and regulatory challenges while maintaining the rigorous quality standards required for these sophisticated medicinal products.

Managing Complex Supply Chains and Short Shelf-Lives for Fresh ATMP Products

Advanced Therapy Medicinal Products (ATMPs), including cell and gene therapies, represent a paradigm shift in medicine toward potentially one-time curative treatments [1]. Unlike conventional pharmaceuticals, these therapies often involve living cells firmly placing the patient at the center of drug production [65]. This personalized nature introduces extraordinary supply chain complexities, particularly for products with extremely short shelf lives ranging from 12 to 96 hours for fresh cell-based materials [65]. The successful delivery of these breakthrough treatments depends on overcoming significant logistical hurdles while navigating an evolving regulatory landscape that is beginning to adapt to these unique challenges through mechanisms like decentralized manufacturing [4].

Quantitative Analysis of ATMP Supply Chain Parameters

Table 1: Critical ATMP Supply Chain and Product Characteristics

Parameter	Value/Range	Impact on Supply Chain Design
Shelf Life	12 - 96 hours (fresh cells/tissues) [65]	Requires point-of-care manufacturing or regional manufacturing networks [65]
Storage Temperature	Cryogenic or deep-frozen [65]	Demands specialist shippers with stable temperature tracking [65]
Batch Size	Individual patient (autologous) or small group (allogeneic) [4]	Eliminates efficiency of classical scale-up; necessitates personalized batch handling [4]
Regulatory Review Delay (EU Import)	Up to 2 days for autologous therapies [65]	Presents critical risk for patients awaiting urgent, often life-saving therapy [65]
Contrast Ratio (Visualization)	Minimum 4.5:1 (normal text), 3:1 (large text/UI) [66]	Ensures accessibility of diagrams and documentation for all stakeholders

Table 2: EU Regulatory Framework for ATMPs and Supply Chains

Regulatory Aspect	Requirement	Supply Chain Implication
Manufacturing & Distribution Standards	Current Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) guidelines [65]	Requires validated processes, facilities, and equipment across entire chain [65]
Documentation	Government-stipulated docs for storage conditions, transport, precautions [65]	Necessitates seamless chain of custody, especially for autologous therapies [65]
Labeling	No exemption from labeling and re-test labeling requirements [65]	Impacts integrity of cryopreserved ATMPs; requires GMP-licensed facilities for secondary packaging [65]
New UK Framework (Effective July 2025)	Manufacturer's license (MM or POC) with Master File (MF) for satellite sites [4]	Allows product release at main manufacturing site, not bedside [4]

Regulatory Frameworks and Decentralized Manufacturing

The regulatory environment for ATMPs is evolving rapidly to address supply chain complexities. The European Union's Horizon HLTH-2025-01-IND-01 program focuses on optimizing ATMP manufacturing, emphasizing the need for flexible manufacturing (centralized or decentralized) and deployment in a patient-centric manner [1]. This includes exploring platform technologies and integrating computational modeling, automation, or digital/AI solutions to reduce timeframe and costs while maintaining quality [1].

A significant regulatory advancement is the UK's MHRA issuance of "The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025," effective July 2025 [4]. This framework introduces two innovative models for decentralized manufacturing:

• Modular Manufacturing (MM): Manufacturing activity performed away from the classic manufacturing site, potentially at a clinic or hospital laboratory, with the unit being potentially relocatable [4].
• Point of Care (POC) Manufacturing: Activity performed very close to the patient or at the bedside, applicable due to method of manufacture, shelf life, constituents, or administration route [4].

In both models, a "control site" holds the manufacturer's license (MM or POC) and maintains responsibility for supervising satellite sites that execute final manufacture or assembly via a Master File system. Crucially, product release occurs at the main manufacturing site, not the bedside, streamlining the process [4].

Experimental Protocols for Supply Chain Validation

Protocol: Validating Cryogenic Shipping Conditions

Objective: To verify that specialist shippers maintain stable cryogenic temperatures throughout simulated transport durations, ensuring product viability for short-shelf-life ATMPs [65].

Methodology:

• Equipment Calibration: Validate temperature logging devices against certified reference standards prior to testing.
• Shipment Simulation: Place ATMP product simulants in qualified cryogenic shippers and expose to defined thermal challenge profiles representing summer and winter extreme conditions.
• Data Collection: Record internal temperature at 5-minute intervals using independent, redundant logging systems. Monitor external location and conditions in real-time [65].
• Duration Testing: Extend testing to 150% of maximum expected transit time (e.g., 36 hours for a 24-hour shelf life) to establish safety margins.
• Failure Mode Analysis: Intententionally introduce interruptions (e.g., temporary power loss to freezer units) to establish recovery protocols and stability limits.

Acceptance Criteria: Temperature must remain within validated cryogenic range (e.g., ≤ -150°C) for 100% of the minimum required transport duration without deviation.

Protocol: Chain of Identity and Custody Verification

Objective: To ensure a seamless chain of custody for autologous therapies, guaranteeing patient safety through perfect material tracking [65].

Methodology:

• System Integration: Implement a multi-modal tracking system combining barcodes, RFID, and human-readable identifiers on all primary containers.
• Process Mapping: Document every material transfer point from apheresis through final administration, identifying verification checkpoints.
• Blinded Testing: Introduce intentional mismatches (0.5% of test runs) to verify system detection sensitivity and staff compliance with verification protocols.
• Time-Motion Study: Measure time required for identity verification at each checkpoint to identify potential bottlenecks that could compromise shelf life.
• Failure Recovery Simulation: Test backup identification procedures under scenarios including power outage, network failure, and damaged primary labels.

Acceptance Criteria: 100% accuracy in patient-material matching with zero undetected mismatches during blinded testing. Verification at any single checkpoint must not exceed 2 minutes.

Essential Research Reagent Solutions for ATMP Supply Chain Research

Table 3: Key Research Reagents and Materials for ATMP Supply Chain Studies

Reagent/Material	Function in Supply Chain Research
Cryopreservation Media	Protects cell viability during cryogenic storage and transport; formulation impacts post-thaw recovery rates [65].
Temperature Monitoring Devices	Validates maintenance of cold chain parameters; provides data for regulatory submission on transport conditions [65].
Viability Assays (e.g., flow cytometry reagents)	Quantifies product potency and quality at various supply chain points; critical for establishing shelf life [1].
Specialized Cryogenic Shipping Containers	Maintains stable cryogenic temperatures during distribution; requires qualification for each ATMP type [65].
Cell Culture Media Components	Supports functional potency testing upon receipt at point of care; validates product maintained integrity during transit [1].

Visualization of ATMP Supply Chain Models

Conventional vs. Decentralized ATMP Manufacturing

ATMP Supply Chain with Critical Control Points

The successful management of complex supply chains for short-shelf-life ATMP products requires an integrated approach combining specialized logistical capabilities, evolving regulatory frameworks, and robust quality systems. The emergence of decentralized manufacturing models represents a significant advancement in addressing the unique challenges of these personalized therapies. Future developments will likely focus on further harmonization of international regulations, advanced predictive analytics for supply chain optimization, and continued innovation in cryopreservation technologies to extend product stability. As the ATMP pipeline continues to grow, with approximately 1,000 cell and gene therapies in development and clinical trial [65], the creation of resilient, patient-centric supply chains will be essential to realizing the transformative potential of these advanced therapies.

Navigating the Regulatory Nuances of Starting Materials and Substances of Human Origin (SoHO)

The development of Advanced Therapy Medicinal Products (ATMPs) within the European Union operates within a complex dual regulatory framework governed by both the new Substances of Human Origin (SoHO) Regulation and the established ATMP Regulation. This interplay is particularly critical for professionals managing decentralized manufacturing sites, where the classification of starting materials directly impacts regulatory pathways and compliance strategies. The SoHO Regulation, which was formally adopted in July 2024 and will apply from August 2027, establishes updated standards of quality and safety for substances of human origin intended for human application [67]. This regulation replaces the previous Blood Directive (2002/98/EC) and Tissues and Cells Directive (2004/23/EC), creating a more comprehensive framework that encompasses emerging therapies and technologies [68].

For ATMP developers, understanding this regulatory intersection is essential because SoHOs frequently serve as critical starting materials in the manufacture of advanced therapies [69] [68]. The regulatory classification of these materials dictates whether they fall under the scope of the SoHO Regulation, the ATMP Regulation, or both, creating significant implications for manufacturing requirements, clinical trial design, and market authorization pathways. This landscape is further complicated by the trend toward decentralized manufacturing models, which present unique challenges for maintaining compliance across multiple production sites [27]. The European Medicines Agency (EMA) has recognized these complexities and has proposed revisions to Part IV of the EU Good Manufacturing Practice (GMP) guidelines specific to ATMPs, aiming to harmonize requirements with the updated SoHO framework and address technological advancements in manufacturing [52].

Defining Substances of Human Origin (SoHO) and Their Role as Starting Materials

What Constitutes a SoHO?

According to the new EU regulation, Substances of Human Origin (SoHO) encompass a broad range of biological materials, including blood, plasma, tissues, cells (such as haematopoietic and embryonic stem cells), breast milk, embryos, foetal tissues, reproductive cells, and intestinal microbiota [69]. The regulation also covers blood preparations that are not used for transfusion and allows for the inclusion of other human-origin substances that might be developed for human application in the future [69]. A key defining requirement is that the substance must have a biological interaction with the human body when applied [69].

The scope of the SoHO Regulation is intentionally comprehensive, designed to accommodate future scientific innovations while maintaining consistent safety and quality standards across all member states. This breadth, however, creates challenges for ATMP developers who must determine whether their starting materials fall under medicinal product legislation, SoHO legislation, or both regimes simultaneously. The regulation explicitly states that its objective is to "support the continued provision of SoHO therapies, now and in the future, based on high safety and quality standards and up-to-date technical rules" while "improving harmonisation across Member States" [67].

SoHO as Starting Materials for ATMPs

For ATMP manufacturers, SoHOs often serve as critical raw materials in the production of gene therapies, somatic cell therapies, and tissue-engineered products. The quality, safety, and traceability of these starting materials directly impact the final ATMP's safety profile and efficacy. As such, the SoHO Regulation establishes stringent requirements for the procurement, donation, and testing of these materials that ATMP manufacturers must incorporate into their quality systems [70].

Table: SoHO Categories and Their Applications in ATMP Development

SoHO Category	Examples	Common ATMP Applications	Key Regulatory Considerations
Blood and Components	Plasma, hematopoietic stem cells	Gene therapies, immunotherapies	Donor screening, infectious disease testing, traceability
Tissues and Cells	Skin cells, cartilage, limbal cells	Tissue-engineered products, somatic cell therapies	Processing standards, preservation techniques, quality controls
Reproductive Materials	Sperm, oocytes, embryos	Fertility treatments, regenerative medicine	Consent requirements, ethical considerations, storage conditions
Other Substances	Breast milk, intestinal microbiota	Microbiome therapies, specialized nutrition	Collection standards, processing methods, safety profiling

The relationship between SoHO establishments and ATMP developers is particularly synergistic. Blood establishments and other SoHO providers often possess the trained personnel, infrastructure, equipment, and storage capacity required for the development and production of ATMPs [22]. This existing expertise in handling human-derived materials makes them natural partners in the ATMP manufacturing ecosystem, especially as decentralized production models gain traction.

The Evolving Regulatory Framework: SoHO Regulation vs. ATMP Regulation

Key Provisions of the New SoHO Regulation

The SoHO Regulation (EU) 2024/1938, which will fully apply from 7 August 2027, introduces several significant updates to the regulatory landscape for substances of human origin [67]. The regulation aims to achieve multiple objectives: enhancing safety and quality standards, improving transparency and traceability, extending protection to donors and recipients, facilitating cross-border exchange of SoHOs, and supporting innovation in the sector [69]. A three-year transition period following its publication allows stakeholders to adapt to the new requirements, with certain provisions having an additional year for implementation [67] [69].

One of the most notable aspects of the SoHO Regulation is its broader protective scope, which extends to new groups of patients, donors, and offspring born from medically assisted reproduction [67]. The regulation also strengthens the principle of voluntary and unpaid donation, stating that "donation of SoHO should be voluntary and unpaid" and allowing compensation only "to prevent that SoHO donors are financially disadvantaged by their donation" [71]. This approach has generated significant discussion, particularly regarding its potential impact on plasma collection and self-sufficiency within the EU, as evidence shows that countries allowing compensation for plasma donors achieve higher self-sufficiency rates [71].

Table: Implementation Timeline for the SoHO Regulation

Timeline	Regulatory Milestone	Implications for ATMP Developers
July 2022	European Commission proposal tabled	Initial framework presented for stakeholder feedback
April 2024	European Parliament approval	Formal political endorsement of the regulation
July 2024	Publication in Official Journal of the EU	Regulation enters into force
August 2027	Full application of SoHO Regulation	Compliance mandatory for all SoHO activities
August 2028	Additional year for certain provisions	Extended timeline for specific requirements

Interface with the ATMP Regulation

The boundary between the SoHO Regulation and the ATMP Regulation (EC) No 1394/2007 represents a critical jurisdictional interface that often creates regulatory uncertainty for developers [72] [68]. This ambiguity stems from the fact that many ATMPs utilize SoHOs as their starting materials, blurring the lines between the transplantation-focused SoHO framework and the medicine-focused ATMP framework [22]. The classification of a product as either a SoHO preparation or an ATMP carries significant consequences for developers, affecting the applicable quality standards, clinical evidence requirements, and market authorization pathways [68].

The Committee for Advanced Therapies (CAT) at the EMA provides classification guidance for borderline products, but its authority is limited to determining whether a product falls under the ATMP Regulation—it cannot advise on whether a product should be considered a medicinal product, tissue, or cell [68]. This has led to situations where products previously regulated under the Tissues and Cells Directive have been reclassified as ATMPs, requiring manufacturers to transition from one regulatory framework to another mid-development [68]. Examples of such reclassified products include cultured limbal cells and cultured keratinocytes, creating significant additional costs and administrative burdens for developers [68].

Critical Regulatory Challenges and Borderline Classification Issues

The Problem of Borderline Products

The regulatory uncertainty surrounding borderline products represents one of the most significant challenges for ATMP developers using SoHOs as starting materials. Stakeholders have consistently reported that regulatory uncertainty and complexity negatively impact investment in research and development, reducing innovation and interest from commercial actors in Europe [68]. A 2018 survey identified divergent regulatory requirements as a primary challenge for European ATMP companies, with small and medium-sized enterprises (SMEs) facing particular difficulties in funding and compliance [68].

The consequences of misclassification or reclassification can be severe. Developers may invest significant resources into complying with one regulatory framework only to discover that their product is subsequently reclassified, necessitating a complete overhaul of their quality system, manufacturing processes, and clinical development plan. The high costs associated with reclassification and the need to obtain marketing authorization as medicines have been cited as major barriers to innovation in the European ATMP sector [68]. This regulatory instability creates particular challenges for decentralized manufacturing models, where consistency across multiple production sites is essential for maintaining quality and compliance.

Consultation Procedures for Regulatory Uncertainty

To address these classification challenges, the SoHO Regulation introduces a formal consultation procedure in Article 14 for situations of uncertainty regarding the regulatory qualification of substances, products, or activities [68]. This mechanism requires authorities responsible for SoHO legislation to consult with other authorities governing alternative regulatory frameworks when facing qualification uncertainties. Additionally, these authorities may seek an opinion from the SoHO Coordination Board (SCB), which compiles and maintains its decisions in a compendium for reference [68].

The consultation process involves several steps. SoHO competent authorities involved in the consultation must consult the SoHO compendium and consider any relevant regulatory status decisions and opinions included therein [68]. While authorities may submit a request to the SCB for an opinion on regulatory status, they are required to do so in "all cases where the consultations have not led to a decision on the regulatory status of such substance, product or activity in the Member State concerned" [68]. The European Commission also retains the competence to determine regulatory status either after a substantiated request from a Member State or on its own initiative [68].

Figure 1: SoHO Borderline Classification Consultation Procedure

While this consultation procedure represents a step toward addressing regulatory uncertainty, some critics argue that it does not go far enough. The SoHO Regulation does not establish a legal obligation for consulting the CAT on ATMP-related classification issues, nor does it create a European-level hierarchy for deciding borderline cases [68]. This means that pharmaceutical companies may still need to consult with multiple competent authorities in cases of regulatory status uncertainty, potentially leading to fragmented and inconsistent outcomes across Member States.

Compliance Strategies for Decentralized Manufacturing Sites

Implementing Robust Quality Systems

For decentralized manufacturing sites producing ATMPs that utilize SoHOs as starting materials, implementing comprehensive quality systems that address both regulatory frameworks is essential. The European Commission has published a set of GMP guidelines specific to ATMPs, which adapt the EU GMP requirements to the unique characteristics of these products [70]. These guidelines address the novel and complex manufacturing scenarios utilized for ATMPs and foster a risk-based approach to manufacture and testing [70].

The EMA has also proposed revisions to Part IV of the EU GMP guidelines specific to ATMPs, aiming to align them with the updated Annex 1 (which introduced modifications in the manufacture of sterile medicinal products) and incorporate principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) [52]. These revisions will emphasize the development and implementation of a contamination control strategy (CCS) and provide clarifications on qualifying, controlling, and managing new technologies such as automated systems, closed single-use systems, and rapid microbiological testing methods [52].

Table: Key Quality System Elements for SoHO-Based ATMP Manufacturing

Quality System Element	SoHO Regulation Requirements	ATMP Regulation Requirements	Integration Strategy for Decentralized Sites
Donor Eligibility Screening	Strict donor selection criteria based on SoHO type [71]	Compliance with relevant legislation for procurement and testing [70]	Unified donor screening protocol satisfying both frameworks
Traceability Systems	Full traceability from donor to recipient [69]	Batch tracing and unique product identifiers	Integrated tracking system covering both donation and manufacturing
Quality Control Testing	Safety testing for transmissible diseases [71]	Product-specific quality controls and potency assays	Consolidated testing strategy with defined acceptance criteria
Documentation Management	Donation records and processing documentation	IMPD/MAAP documentation per CTD structure	Unified document system with controlled access across sites
Change Control Procedures	Notification of material changes to competent authorities	Variation procedures for manufacturing changes	Centralized change control with site-specific assessments

Leveraging the Hospital Exemption Pathway

The Hospital Exemption (HE) pathway under the ATMP Regulation provides an important route for decentralized manufacturing of ATMPs using SoHOs as starting materials. This exemption allows ATMPs to be produced and used within a single Member State without going through the centralized marketing authorization procedure, provided they are manufactured on a non-routine basis and used in a hospital setting under the exclusive professional responsibility of a medical practitioner to meet the special needs of an individual patient [22].

The European Blood Alliance (EBA) strongly advocates for expanding, not limiting, the use of HE for ATMPs, suggesting that it should become a "harmonized regular approach" for producing ATMPs, including those with marketing authorization that are not available nationally [22]. The EBA also recommends modifying the ATMP framework to include elements from the SoHO regulation and reassessing the classification of products as either SoHO products or ATMPs [22]. This approach could potentially allow lower-risk cell-based ATMPs to be reclassified as SoHO products under specific conditions, simplifying their regulatory pathway while maintaining appropriate oversight.

For decentralized manufacturing sites, the HE pathway offers flexibility but also presents challenges related to scaling and consistency across multiple production sites. The current HE provisions—restricting production to the same Member State, requiring non-routine preparation within the hospital, and assigning responsibility to a single practitioner—are increasingly seen as "ill-suited to today's clinical and manufacturing realities" [22]. These limitations reduce the scalability and broader applicability of ATMP production, affecting supply and potentially limiting patient access to these innovative therapies.

Practical Implementation Guide

Step-by-Step Compliance Protocol

Navigating the dual regulatory requirements for ATMPs utilizing SoHOs requires a systematic approach to compliance. The following step-by-step protocol provides a framework for developers and manufacturers to ensure they meet their obligations under both regulatory frameworks:

• Material Classification Assessment: Determine whether your starting materials and final product fall under the SoHO Regulation, ATMP Regulation, or both. Document the rationale for this classification decision thoroughly, referencing the definitions in both regulations and any relevant borderline case decisions [68].

• Regulatory Pathway Mapping: Based on the classification, map the applicable regulatory pathway, including any potential exemptions (such as the Hospital Exemption) that may apply. Identify the specific requirements for each stage of development, from preclinical research through to marketing authorization [22].

• Quality System Integration: Develop an integrated quality system that addresses the requirements of both frameworks. This should include standardized procedures for donor screening and testing (for SoHOs) as well as product-specific quality controls and manufacturing standards (for ATMPs) [70].

• Documentation Strategy: Implement a comprehensive documentation strategy that satisfies the Common Technical Document (CTD) requirements for ATMPs while also maintaining the traceability and donor records mandated by the SoHO Regulation [44].

• Competent Authority Engagement: Proactively engage with relevant competent authorities through existing consultation procedures. For borderline products, utilize the Article 14 consultation process under the SoHO Regulation and seek classification guidance from the CAT where appropriate [68].

• Pharmacovigilance System Establishment: Establish a robust pharmacovigilance system that can track adverse events across decentralized manufacturing sites while maintaining the ability to trace back to original SoHO donations if required [27].

• Technology Implementation: Invest in technology solutions that support integrated data management across decentralized sites, particularly for traceability and quality control purposes. This is especially important for manufacturers utilizing point-of-care or modular manufacturing approaches [27].

The Scientist's Toolkit: Essential Research Reagents and Materials

Working with SoHOs as starting materials for ATMP development requires specialized reagents and materials to ensure compliance with regulatory requirements while maintaining product quality and safety. The following table outlines key solutions and their applications in this field:

Table: Research Reagent Solutions for SoHO-Based ATMP Development

Reagent/Material Category	Specific Examples	Function in SoHO-Based ATMP Development	Regulatory Considerations
Donor Screening Assays	Nucleic acid tests (NAT) for HIV/HBV/HCV, serological test kits	Detection of transmissible diseases in SoHO donations	Must use approved tests with demonstrated sensitivity/specificity [71]
Cell Culture Media	Serum-free media, cytokines, growth factors	Expansion and differentiation of SoHO-derived cells	Must meet quality standards for medicinal products; require qualification [44]
Cryopreservation Solutions	DMSO-containing cryoprotectants, controlled-rate freezing devices	Preservation of SoHO starting materials and intermediate/final ATMP products	Validation of post-thaw viability and functionality required [70]
Quality Control Reagents	Flow cytometry antibodies, potency assay reagents, sterility testing kits	Characterization and release testing of ATMPs	Require validation following ICH guidelines; critical reagent management [44]
Gene Editing Tools	CRISPR-Cas9 systems, viral vectors, mRNA	Modification of SoHO-derived cells for genetic therapies	Additional regulatory considerations for genetically modified organisms [44]

Future Outlook and Strategic Recommendations

Evolving Regulatory Landscape

The regulatory landscape for SoHOs and ATMPs continues to evolve, with several important developments on the horizon. The EMA's Guideline on clinical-stage ATMPs, which came into effect in July 2025, provides a multidisciplinary reference document covering quality, non-clinical, and clinical requirements for investigational ATMPs in clinical trials [44]. This guideline consolidates information from over 40 separate guidelines and reflection papers, representing a significant step toward harmonizing regulatory expectations for ATMP development [44].

Simultaneously, regulatory authorities are adapting to new manufacturing paradigms, including decentralized production models. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has introduced amendments to the Human Medicines Regulations 2012 that will facilitate the manufacture of medicines at the point of care (POC) and through modular manufacturing (MM) approaches [27]. These regulatory innovations, which take effect in July 2025, create flexibility for manufacturers while enabling patients to access medicines with short shelf lives or specialized handling requirements [27]. While this specific regulation applies to the UK, it may influence thinking across the European regulatory landscape.

Strategic Recommendations for Stakeholders

Based on the evolving regulatory framework and emerging trends in ATMP development, the following strategic recommendations are provided for stakeholders navigating the intersection of SoHO and ATMP regulations:

• Engage Early with Regulatory Authorities: Given the complexity and potential for reclassification of borderline products, developers should engage with competent authorities early in the development process to seek guidance on regulatory classification and pathway [68] [44]. Utilizing the consultation procedures available under both regulations can prevent costly mid-development changes to manufacturing processes or quality systems.

• Invest in Integrated Quality Systems: Rather than maintaining separate quality systems for SoHO and ATMP requirements, develop integrated systems that efficiently address the requirements of both frameworks. This approach is particularly important for decentralized manufacturing sites, where consistency across locations is essential [70] [27].

• Participate in Stakeholder Consultations: The European Commission regularly conducts public consultations on implementing regulations and guidelines. Active participation in these consultations allows stakeholders to share practical insights and help shape a more workable regulatory framework [72].

• Monitor Regulatory Convergence Initiatives: As noted in the EMA's guideline on clinical-stage ATMPs, there is ongoing effort toward global regulatory convergence in the ATMP field [44]. Monitoring these developments can help developers align their strategies with emerging international standards, potentially facilitating global development programs.

• Explore Hybrid Manufacturing Models: Consider hybrid approaches that leverage both traditional centralized manufacturing and emerging decentralized models. The MHRA's framework for decentralized manufacturing provides a useful reference for how such models might be implemented in compliance with regulatory requirements [27].

The successful navigation of the regulatory nuances between SoHOs and ATMPs requires a proactive, informed approach that anticipates regulatory evolution while maintaining rigorous quality standards. By understanding the interfaces between these frameworks and implementing strategic compliance measures, developers can advance innovative therapies while ensuring patient safety and regulatory compliance.

Maintaining Sterility and GMP Compliance in Non-Traditional Manufacturing Environments

The manufacturing of Advanced Therapy Medicinal Products (ATMPs), including cell and gene therapies, is undergoing a significant transformation driven by the need for more accessible and scalable production models. Decentralized manufacturing represents a fundamental shift from traditional centralized facilities to networks of smaller manufacturing sites, often located at or near the point of patient care (POCare) [17]. This approach is particularly crucial for autologous therapies, where patient-specific cells must be manipulated and returned within constrained timelines, making traditional logistics challenging [17]. For these products with very short shelf lives, manufacturing close to the patient significantly improves feasibility and accessibility [42].

This transition introduces unique challenges for maintaining sterility and Good Manufacturing Practice (GMP) compliance outside conventional cleanroom facilities. The European regulatory framework has evolved to accommodate this shift, with the revised EU GMP Annex 1 introducing stricter sterility requirements and emphasizing a risk-based approach to contamination control [73]. Simultaneously, regulatory bodies like the MHRA have created specific licensing categories for Point of Care (POC) and Modular Manufacturing (MM) to provide regulatory pathways for these innovative production models [42]. This technical guide examines the critical considerations for maintaining product quality, sterility, and regulatory compliance within these non-traditional manufacturing environments.

Regulatory Framework for Decentralized Manufacturing

EU GMP Annex 1 Revision and Its Impact

The recent revision of EU GMP Annex 1 represents a paradigm shift in sterile pharmaceutical manufacturing, with significant implications for decentralized production. The updated guidelines mandate a comprehensive Contamination Control Strategy (CCS) that requires manufacturers to systematically identify and control all potential contamination risks throughout the production process [73]. This holistic approach must cover environmental controls, process parameters, personnel training, and monitoring systems tailored to each manufacturing site's specific characteristics.

A key change in the revised Annex 1 is the strengthened requirement for real-time environmental monitoring in Grade A and B areas, moving beyond periodic testing to continuous, data-driven contamination prevention [73]. For decentralized sites, this necessitates compact, automated monitoring systems that can operate effectively in smaller spaces. The guidelines also place greater emphasis on barrier technologies such as isolators and Restricted Access Barrier Systems (RABS), which are particularly valuable in non-traditional environments where achieving full cleanroom classification may be challenging [73].

Emerging Regulatory Pathways for Decentralized Production

Regulatory agencies have developed new frameworks specifically for decentralized manufacturing models. The UK's MHRA has introduced two new license types: the Manufacturer's License (Point of Care) for products manufactured at or near where the patient receives care, and the Manufacturer's License (Modular Manufacturing) for products made in deployable modular units [42]. These pathways recognize the unique constraints of decentralized manufacturing while maintaining equivalent quality standards.

The Control Site model is a critical regulatory concept for decentralized networks. This central facility serves as the regulatory nexus, maintaining overall quality oversight and housing the Qualified Person (QP) responsible for product release [17]. The Control Site maintains the Decentralized Manufacturing Master File (DMMF), which comprehensively describes how manufacturing is completed at decentralized sites and ensures consistency across the network [42]. This model allows regulatory agencies to conduct focused inspections while ensuring robust oversight of distributed manufacturing activities.

Table: Key Regulatory Changes Impacting Decentralized Manufacturing

Regulatory Element	Traditional Requirement	Revised Approach for Decentralized Sites
Oversight Model	Single-site inspections	Control Site with Decentralized Manufacturing Master File (DMMF)
Environmental Monitoring	Periodic testing	Continuous, real-time monitoring with trend analysis
Contamination Control	Procedural controls	Comprehensive Contamination Control Strategy (CCS)
Facility Standards	Fixed cleanroom classifications	Barrier technologies with equivalent protection
Product Release	Centralized batch release	Qualified Person release at Control Site with remote oversight

Critical Sterility Challenges in Non-Traditional Environments

Infrastructure and Facility Limitations

Non-traditional manufacturing environments such as hospital pharmacies, mobile units, or modular facilities present distinct challenges for maintaining sterility. These sites often lack the structural integrity of purpose-built pharmaceutical facilities, with potential vulnerabilities in HVAC systems, material flows, and pressure cascades that are fundamental to contamination control [73]. The limited physical space also complicates the separation of critical manufacturing activities, increasing the risk of cross-contamination between process steps.

Environmental control becomes particularly challenging in these settings due to higher personnel proximity to critical zones and more frequent interventions compared to traditional cleanrooms [74]. Without the robust architectural features of conventional facilities, decentralized sites must rely more heavily on closed processing systems and advanced barrier technologies to maintain the required air quality and microbial controls [17]. The revised EU GMP Annex 1 explicitly acknowledges that alternative approaches may be necessary in these environments, but requires manufacturers to scientifically justify that such approaches provide equivalent sterility assurance [73].

Process Consistency and Personnel Factors

Maintaining process consistency across multiple manufacturing sites represents another significant challenge in decentralized models. Process variability between sites can lead to product quality differences, potentially impacting patient safety and therapy efficacy [17]. This is particularly critical for autologous therapies where each batch is patient-specific and traditional batch release testing may not be feasible due to time constraints.

Personnel factors present additional sterility risks in decentralized manufacturing. Operators in hospital-based or modular settings may have variable training backgrounds and less frequent exposure to aseptic processing compared to dedicated pharmaceutical manufacturing staff [73]. The revised Annex 1 emphasizes that personnel must undergo regular retraining and aseptic technique verification, with particular attention to gowning qualifications and behavior monitoring in clean areas [73]. These requirements can be challenging to implement consistently across distributed networks with high staff turnover or part-time involvement in manufacturing activities.

Technological Enablers for Sterility Assurance

Advanced Barrier Systems and Isolator Technology

Isolator technology represents a cornerstone for maintaining sterility in non-traditional manufacturing environments. Modern isolators provide a physically sealed workspace that separates the product from operators and the surrounding environment, drastically reducing contamination risks during critical processing steps [74]. By 2025, isolator systems have evolved to incorporate advanced filtration systems using HEPA or ULPA filters to maintain a sterile atmosphere, with constant positive pressure preventing contaminant ingress [74].

The latest advancements in isolator design focus on enhancing automation and monitoring capabilities. Next-generation isolators incorporate AI-driven environmental control systems that enable predictive maintenance and autonomous adjustment of testing conditions, reducing human intervention by up to 50% compared to previous models [74]. These systems are particularly valuable in decentralized settings where technical support may not be immediately available. Furthermore, modern isolators feature modular designs that allow for flexible configuration in space-constrained environments such as hospital pharmacies or mobile manufacturing units.

Closed and Automated Processing Systems

Closed processing systems are essential technological enablers for decentralized manufacturing, as they minimize the infrastructure requirements at treatment facilities while maintaining compliance with regulatory standards [17]. These systems maintain product integrity through pre-sterilized, single-use flow paths that eliminate the need for complex cleaning validation and reduce the risk of cross-contamination between batches. For ATMP manufacturing, which often involves multiple processing steps, closed systems provide an integrated approach to maintaining aseptic conditions throughout the entire workflow.

Automation plays a complementary role to closed processing by reducing operator-dependent steps and associated contamination risks. Automated systems can handle tasks ranging from sample preparation to final product formulation with minimal human intervention, enhancing both sterility assurance and process consistency [74]. In the context of decentralized manufacturing, automated platforms can process up to 200% more samples per day compared to semi-automated systems while maintaining stringent sterility standards [74]. This increased throughput is particularly valuable for distributed networks where multiple patients may require simultaneous treatment.

Table: Technology Comparison for Sterility Assurance

Technology	Traditional Application	Decentralized Manufacturing Application	Sterility Benefit
Isolators	Large-scale production lines	Compact, mobile units for point-of-care use	Physical separation from operators
Closed Systems	Individual process steps	End-to-end processing in single-use kits	Elimination of open processing steps
Automated Platforms	Dedicated cleanrooms	Benchtop systems in reduced-classification spaces	Reduced human intervention
Real-time Monitoring	Fixed sensors in cleanrooms	Portable, compact sensors with wireless connectivity	Immediate contamination detection

Quality Management System Framework

Control Site Model and Oversight Mechanisms

The Control Site model forms the foundation of an effective Quality Management System (QMS) for decentralized manufacturing networks. The Control Site serves as the central regulatory interface, holding the manufacturing authorization and maintaining overall responsibility for product quality across all manufacturing sites [17]. This centralized oversight structure is essential for ensuring consistent application of GMP standards and providing a single point of accountability for regulatory agencies.

The Control Site maintains several critical quality functions, including management of the Quality Management System (QMS), oversight of the Contamination Control Strategy, and administration of the Decentralized Manufacturing Master File (DMMF) [42]. The site also houses the Qualified Person (QP) who bears ultimate responsibility for batch certification and release, leveraging data from remote manufacturing sites to make release decisions [17]. This model enables effective quality oversight while allowing manufacturing to occur at multiple distributed locations, often far from the Control Site itself.

Contamination Control Strategy for Distributed Sites

A comprehensive Contamination Control Strategy (CCS) is mandatory under the revised EU GMP Annex 1 and requires particular attention in decentralized manufacturing models. The CCS must be a proactive, science-based approach that identifies all potential contamination risks specific to each manufacturing location and implements appropriate control measures [73]. For distributed networks, the CCS should address site-specific variables while maintaining consistent quality standards across the entire network.

Key elements of the CCS for decentralized manufacturing include environmental monitoring programs tailored to each facility's design and operational patterns, personnel qualification and monitoring programs that account for variable experience levels, and process controls that accommodate potential differences in equipment and layouts between sites [73]. The strategy must also include robust data management systems that aggregate and analyze monitoring data from all sites to identify trends and implement preventive actions before deviations occur. This data-driven approach is fundamental to maintaining sterility across distributed manufacturing networks.

Implementation Methodology and Protocols

Environmental Monitoring Protocol for Non-Traditional Environments

Environmental monitoring in non-traditional manufacturing environments requires adapted protocols that address the specific constraints of these settings while maintaining adequate contamination control. The following methodology provides a framework for implementation:

Air Quality Monitoring: Deploy continuous particle monitoring systems in Grade A and B equivalent zones, with alarm thresholds set according to Annex 1 requirements. In space-constrained environments, use compact sensors with wireless connectivity to minimize infrastructure impact. Monitoring should include viable particle counts using settle plates, active air samplers, and contact plates at predetermined frequencies based on risk assessment [73].

Surface and Personnel Monitoring: Implement rigorous surface monitoring programs for all critical zones, with particular attention to equipment interfaces and transfer points. Personnel monitoring should include glove fingertip testing after critical aseptic operations and regular gowning qualification. In decentralized settings with less experienced operators, increase monitoring frequency during initial operations and gradually reduce based on demonstrated proficiency [73].

Data Management and Trend Analysis: Establish centralized data collection systems that aggregate environmental monitoring data from all manufacturing sites. Apply statistical process control methods to identify trends and initiate corrective actions before excursion events occur. The Contamination Control Strategy should define specific response actions for trending signals, including increased monitoring, process adjustments, or additional training [73].

Process Validation Approach for Distributed Manufacturing

Validating manufacturing processes across multiple decentralized sites requires a systematic approach to demonstrate comparability and consistency:

Comparative Process Qualification: Execute parallel validation runs at multiple manufacturing sites using identical materials, equipment, and procedures. Measure critical quality attributes for each run and apply statistical analysis to demonstrate that inter-site variability does not exceed pre-defined acceptance criteria [17]. This approach is particularly important for autologous therapies where traditional batch release testing may not be feasible.

Closed System Validation: For processes utilizing closed manufacturing systems, validate system integrity through media fill simulations that represent worst-case scenarios including maximum intervention frequency and operator manipulation. Perform these simulations at each manufacturing site to confirm that closed systems maintain sterility under local operating conditions [17].

Ongoing Process Verification: Implement continuous monitoring of critical process parameters across all manufacturing sites using automated data capture systems. Apply multivariate analysis to identify potential drift in process performance and trigger preventive maintenance before product quality is impacted. This approach is essential for maintaining process consistency in decentralized networks with variable operational factors [17].

Diagram: Quality Oversight Model for Decentralized Manufacturing

Essential Research Reagents and Materials

The implementation of sterility controls in non-traditional manufacturing environments requires specific reagents and materials tailored to the constraints of these settings. The following table details critical components for maintaining GMP compliance in decentralized manufacturing:

Table: Essential Materials for Sterility Maintenance in Non-Traditional Environments

Material/Reagent	Function	Application in Decentralized Sites
Ready-to-Use Culture Media	Supports cell growth and expansion	Pre-qualified, sterile-filtered media reduces preparation steps and contamination risk
Closed System Transfer Devices	Maintains sterility during fluid transfers	Enables aseptic connections in non-classified spaces
Rapid Microbial Detection Systems	Detects contamination in process samples	Provides faster results critical for short-shelf-life products
Single-Use Bioreactors	Provides controlled environment for cell culture	Eliminates cleaning validation and reduces infrastructure needs
Environmental Monitoring Kits	Monitors air and surface microbial quality	Compact, portable systems for space-constrained facilities
Validated Sterilizing Agents	Eliminates microbial contamination	Spray-based sterilants for isolators and barrier systems
Class A Simulation Media	Validates aseptic processing operations	Supports media fill studies for process qualification

Maintaining sterility and GMP compliance in non-traditional manufacturing environments requires a fundamentally different approach than traditional pharmaceutical production. The control site model with robust quality oversight provides the foundation for distributed manufacturing networks, while technological enablers such as closed processing systems and advanced isolators mitigate the contamination risks inherent in these settings. Implementation of a comprehensive, science-based contamination control strategy tailored to each manufacturing site's specific characteristics is essential for maintaining product quality and regulatory compliance.

As the regulatory landscape continues to evolve to accommodate these innovative manufacturing models, the fundamental principle remains unchanged: patient safety through assured product sterility. The approaches outlined in this technical guide provide a framework for achieving this goal while enabling the broader accessibility of advanced therapies through decentralized manufacturing networks.

Implementing Effective Pharmacovigilance and Product Traceability Across Multiple Healthcare Settings

The manufacturing of Advanced Therapy Medicinal Products (ATMPs) is undergoing a fundamental transformation, shifting from traditional centralized facilities to decentralized manufacturing (DM) models that bring production closer to patients. This paradigm shift, driven by the need for personalized, often patient-specific therapies with short shelf-lives, introduces unprecedented complexity into pharmacovigilance (PV) and traceability systems. The European regulatory landscape is rapidly evolving to accommodate this change, with the UK's Medicines and Healthcare products Regulatory Agency (MHRA) implementing a pioneering framework in January 2025 that formally recognizes modular manufacture (MM) and point-of-care (POC) manufacturing as legitimate pathways for medicinal products, including ATMPs [27] [58]. Simultaneously, the European Commission has strengthened the EU pharmacovigilance framework through Implementing Regulation (EU) 2025/1466, which becomes fully applicable in February 2026 [75] [76]. This technical guide provides drug development professionals with methodologies to implement robust PV and traceability systems capable of ensuring patient safety across distributed manufacturing networks, aligning with the broader thesis that regulatory innovation is essential for enabling safe, effective decentralized ATMP production.

Regulatory Framework for Decentralized Operations

Evolving EU Pharmacovigilance Requirements

The revised EU pharmacovigilance legislation, Implementing Regulation (EU) 2025/1466, introduces significant enhancements to post-marketing surveillance obligations that are particularly consequential for decentralized manufacturing models. These requirements are being implemented on a phased timeline, creating specific compliance milestones for marketing authorisation holders (MAHs) [75] [76].

Table 1: Key Requirements of Implementing Regulation (EU) 2025/1466

Requirement	Application Date	Impact on Decentralized Manufacturing
Expanded safety monitoring of EudraVigilance data	August 12, 2025	MAHs must monitor all EudraVigilance data alongside other sources, requiring enhanced data integration capabilities across distributed sites [75].
Updated signal management processes	August 12, 2025	Removal of standalone signal notification requirement; signals must be handled through MAH's own processes per GVP Module IX [75].
Strengthened subcontractor obligations	February 12, 2026	Contracts must clearly define roles, safety data exchange methods, and audit arrangements for all third parties with subcontracted PV obligations [75].
Revised deviation management	February 12, 2026	Only major and critical deviations from PV procedures must be documented in the Pharmacovigilance System Master File (PSMF) until resolved [75].
Enhanced Periodic Safety Update Reports (PSURs)	February 12, 2026	PSURs must include updates on implementation of risk minimization measures (RMMs) and assessment of their effectiveness [75].
Post-Authorisation Safety Studies (PASS) transparency	February 12, 2026	Study protocol, abstract, and final study report must be entered into EMA electronic PASS register with strict timing [75].

MHRA's Framework for Decentralized Manufacturing

The MHRA's 2025 regulatory innovations create a structured pathway for decentralized production while imposing specific pharmacovigilance and traceability obligations. The framework introduces two distinct license types: Manufacturer's License (MM) for modular manufacture and Manufacturer's License (POC) for point-of-care manufacture [27] [58]. For POC licenses, manufacturers must demonstrate to the MHRA that their product "can only be manufactured" at or near the place of administration, typically due to extreme shelf-life constraints or highly personalized nature [27]. Both license types operate under a "control site" model, where only the control site appears on the manufacturer's authorization, while individual secondary sites are authorized through inclusion in a Decentralised Manufacturing Master File (DMMF) [27]. This master file must comprehensively capture all manufacturing locations, their operational status, contact details, products, processes, and procedures, creating a centralized repository for regulatory oversight of distributed operations [27].

Implementing Traceability in Distributed Networks

Strategic Foundations

In decentralized manufacturing environments, traceability extends beyond regulatory compliance to become a fundamental patient safety imperative. The ISO 9000:2015 standard defines traceability as "the ability to trace the history, application, location or source(s) of a material or product throughout the supply chain" [77]. For ATMPs, this definition must encompass the entire product journey from starting materials through administration to the patient, including all intermediate handling steps across geographically dispersed locations. A holistic traceability strategy must integrate multiple data layers: company data (information about the organization and its processes), product data (composition, origin, environmental attributes), shipment data (movement records between supply chain actors), and order data (transaction documentation) [77]. This multi-layered approach enables comprehensive visibility essential for both quality oversight and pharmacovigilance activities.

Technical Implementation Framework

The MHRA mandates specific traceability requirements for decentralized manufacturing operations that necessitate sophisticated technical implementation. All DM products must maintain batch traceability across the manufacturing network, with decentralized medicines, including control and manufacturing site lists, incorporated into the Pharmacovigilance System Master File (PSMF) [27]. For products manufactured at the point-of-care for immediate administration, where no portion of the medicinal product is retained after administration, there is a labeling exemption; however, the use of "pre-applied patient identified" on primary packaging is recommended to maintain patient-level traceability [27]. Manufacturers must demonstrate robust processes to show how adverse events are collected, allocated, and evaluated across multiple healthcare settings, with particular emphasis on integration between different sites involved in the DM product lifecycle [27]. The qualified person for pharmacovigilance (QPPV) must maintain clear oversight of all processes and sites, establishing defined linkages to other personnel and departments such as the responsible person (RP) and quality department [27].

Diagram 1: End-to-End Traceability and PV Workflow

Pharmacovigilance System Adaptation

Signal Detection and Management

Decentralized manufacturing necessitates enhanced signal detection capabilities that can differentiate between product-specific and manufacturing site-specific safety signals. Marketing Authorization Holders must implement processes sensitive enough to detect acute and serious new risks that may emerge at individual manufacturing site levels [78]. Critically, product quality information must be integrated into signal detection activities, as variations in production across different sites may impact product safety profiles [78]. Under the revised EU regulations, MAHs are no longer expected to submit validated signals via standalone notification forms but must instead handle all signals detected through EudraVigilance and other sources according to their own validated signal management processes, following Good Pharmacovigilance Practices (GVP) Module IX [75]. This approach requires sophisticated data analytics capable of correlating adverse event patterns with specific manufacturing sites, processes, or product batches across the distributed network.

Risk Management Plan Enhancement

Risk Management Plans (RMPs) for decentralized manufactured products require specific adaptations to address the unique risk profile of distributed production. The pharmacovigilance plan within the RMP must clearly articulate how decentralized manufacturing affects product use and specify any additional safety measures required, such as enhanced monitoring or tracking by batch and manufacturing site [78]. MAHs must gather comprehensive safety data on how the product is used across different settings, with Periodic Safety Update Reports (PSURs) including safety data categorized by manufacturing site to ensure transparency and traceability [78]. Beginning February 12, 2026, PSURs must also contain updates on the implementation of risk minimization measures (RMMs) in addition to assessments of their effectiveness, requiring systematic tracking of RMM deployment across all manufacturing and administration sites [75].

Table 2: Signal Detection Requirements for Decentralized Manufacturing

Signal Detection Aspect	Traditional Manufacturing	Decentralized Manufacturing	Implementation Methodology
Data Source Integration	Primarily spontaneous reports, literature	EudraVigilance plus site-specific quality data	Automated data feeds from all manufacturing sites to central safety database [75] [78]
Signal Analysis	Product and substance-focused	Additional analysis by manufacturing site	Statistical algorithms comparing AE rates across sites; control charts for quality parameters [78]
Quality-Safety Correlation	Limited integration	Mandatory integration	Cross-functional review committees assessing quality deviations and adverse event patterns [78]
Regulatory Reporting	Standalone signal notifications	Integrated into MAH's signal management process	Validated SOPs aligned with GVP Module IX; documentation in PSMF [75]

Experimental Protocols for System Validation

Traceability Protocol Validation

Validating traceability systems in decentralized environments requires rigorous experimental protocols that simulate real-world conditions across multiple nodes in the manufacturing network. The following methodology provides a framework for establishing traceability protocol effectiveness:

• System Architecture Mapping: Document all data capture points across the manufacturing network, including material receipt, processing steps, quality control checkpoints, packaging, and administration. For each point, identify the specific data elements captured, format (automated electronic, manual entry), and transmission mechanism to central repositories [27] [77].

• Data Integrity Testing: Implement challenge tests using synthetic patient and batch data introduced at multiple points in the system. Measure data capture accuracy, transmission latency, and reconciliation capability across an increasingly distributed network (beginning with 3 nodes, expanding to 10+ nodes for robust validation) [77].

• Failure Mode Simulation: Intentionally introduce system failures (network outages, database failures, manual entry errors) at different nodes to verify system resilience and data recovery capabilities. Document time to full system recovery and any data loss incidents [27].

• End-to-End Traceability Verification: For simulated product batches, verify the percentage of units achieving complete traceability from starting materials through final administration. Establish acceptance criteria of >99.5% complete traceability across all manufactured units [78].

• Regulatory Audit Preparedness Testing: Conduct mock audits requesting specific traceability documentation for randomly selected product batches and manufacturing sites. Measure response time and completeness of documentation retrieval [75].

Pharmacovigilance Process Validation

Ensuring robust adverse event capture and analysis across distributed manufacturing sites requires validation of pharmacovigilance processes through the following experimental protocol:

• Adverse Event Capture Completeness Assessment: Deploy standardized test cases of adverse events of varying seriousness and relatedness probabilities across different manufacturing sites. Measure detection rates and time-to-capture for each test case, with particular attention to differences in performance across sites [27] [78].

• Signal Detection Sensitivity Analysis: Introduce known safety signals into the safety database with specific patterns correlating with manufacturing site parameters. Validate that statistical detection algorithms identify site-correlated signals within established timeframes (e.g., 30 days for strong signals, 60 days for emerging signals) [75] [78].

• Quality-PV Data Integration Testing: Create scenarios where quality events (deviations, out-of-specification results) at specific manufacturing sites should trigger enhanced safety monitoring. Verify that the quality system appropriately flags these events to the PV team and that predetermined actions are initiated [78].

• Cross-Functional Communication Validation: Simulate urgent safety issues requiring coordinated responses across quality, manufacturing, and PV functions. Measure response times and effectiveness of implemented actions across the decentralized network [27] [75].

The Scientist's Toolkit: Essential Research Reagent Solutions

Table 3: Essential Research Reagents for Decentralized Manufacturing Studies

Reagent/Technology	Function in Experimental Studies	Application in Decentralized Models
Digital Object Identifiers (DOIs)	Unique persistent identifiers for literature references	Mandatory under EU 2025/1466 for tracking scientific literature in safety reports; enables accurate reference management across distributed teams [75] [76].
MedDRA Terminology	Standardized medical terminology for adverse event classification	Required for regulatory reporting; ensures consistent coding of safety data across multiple sites and facilitates aggregated analysis [76].
ISO Standards Suite	Interoperability standards for data exchange (EN ISO 11615, 11616, 11238, 11239, 1124)	Provides framework for consistent data architecture across decentralized manufacturing sites; essential for regulatory compliance [76].
Platform Technologies	Standardized manufacturing processes adaptable across multiple products	Enables harmonized manufacturing approaches across distributed sites; critical for modular manufacturing scalability [1].
Advanced Sensor Technologies	Real-time monitoring of critical process parameters	Provides continuous quality assurance in remote manufacturing locations; enables real-time release and reduces onsite QC footprint [1].
AI-Powered Predictive Quality Tools	Machine learning algorithms for quality prediction	Detects deviations before they impact product quality; essential for maintaining quality oversight across multiple decentralized sites [58].

Implementing effective pharmacovigilance and product traceability across decentralized manufacturing networks represents both a formidable challenge and an imperative for the future of ATMPs. The regulatory framework is rapidly evolving on multiple fronts, with the MHRA's 2025 decentralized manufacturing regulations and the EU's Implementing Regulation 2025/1466 creating a comprehensive structure for ensuring patient safety in distributed production models. Success in this environment requires a proactive, integrated approach that leverages digital technologies, establishes robust quality management systems spanning all manufacturing sites, and maintains continuous regulatory vigilance. As treatment methods continue to evolve, the guidance governing decentralized manufacturing will inevitably undergo further refinement [27]. Drug development professionals must therefore implement systems that are not only compliant with current requirements but also sufficiently adaptable to accommodate future regulatory developments. Through strategic implementation of the methodologies outlined in this guide, manufacturers can navigate the complexities of decentralized production while upholding the highest standards of patient safety and regulatory compliance.

Addressing the High Costs and Infrastructure Requirements for Scalable Deployment

The field of Advanced Therapy Medicinal Products (ATMPs), encompassing gene therapies, cell-based therapies, and tissue-engineered products, represents a transformative shift in medicine toward potentially curative treatments for diseases with high unmet needs [9] [1]. However, the development and manufacturing of ATMPs face significant challenges, including long development times, expensive manufacturing processes, and a fragmented biomanufacturing landscape [9] [1]. Unlike classical biologics where a single batch can treat thousands of patients, many ATMPs are personalized medicines designed for individual patients, making efficiency gains through traditional scale-up impossible [4]. This manufacturing paradigm creates substantial economic and logistical barriers to widespread patient access, with production costs sometimes reaching several million euros per patient [79]. This whitepaper examines the regulatory, technical, and operational strategies available to overcome these barriers and enable scalable, cost-effective deployment of ATMPs within the European regulatory framework.

Regulatory Frameworks Enabling Distributed Manufacturing

EU Regulatory Landscape and Support Initiatives

The European regulatory framework for ATMPs is established principally under Regulation (EC) No 1394/2007, with the Committee for Advanced Therapies (CAT) within the European Medicines Agency (EMA) providing scientific evaluation and guidance [56] [80]. Several regulatory mechanisms specifically support the development of more efficient ATMP manufacturing:

• PRIME (Priority Medicines) Scheme: Provides enhanced support and accelerated assessment for therapies addressing unmet medical needs, including early and interactive regulatory guidance [56] [81].
• Horizon Europe Funding Program: Topic HORIZON-HLTH-2025-01-IND-01 specifically targets optimization of ATMP manufacturing, with a €40 million budget supporting projects that integrate computational modeling, automation, robotics, or digital/AI solutions [9] [1].
• Hospital Exemption (HE) Scheme: Allows use of unlicensed ATMPs manufactured on a non-routine basis for individual patients within specific member states, though utilization varies significantly across countries [37].

The recent EU Health Technology Assessment Regulation (EU 2021/2282), fully enforced in January 2025, introduces joint clinical assessments for ATMPs to streamline evaluation across member states [82]. Additionally, the upcoming Substances of Human Origin Regulation (SoHO-R) will create a unified framework for human-derived materials used in ATMP manufacturing [83].

Emerging Models for Decentralized Manufacturing

Regulatory innovation is specifically addressing the challenges of decentralized manufacturing. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has introduced a pioneering framework for modular manufacturing (MM) and point-of-care (POC) manufacturing that offers a template for regulatory evolution in the EU [4].

Table 1: Comparison of Emerging Decentralized Manufacturing Models

Model Aspect	Modular Manufacturing (MM)	Point-of-Care (POC) Manufacturing
Definition	Manufacturing activity performed away from the classic manufacturing site (e.g., at a clinic or hospital laboratory)	Manufacturing activity performed very close to the patient or at the bedside
Regulatory License	Manufacturer's license (MM)	Manufacturer's license (POC)
Product Release	At the main manufacturing site (control site)	At the main manufacturing site (control site)
Documentation	Master File (MF) with full instructions for satellite sites	Master File (MF) with full instructions for satellite sites
Suitable Scenarios	Short shelf life, personalized treatments requiring specialized facilities	Immediate administration needed, highly patient-specific manufacturing

This model utilizes a Master File (MF) process similar to the Drug Master File system, where a central "control site" holds the manufacturing license and creates the MF that satellite sites follow [4]. This approach moves product release from the bedside back to the factory, maintaining quality control while enabling geographic distribution of manufacturing activities [4].

Technical Strategies for Cost Reduction and Process Optimization

Manufacturing Process Intensification and Automation

Addressing the high costs of ATMP manufacturing requires fundamental rethinking of production processes. The following technical approaches demonstrate significant potential for cost reduction and scalability:

• Platform Technologies: Developing standardized manufacturing platforms for similar product classes can reduce process development time and capital investment [9]. Evidence suggests that exploring platform technologies in manufacturing, quality control, and testing can lead to substantial efficiency gains [9] [1].

• Process Analytical Technology (PAT) and Digital Solutions: Integrating advanced sensors and digital monitoring enables real-time quality control and reduces extensive offline testing. Proposals should integrate "computational modelling, automation, robotics or digital/Artificial Intelligence solutions with meaningful and measurable impact" [9] [1].

• Closed and Automated Systems: Implementing closed, automated bioreactor systems and processing equipment reduces manual operations, contamination risk, and cleanroom requirements [80]. This is particularly valuable in decentralized settings where highly specialized facilities may be limited.

The experimental approach to process optimization should follow a structured methodology: (1) Process Characterization to identify Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs); (2) Design of Experiments (DoE) to understand parameter interactions and establish proven acceptable ranges; (3) Process Validation according to a Process Validation Master Plan; and (4) Continuous Verification using advanced monitoring technologies [80].

Chemistry, Manufacturing, and Controls (CMC) Optimization

A robust Chemistry, Manufacturing, and Controls (CMC) strategy is foundational to reducing costs while maintaining quality. Key elements include:

• Potency Assay Development: Establishing a relevant, quantitative, and stability-indicating potency assay as a Critical Quality Attribute (CQA) is essential for demonstrating product consistency [81]. This assay should be "measurable, scalable and reasonable to assess during the compressed timelines of a commercial programme" [81].

• Raw Material Strategy: Implementing a comprehensive approach to raw material selection, qualification, and testing reduces variability. This includes careful selection and sourcing of raw materials (e.g., culture media) and starting materials (e.g., cells from healthy donors) [80].

• Comparability Protocols: Planning for manufacturing changes through structured comparability studies, retaining Phase I samples for later comparison, and building a clear comparability narrative [81].

Table 2: Cost Distribution in ATMP Manufacturing and Optimization Opportunities

Cost Category	Traditional Approach	Optimization Strategy	Potential Impact
Raw Materials	25-35% of total cost	Platform media formulations, centralized sourcing	20-30% reduction
Labor	30-40% of total cost	Automation, closed systems	40-50% reduction
Quality Control	15-25% of total cost	Process Analytical Technology, real-time release	30-40% reduction
Facilities	10-20% of total cost	Modular facilities, decentralized manufacturing	25-35% reduction
Product Failures	5-15% of total cost	Enhanced process control, predictive analytics	50-70% reduction

The diagram below illustrates a comprehensive framework for optimizing ATMP manufacturing processes from technology transfer through continuous monitoring:

Implementation Framework for Decentralized Manufacturing Networks

Infrastructure Design and Operational Considerations

Implementing successful decentralized manufacturing networks requires careful infrastructure planning. Two complementary models have emerged:

• Hub-and-Spoke Model: A central GMP-compliant facility (hub) handles complex manufacturing steps, while satellite units (spokes) perform final formulation, administration, or less complex manufacturing steps [4] [79]. This approach is particularly suitable for products with shorter shelf lives or significant personalization requirements.

• Modular Facility Approach: Utilizing standardized, potentially relocatable modular manufacturing units that can be deployed at multiple locations [4]. These units can operate under a single marketing authorization through the Master File system, with the license holder responsible for supervision and control of all sites.

Critical operational considerations include: (1) Supply Chain Logistics for timely delivery of materials and products; (2) Personnel Training to ensure consistent operations across sites; (3) Quality Management Systems that function across the network; and (4) Data Management infrastructure for real-time monitoring and documentation [4] [80].

Regulatory Strategy and Documentation

Navigating the regulatory requirements for decentralized manufacturing demands a proactive strategy:

• Early Regulatory Engagement: Seeking scientific advice and engaging with regulators through mechanisms like the EMA's Innovation Task Force (ITF) briefing meetings early in development [81] [83]. "Regulators are happy to offer scientific advice and early engagement helps developers understand the regulatory agency and build key relationships" [81].

• Integrated Evidence Generation: Designing development programs that generate evidence for both regulatory and health technology assessment (HTA) requirements simultaneously [82] [81]. The new EU HTA regulation requires joint clinical assessments for ATMPs, making early consideration of HTA evidence requirements essential.

• Master File Preparation: Developing comprehensive Master Files that provide detailed instructions for all manufacturing sites, including contingency plans for process deviations and quality investigations [4].

The diagram below illustrates the relationship between different stakeholders in a decentralized ATMP manufacturing network:

Essential Research Tools and Reagent Solutions

Successful implementation of scalable ATMP manufacturing requires specific research tools and reagents designed to meet regulatory requirements while maintaining cost-effectiveness.

Table 3: Essential Research Reagent Solutions for Scalable ATMP Manufacturing

Reagent Category	Specific Examples	Function	Regulatory Considerations
Cell Culture Media	Serum-free, xeno-free media formulations	Cell expansion and maintenance	Full traceability, GMP-grade where applicable
Cell Separation Reagents	Magnetic-activated cell sorting (MACS) reagents, density gradient media	Isolation of specific cell populations	Validation of separation efficiency and purity
Gene Editing Tools	CRISPR-Cas9 systems, viral vector packaging kits	Genetic modification of cells	Documentation of purity, specificity, and off-target effects
Cryopreservation Solutions	Defined cryoprotectant solutions	Long-term storage of cell products	Validation of post-thaw viability and functionality
Quality Control Assays	Flow cytometry panels, PCR kits, potency assay reagents	Characterization of critical quality attributes	Analytical validation, qualification, and transferability

The high costs and infrastructure requirements for ATMP deployment represent significant but surmountable challenges. Success requires an integrated approach combining regulatory innovation, technical optimization, and operational excellence. The emerging regulatory frameworks for decentralized manufacturing, particularly the modular and point-of-care models, provide a foundation for more accessible ATMP deployment. By implementing platform technologies, automation, and robust CMC strategies, developers can significantly reduce manufacturing costs while maintaining product quality and consistency. The ongoing evolution of the EU regulatory landscape, including the new HTA regulation and SoHO framework, creates both requirements and opportunities for more efficient ATMP development and deployment. As the field advances, continued collaboration between industry, regulators, healthcare providers, and patients will be essential to realize the full potential of these transformative therapies. The imperative is clear: to develop sustainable manufacturing and deployment models that enable broad patient access to the remarkable benefits offered by ATMPs.

Ensuring Regulatory Compliance and Success: Validation Strategies and Cross-Border Insights

Designing Robust Process Validation and Phase-Appropriate CMC Strategies

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), robust process validation and phase-appropriate Chemistry, Manufacturing, and Controls (CMC) strategies are critical components for successful regulatory approval and patient access. The complex nature of ATMPs, combined with an evolving European regulatory landscape and the unique challenges of decentralized manufacturing, demands a sophisticated approach to process design and quality management.

The modern paradigm of process validation represents a fundamental shift in regulatory philosophy, moving from a discrete, one-time event to a continuous lifecycle approach that spans the entire product lifespan. This concept is explicitly embedded in the foundational definitions of major regulatory bodies, including the FDA and EMA, and is aligned with International Council for Harmonisation (ICH) principles [84]. For ATMPs utilizing decentralized manufacturing models, this approach becomes even more critical as processes must be replicated across multiple sites while maintaining consistent product quality and safety profiles.

This technical guide examines current regulatory frameworks, provides detailed methodologies for implementation, and addresses the specific challenges of designing validation and CMC strategies for decentralized ATMP manufacturing within the European context.

Regulatory Framework and Current EU Landscape

EU Process Validation Requirements

The European Medicines Agency (EMA) framework for process validation offers a flexible, multi-pathway system tailored based on development maturity and process risk. The EU guideline explicitly links validation to the principles of pharmaceutical development outlined in ICH Q8 and recognizes two primary development pathways [84]:

• Traditional Approach: Where set points and operating ranges are defined based on established knowledge
• Enhanced Approach: Where scientific knowledge and risk management are used more extensively to identify and understand parameters influencing product quality

A key differentiator in the EU framework is the formal distinction between 'standard' and 'non-standard' manufacturing processes. ATMPs universally fall into the 'non-standard' category, requiring submission of full production-scale validation data in the marketing authorization dossier prior to approval [84]. This classification triggers more extensive regulatory scrutiny and data requirements throughout the development lifecycle.

The EU validation framework explicitly outlines a spectrum of acceptable approaches for Process Qualification (Stage 2) [84]:

• Traditional Approach: Based on a predetermined number of consecutive successful batches
• Continuous Process Verification (CPV): Using ongoing monitoring and statistical analysis
• Hybrid Approach: Combining elements of both traditional and CPV methods

Recent and Upcoming Regulatory Changes

The European regulatory environment for pharmaceuticals is undergoing significant transformation, with important implications for ATMP manufacturers:

• New EU Variations Guidelines: Effective January 15, 2026, these guidelines introduce a completely updated classification system and procedural framework designed to accelerate assessments and reduce timelines. The changes emphasize two key lifecycle management tools: the Post-Approval Change Management Protocol (PACMP) for pre-agreed evidence generation pathways, and the Product Lifecycle Management (PLCM) document for establishing long-term quality intentions [85].

• ICH Q12 Implementation: This guideline provides a globally agreed framework to facilitate the management of post-approval CMC changes in a predictable and efficient manner across the product lifecycle, promoting innovation and continual improvement while strengthening quality assurance and product supply [86].

• Revised EU GMP Annex 1: The 2023 revision reinforces contamination control requirements, with particular significance for sterile ATMPs. It mandates a comprehensive, documented Contamination Control Strategy (CCS) covering all potential contamination sources throughout production [87].

Table: Comparative Analysis of Process Validation Frameworks

Aspect	EU EMA	US FDA	WHO
Core Philosophy	Lifecycle approach linked to ICH Q8, Q9, Q10	Lifecycle approach from process design through commercial production	Lifecycle approach for reproducible, reliable, robust processes
Stage 2 Approach	Flexible: Traditional, CPV, or Hybrid	Centered on Process Performance Qualification (PPQ)	Flexible, justified by risk assessment
Validation Batches	Justified based on approach and risk	Typically 3 PPQ batches with heightened sampling	Number justified by risk assessment, not fixed
Special Categories	'Standard' vs. 'Non-standard' processes	No formal categorization	Accommodates various approaches with justification
ATMP Consideration	Non-standard, case-by-case basis	Considered complex products	Adapted based on product characteristics

The Process Validation Lifecycle: A Detailed Framework

The modern validation lifecycle is universally structured around three interconnected stages that provide a comprehensive framework for ensuring continued process control. For ATMPs in decentralized manufacturing models, each stage requires careful adaptation to address product and site-specific challenges.

Stage 1: Process Design

Process Design represents the foundation of the validation lifecycle, focusing on proactively building process understanding and establishing a robust control strategy before commercial manufacturing. For ATMPs, this stage is particularly critical due to product complexity and manufacturing constraints.

Experimental Protocol: Process Characterization Using Design of Experiments (DOE)

Objective: To systematically identify and quantify the relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) through statistically designed experiments.

Methodology:

• Define Risk Assessment Boundaries: Based on prior knowledge from development, identify potential CPPs using tools such as Failure Mode Effects Analysis (FMEA)
• Select Experimental Design: Choose appropriate screening designs (Plackett-Burman) for parameter identification or response surface methodologies (Central Composite Design) for optimization
• Establish Scaling Model: For ATMPs, develop a scaling strategy that maintains physiological relevance across manufacturing scales
• Execute DOE Batches: Manufacture multiple batches at different parameter setpoints according to the experimental design matrix
• Analyze Multivariate Data: Use statistical analysis to model relationships and identify proven acceptable ranges for each CPP
• Establish Design Space: Document the multidimensional combination of input variables that demonstrate assurance of quality

Key Outputs: Quantitative model relating CPPs to CQAs, established proven acceptable ranges, preliminary design space, and knowledge-based justification for control strategy.

Stage 2: Process Qualification

Process Qualification serves as the formal evaluation of the process design to confirm its capability for reproducible commercial manufacturing. For decentralized ATMP manufacturing, this stage must demonstrate equivalence across multiple manufacturing sites.

Experimental Protocol: Process Performance Qualification (PPQ) for Multi-Site Manufacturing

Objective: To demonstrate with high confidence that the manufacturing process is capable of consistently producing product meeting its critical quality attributes when replicated across multiple sites.

Methodology:

• Site Readiness Verification: Confirm all manufacturing sites have equivalent facilities, equipment, utilities, and trained personnel through formal qualification
• PPQ Protocol Development: Create comprehensive protocol specifying manufacturing conditions, controls, scientifically justified sampling plan, and predetermined acceptance criteria
• Staged Execution: Implement PPQ across sites in a staggered approach, incorporating lessons learned from initial sites into subsequent executions
• Enhanced Sampling: Employ more extensive sampling than routine production, including in-process, hold-time, and final product testing
• Intermediate Comparison: Statistically compare critical quality attributes between sites to demonstrate process equivalence
• Formal Report and Conclusion: Document results and provide justified conclusion regarding state of control at each site

Key Outputs: PPQ protocol and report, statistical analysis of between-site equivalence, formal conclusion of process validation for each manufacturing site.

Table: Essential Research Reagent Solutions for ATMP Process Validation

Reagent/Material	Function in Validation	Critical Quality Attributes
Cell Culture Media	Provides nutrients and growth factors for cell expansion and maintenance	Composition, endotoxin levels, growth promotion testing, performance qualification
Critical Raw Materials	Components that directly impact product quality (e.g., cytokines, activation reagents)	Identity, purity, potency, consistency between lots and suppliers
Analytical Reference Standards	Qualified materials used as comparators for potency and characterization assays	Well-characterized potency, purity, stability, traceability to international standards
Process-Related Impurity Standards	Standards for detecting and quantifying process residuals (e.g., antibiotics, serum)	Identity, purity, concentration accuracy, stability
Container-Closure Systems	Primary packaging materials that contact the product	Extractables and leachables profile, compatibility, integrity, functionality

Stage 3: Continued Process Verification

Continued Process Verification provides ongoing assurance that the manufacturing process remains in a state of control throughout the product's commercial life. For decentralized ATMP manufacturing, this stage requires careful coordination and data management across sites.

Experimental Protocol: Ongoing Process Verification Program for Multi-Site Operations

Objective: To establish an ongoing program for collecting and analyzing product and process data that relate to product quality across all manufacturing sites, enabling timely detection of process drift or deviation.

Methodology:

• Statistical Control Strategy: Establish statistical process control (SPC) charts for critical process parameters and quality attributes with appropriate control limits
• Data Management Infrastructure: Implement centralized data repository capable of aggregating and analyzing data from all manufacturing sites in near real-time
• Periodic Assessment Rhythm: Conduct regular (quarterly) reviews of process performance data with cross-functional team including site representatives
• Out-of-Trend Investigation Protocol: Define clear procedures for investigating and addressing out-of-trend (OOT) or out-of-specification (OOS) results across sites
• Continuous Improvement Integration: Use trend analysis to identify opportunities for process improvement and refinement of control strategies
• Annual Product Quality Review: Compile comprehensive annual review of all process and product data across sites to verify consistency of manufacturing and control strategy

Key Outputs: Ongoing process verification plan, statistical process control charts with defined alert and action limits, periodic process performance reports, annual product quality review documents.

Phase-Appropriate CMC Strategy for ATMP Development

A phase-appropriate CMC strategy applies regulatory and quality requirements in a manner that aligns with product development stage and risk. For ATMPs with decentralized manufacturing, this approach must balance flexibility with control across multiple sites.

Early Phase CMC Strategy (Preclinical to Phase I)

The primary goal during early development is to ensure patient safety while generating sufficient data to justify continued development.

Key Considerations for ATMPs:

• Manufacturing Consistency: Focus on demonstrating consistency between non-clinical and clinical batches, particularly important when scaling from centralized to decentralized models [88]
• Critical Quality Attribute Identification: Identify and monitor a limited set of high-risk CQAs with established analytical methods
• Container-Closure Compatibility: For drug-device combination products, confirm compatibility and assess effect of delivery device on dosing [88]
• Raw Material Controls: Implement appropriate controls for critical raw materials, with particular attention to cell culture media and growth factors

Late Phase CMC Strategy (Phase II to Phase III)

As products advance through clinical development, the CMC strategy should evolve toward commercial standards with increased rigor and completeness.

Key Considerations for ATMPs:

• Process Characterization: Conduct formal process characterization studies to define proven acceptable ranges for critical process parameters
• Method Validation: Complete full validation of analytical methods for release and stability testing
• Site Qualification: Formalize technology transfer to all manufacturing sites with demonstration of comparability
• Stability Data Generation: Accumulate comprehensive stability data to support proposed shelf life and storage conditions

Commercial Phase CMC Strategy (Post-Approval)

Following marketing authorization, the focus shifts to maintaining a state of control while implementing improvements across all manufacturing sites.

Key Considerations for ATMPs:

• Lifecycle Management: Implement tools such as Post-Approval Change Management Protocols (PACMPs) and Product Lifecycle Management (PLCM) documents to efficiently manage changes [85]
• Multi-Site Monitoring: Establish rigorous ongoing process verification programs with centralized data management
• Change Management: Develop robust change management procedures that account for coordination across multiple sites
• Continual Improvement: Use data from commercial manufacturing to identify and implement process improvements

Implementation Challenges and Solutions for Decentralized ATMP Manufacturing

Decentralized manufacturing of ATMPs presents unique challenges for process validation and CMC strategy implementation. Below are key challenges and proposed solutions:

Table: Challenges and Solutions for Decentralized ATMP Manufacturing

Challenge	Impact on Validation/CMC	Proposed Solution
Process Consistency Across Sites	Variable product quality leading to regulatory non-approval	Implement enhanced process characterization, standardized training, and centralized data monitoring
Raw Material Sourcing Variability	Differences in product quality attributes between sites	Establish dual qualified suppliers for critical materials and implement material equivalence testing
Technology Transfer Complexity	Failure to replicate process at new sites	Develop comprehensive technology transfer protocol with demonstrated comparability at receiving site
Regulatory Coordination	Inconsistent regulatory submissions and approvals across regions	Implement ICH Q12 principles and establish PACMPs for efficient post-approval change management [86]
Data Management and Analysis	Inability to detect process trends across sites	Establish centralized data repository with statistical process monitoring capabilities

Designing robust process validation and phase-appropriate CMC strategies for ATMPs in decentralized manufacturing environments requires a holistic approach that integrates deep process understanding, risk-based decision making, and adaptive regulatory strategies. The implementation of a comprehensive validation lifecycle approach—spanning Process Design, Process Qualification, and Continued Process Verification—provides a framework for ensuring consistent product quality across multiple manufacturing sites.

The evolving European regulatory landscape, particularly the new Variations Guidelines effective January 2026, emphasizes proactive planning and use of tools such as PACMPs and PLCM documents [85]. For ATMP manufacturers, adopting these approaches early in development will facilitate more efficient lifecycle management and regulatory compliance.

As the field of ATMPs continues to evolve, manufacturers must remain agile in their validation and CMC approaches, leveraging scientific advances and regulatory frameworks to ensure that these innovative therapies can reach patients safely and efficiently, regardless of manufacturing location.

Leveraging Orthogonal Analytical Methods and Real-Time Release Testing (RTRT)

The field of Advanced Therapy Medicinal Products (ATMPs), encompassing cell and gene therapies, represents a groundbreaking shift in medicine towards potentially curative treatments for a range of diseases [1]. However, the traditional centralized manufacturing model faces significant challenges with these personalized, often patient-specific therapies, particularly concerning product shelf-life and logistics. In response, regulatory frameworks are evolving to support decentralized manufacturing (DM), where manufacturing activities occur at or near the point of patient care (POC) or within modular units (MM) [27] [4]. This shift from a single production site to a network of manufacturing locations introduces new complexities in ensuring consistent product quality, safety, and efficacy across all sites.

Within this new paradigm, a robust and innovative quality control strategy is paramount. Real-Time Release Testing (RTRT) is defined as “the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls” [89]. When combined with orthogonal analytical methods—multiple independent test methods that provide complementary information on product quality attributes—it creates a powerful framework for quality assurance. This guide details how the integration of these approaches is not merely an enhancement but a fundamental requirement for the successful and scalable deployment of ATMPs within decentralized manufacturing networks, in alignment with emerging European regulatory expectations.

Regulatory Landscape for Decentralized Manufacturing

Evolving EU and UK Frameworks

The regulatory landscape is rapidly adapting to accommodate the unique needs of ATMPs. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has been a pioneer, introducing a definitive regulatory pathway for DM that took effect in July 2025 [27] [4]. This framework introduces two key concepts:

• Point of Care (POC) Manufacturing: Medicinal products that, due to their method of manufacture, short shelf life, or constituents, can only be manufactured at or near the place of administration [42].
• Modular Manufacturing (MM): Manufacturing activities performed in a modular unit that can be relocated, justified by reasons of deployment such as public health needs or significant clinical advantage [27] [42].

While this specific legislation is from the UK, it was developed in consultation with 16 regulatory bodies via the International Coalition of Medicines Regulatory Authorities (ICMRA), signaling a global regulatory trend [4]. Furthermore, the European Commission's Horizon 2025 funding program explicitly calls for research to optimize ATMP manufacturing, highlighting the need for “flexible manufacturing (centralised or decentralised)” and the integration of “digital/Artificial Intelligence solutions” [1]. This aligns perfectly with the goals of RTRT.

Quality and Regulatory Implications for DM

The DM model fundamentally changes the quality assurance workflow. In a conventional model, the final product release for an autologous CAR-T therapy, for instance, might occur at the patient's bedside. Under the new MHRA framework, the control site—holding the manufacturing license—is responsible for product release, while secondary sites (e.g., hospital labs) follow a detailed Decentralized Manufacturing Master File (DMMF) [42] [4]. This places a heavy emphasis on process consistency and control across all sites.

Regulators will focus intensely on the control strategy. As noted in the MHRA guidance, “since a lot of autologous products use real time release testing (RTRT), particular emphasis should be placed on the data to support this strategy” in Marketing Authorization Applications (MAAs) [42]. The overall regulatory focus areas for DM are summarized in the table below.

Table 1: Key Regulatory Focus Areas for Decentralized Manufacturing of ATMPs

Area	Regulatory Expectation	Reference
Control Strategy	Heavy emphasis on validation of RTRT; demonstration of comparability between products made at different remote sites.	[42]
Oversight	The license holder (control site) must demonstrate robust oversight of all remote manufacturing sites.	[42] [4]
Traceability	Robust processes to ensure product and batch traceability across multiple healthcare settings are critical for pharmacovigilance.	[27] [42]
Pharmacovigilance	The Pharmacovigilance System Master File (PSMF) must encompass all decentralized sites, with clear procedures for adverse event management.	[27] [42]

Orthogonal Analytical Methods: A Multi-Dimensional Assurance System

The Principle of Orthogonality

In the context of ATMPs, orthogonality refers to the use of multiple, independent analytical techniques that probe different physicochemical or biological properties of the product to collectively confirm its identity, purity, safety, potency, and quality [10]. This approach mitigates the risk of a single, potentially flawed method failing to detect a critical quality attribute (CQA) deviation. For example, while flow cytometry might characterize cell surface markers, a complementary PCR method could detect specific genetic modifications, and a functional potency assay would measure biological activity.

Key Orthogonal Methodologies for ATMPs

A comprehensive orthogonal strategy for a cell-based ATMP should cover multiple dimensions. The following table outlines essential reagent solutions and their functions in constructing this analytical framework.

Table 2: Research Reagent Solutions for Orthogonal Analysis of ATMPs

Reagent / Assay Type	Function / Purpose	Key Quality Attributes Measured
Flow Cytometry Reagents (e.g., fluorescently-labeled antibodies)	To identify and quantify specific cell populations based on surface and intracellular markers.	Identity, Purity, Impurities (contaminating cell types).
qPCR/dPCR Assays	To detect, quantify, and verify specific genetic sequences (e.g., transgene insertion, viral vector copy number).	Identity, Purity (residual vector), Safety (genetic stability).
Cell-based Potency Assays (e.g., cytokine release, cytotoxicity)	To measure the biological functional activity of the product, linking a CQA to the intended biological effect.	Potency.
LAL/Microbiological Assays	To detect and quantify endotoxins and other microbial contaminants.	Safety, Purity.
Viability Stains (e.g., Trypan Blue, 7-AAD)	To distinguish between live and dead cells.	Viability, Purity.
Karyotyping/Genomic Assays	To assess genomic stability and rule out tumorigenic potential after extended culture.	Safety (tumorigenicity).

The relationship between these methods and the overall quality control workflow is illustrated in the following diagram, which shows how orthogonal data streams converge to support a final product quality assessment.

Real-Time Release Testing (RTRT): From End-Point Testing to Process-Embedded Quality

The Concept and Benefits of RTRT

RTRT moves quality assurance from the laboratory bench directly into the manufacturing process. It is defined as the ability to evaluate and ensure product quality based on process data, which includes a valid combination of measured material attributes and process controls [89]. Instead of relying solely on end-point testing of a final product sample, RTRT uses Process Analytical Technology (PAT) tools to monitor CQAs during manufacturing itself.

The benefits are transformative for DM of ATMPs:

• Enhanced Process Control: RTRT generates more data during the process, enabling immediate feedback and correction, which is crucial for maintaining consistency across multiple decentralized sites [89].
• Operational Efficiency: It eliminates the time and resources needed for lengthy off-line laboratory testing, reducing inventory costs and accelerating batch release—a critical advantage for products with very short shelf lives [89].
• Increased Quality Assurance: Provides a higher level of assurance by performing integrated, real-time analysis and control, moving beyond the limitations of traditional statistical sampling plans [89].

Implementing RTRT in a Decentralized Context

Successful RTRT implementation relies on deep product and process understanding. It requires identifying the relationship between desired product attributes (e.g., cell viability, potency) and relevant material attributes (e.g., nutrient levels, metabolite concentrations) or process parameters (e.g., pH, dissolved oxygen) that can be monitored in real-time [89].

For ATMPs, this often involves technologies like:

• Near-Infrared (NIR) Spectroscopy: For monitoring blend uniformity or metabolite concentrations in bioreactors.
• Raman Spectroscopy: For real-time identification of cell culture media components and metabolic states.
• Capacitance Probes: For on-line monitoring of viable cell density.
• Flow Cytometry with Automated Sampling: For at-line monitoring of specific cell markers.

A key technical challenge is managing sampling. As one expert notes, “PAT instruments access larger amounts of sample than would be used for lab analysis... automated sampling [is used] in contrast to traditional off-line techniques that tend to rely on grab sampling” [89]. The strategy for implementing RTRT must be carefully designed, as shown in the following workflow.

Integrating Orthogonal Methods and RTRT: A Synergistic Framework

The true power of these approaches is realized when they are integrated into a single, cohesive quality control system. Orthogonal methods are not replaced by RTRT; rather, they provide the foundational data that validates and supports the RTRT strategy.

In this integrated framework, traditional orthogonal methods are used during process development and validation to build the scientific understanding necessary for RTRT. For example, extensive off-line data from PCR, flow cytometry, and potency assays establishes the correlation between a real-time parameter (like a specific metabolic rate) and the final product's CQAs. Once this correlation is validated, the real-time parameter can be used for release, with the orthogonal methods serving as ongoing verification tools for periodic monitoring or in the event of a process deviation.

This synergy is critical for demonstrating “comparability between products made at the variety of the remote manufacturing sites” [42]. The control site can monitor RTRT data feeds from all decentralized sites in near-real-time, ensuring process consistency. Any anomalies can trigger further investigation using the full suite of orthogonal methods.

Experimental Protocols and Validation Strategies

Protocol for Establishing an RTRT Method for Cell Viability

Objective: To develop and validate a RTRT method for final product cell viability using an at-line automated cell counter correlated with the definitive off-line flow cytometry method.

Materials:

• Automated cell counter (e.g., NucleoCounter NC-200 or Vi-CELL BLU)
• Flow cytometer
• Propidium Iodide (PI) or 7-Aminoactinomycin D (7-AAD) viability stain
• Phosphate Buffered Saline (PBS)
• ATMP final product samples

Methodology:

• Sample Collection: Aseptically collect a representative sample from the final product container.
• At-line RTRT Measurement: Immediately analyze the sample using the qualified automated cell counter according to the manufacturer's instructions. Record the viability percentage. Total time should be <5 minutes.
• Orthogonal Confirmatory Testing: Prepare a separate aliquot of the same sample for flow cytometric analysis. Stain cells with PI (e.g., 1 µg/mL) and incubate for 5-15 minutes in the dark. Acquire data on the flow cytometer, gating on the cell population of interest and analyzing PI fluorescence to determine viability. This serves as the reference method.
• Data Correlation: Repeat steps 1-3 for a minimum of 15-20 independent batches (or process runs) covering the expected range of viability (e.g., 60%-95%). Perform linear regression analysis to establish a correlation model between the automated counter results (x-axis) and the flow cytometry results (y-axis).

Validation: The RTRT method is considered validated if the correlation coefficient (R²) is ≥0.95, and the 95% confidence interval of the slope contains the value 1.0. The method must demonstrate precision (e.g., %RSD <10% for repeatability) and accuracy (mean difference from reference method <5%).

Protocol for a Orthogonal Potency Assay Suite for a CAR-T Product

Objective: To implement a multi-faceted potency assay strategy that measures different aspects of CAR-T cell function.

Materials:

• Target cells expressing the specific antigen
• Control cells not expressing the antigen
• Cytokine detection kit (e.g., ELISA or multiplex bead-based for IFN-γ, IL-2)
• Cell culture media and reagents
• Luminometer or flow cytometer (for cytotoxicity assays)

Methodology: This protocol employs two orthogonal methods to assess potency.

A. Antigen-Specific Cytokine Release Assay:

• Co-culture: Seed effector (CAR-T) cells with target cells at multiple effector-to-target (E:T) ratios in a 96-well plate. Include controls of effector cells alone and target cells alone.
• Incubation: Incubate for 18-24 hours at 37°C, 5% CO₂.
• Analysis: Collect supernatant and quantify the concentration of specific cytokines (e.g., IFN-γ) using a validated ELISA. The result is reported as pg/mL/10⁶ cells.

B. Cytotoxicity Assay (e.g., Luciferase-Based):

• Labeling: Engineer target cells to stably express luciferase.
• Co-culture: Seed effector cells with luciferase-expressing target cells at multiple E:T ratios.
• Incubation: Incubate for 4-6 hours.
• Analysis: Add luciferase substrate and measure luminescence. Cytotoxicity is calculated as: [1 - (Luminescence_{sample} / Luminescence_{target cells alone})] * 100%.

Interpretation: The two assays provide complementary data. The cytokine release assay measures T-cell activation and secretory function, while the cytotoxicity assay directly measures target cell killing. Together, they provide a more complete picture of product potency than either assay alone. A well-characterized reference standard must be included in each run to control for inter-assay variability.

The successful decentralization of ATMP manufacturing is inextricably linked to the adoption of advanced quality control strategies. Leveraging orthogonal analytical methods and RTRT is not merely a technical improvement but a fundamental necessity to ensure that every product unit manufactured across a distributed network is safe, potent, and of high quality. This integrated framework, supported by robust experimental protocols and a deep process understanding, provides the control and consistency demanded by regulators. As the ATMP market continues its rapid growth—projected to reach USD 170 billion by 2034 [90]—and regulatory frameworks like the MHRA's DM pathway mature, the industry's ability to implement these sophisticated quality systems will be the key to delivering transformative therapies to patients efficiently and reliably.

The development of Advanced Therapy Medicinal Products (ATMPs) operates within a specialized regulatory framework in the European Union, established to ensure patient safety while fostering innovation. The cornerstone of this framework is Regulation (EC) No 1394/2007, which defines ATMPs as biological medicines for human use based on genes, cells, or tissue engineering [91]. For developers implementing decentralized manufacturing models, engaging with regulatory procedures early is crucial for navigating the complex pathway from concept to market authorization.

The European Medicines Agency (EMA) provides several structured procedures for early regulator interaction. The Committee for Advanced Therapies (CAT) delivers scientific recommendations on ATMP classification, while scientific advice and protocol assistance offer guidance on development plans [92] [93]. These procedures help resolve uncertainties regarding product classification, appropriate study designs, and manufacturing requirements—particularly relevant for decentralized sites facing unique challenges in maintaining consistent quality across multiple manufacturing locations.

Understanding and utilizing these procedures is especially beneficial for complex development scenarios, including those involving decentralized manufacturing approaches where production occurs across multiple geographically separate facilities. Early regulatory engagement helps establish appropriate quality controls and comparability strategies to ensure consistent product quality and facilitate technical transfers.

Understanding CAT Scientific Recommendation on ATMP Classification

The CAT scientific recommendation on ATMP classification is a voluntary procedure established under Article 17 of Regulation (EC) No 1394/2007 [91]. This free-of-charge service allows developers to obtain a formal determination on whether their product qualifies as an ATMP and, if so, which specific category it belongs to: Gene Therapy Medicinal Product (GTMP), Somatic Cell Therapy Medicinal Product (sCTMP), Tissue Engineered Product (TEP), or combined ATMP [91]. The classification recommendation is provided within 60 days after receipt of a valid request [92].

While the procedure is optional, it is strongly recommended for products with borderline classification issues, such as those combining devices with biological components or products with novel mechanisms of action [92]. For decentralized manufacturing models, obtaining formal classification is particularly valuable as it provides regulatory certainty before investing in multi-site manufacturing infrastructure and processes.

Application Process and Timelines

The application process requires submission of specific forms containing administrative and product information via email to the EMA. The CAT follows a strict timetable with predetermined submission dates and meeting schedules. The table below outlines the 2025 submission deadlines and corresponding procedure timelines for CAT classification [92]:

Table: CAT Classification Procedure Timelines for 2025

Deadline for Request Submission	Procedure Start Date	CAT Discussion	CAT Adoption
9 January 2025	24 January 2025	21 February 2025	21 March 2025
6 February 2025	21 February 2025	21 March 2025	16 April 2025
6 March 2025	21 March 2025	16 April 2025	16 May 2025
1 April 2025	16 April 2025	16 May 2025	13 June 2025
30 April 2025	19 May 2025	13 June 2025	18 July 2025

The classification procedure begins with a 15-day validation phase ("Day -15" to "Day 0") followed by a 60-day assessment period culminating in CAT adoption of the recommendation [92]. This predictable timeline enables developers to strategically plan their regulatory activities alongside technical development.

Strategic Importance for Decentralized Manufacturing

For decentralized manufacturing networks, the CAT classification procedure provides critical foundational clarity. A formal classification recommendation helps establish the applicable regulatory framework early, guiding the development of appropriate quality control strategies across multiple manufacturing sites [91]. Since classification impacts which specific regulatory guidance documents apply, obtaining certainty at the development stage enables implementation of consistent standards across all manufacturing locations.

The procedure also offers opportunity for early dialogue with regulators about product-specific characteristics that might impact multi-site manufacturing approaches. While the classification recommendation itself is not legally binding, it is generally followed by national medicines agencies across the EU member states, providing valuable predictability for developers establishing manufacturing networks that span multiple countries [91].

Scientific Advice and Protocol Assistance

Scientific advice from the EMA provides developers with guidance on appropriate methods and study designs to generate robust data on a medicine's efficacy and safety [93]. This formal procedure allows developers to present their development plans and receive feedback on specific questions related to quality, non-clinical, and clinical aspects of medicine development. For orphan medicines, a special form of scientific advice called protocol assistance is available, which additionally addresses criteria for orphan medicine authorization [93].

The scientific advice procedure is particularly valuable for ATMP developers facing unique challenges in decentralized manufacturing, such as demonstrating product comparability across different manufacturing sites, establishing appropriate potency assays for complex living therapies, and designing clinical trials that account for potential site-to-site variability [93]. The procedure helps ensure that development plans will generate evidence sufficient for marketing authorization applications, preventing major objections during later evaluation stages.

Questions Within and Outside Scope

Scientific advice can address diverse aspects of ATMP development. The procedure is most useful when developing innovative medicines where insufficient relevant guidance exists, when choosing to deviate from established scientific guidelines, or when developers have limited regulatory experience [93].

Table: Appropriate and Out-of-Scope Questions for Scientific Advice

Questions Within Scope	Questions Outside Scope
Appropriateness of patient population representation in studies	Questions about compassionate use or ATMP classification
Validity and relevance of planned benefit assessment measures	Changes to paediatric investigation plans
Appropriateness of proposed statistical analysis plans	Adequacy of existing data for regulatory applications
Sufficiency of study duration and patient numbers	Whether phase 3 results adequately support marketing authorization
Appropriate choice of comparator in clinical trials	Purely regulatory matters (submission details)
Design of long-term safety follow-up plans

Scientific advice is prospective in nature—it focuses on future development plans rather than evaluating existing data. The advice is not legally binding for either the EMA or the medicine developer regarding any future marketing authorization application, though compliance increases the likelihood of authorization [93].

Application Methodology and Process

The scientific advice process follows a structured pathway with multiple opportunities for interaction. Developers must first register with the EMA unless previously registered. For complex cases, particularly for first-time users or novel therapies, a preparatory meeting can be organized before the formal request [93].

The formal request submitted via the IRIS platform includes a briefing document with specific scientific questions and the developer's proposed approaches. After validation, two coordinators from the Scientific Advice Working Party (SAWP) are appointed, who form assessment teams and prepare reports addressing the questions [93]. If the SAWP disagrees with proposed plans and suggests alternatives, a meeting with the developer may be organized. The SAWP also consults other relevant committees, external experts, and often patients before consolidating responses to the scientific questions [93].

The entire scientific advice procedure represents a valuable opportunity for developers to align their development strategy with regulatory expectations, particularly important for decentralized manufacturing models where conventional approaches may need adaptation.

Strategic Integration of Regulatory Procedures

Implementing a Coordinated Approach

Successful ATMP developers strategically integrate multiple regulatory procedures to build a comprehensive development plan. While each procedure serves a distinct purpose, they work together to create a coherent regulatory strategy. A typical sequencing might begin with CAT classification to establish the regulatory framework, followed by scientific advice to refine the development plan, with potential parallel scientific advice from HTA bodies to ensure evidence generated will support both regulatory approval and reimbursement [93] [94].

For decentralized manufacturing approaches, this coordinated strategy is particularly important. Early consideration of how manufacturing decisions impact both regulatory and reimbursement requirements can prevent costly redesigns later. The European regulatory system offers opportunities for parallel advice with health technology assessment (HTA) bodies, allowing developers to align evidence generation strategies with both regulatory and payer requirements [94]. This is especially relevant for ATMPs with decentralized manufacturing models, where demonstrating comparability and consistent clinical outcomes across sites is crucial for both regulators and payers.

Addressing Decentralized Manufacturing Challenges

Decentralized manufacturing presents unique challenges that can be addressed through early regulatory engagement. The CAT classification procedure helps determine whether product modifications at different sites create essentially different products requiring separate classifications [91]. Scientific advice can provide guidance on establishing comparability protocols, implementing process controls across multiple sites, and designing studies that account for potential site-to-site variability [93].

The European regulatory framework increasingly recognizes the importance of flexible manufacturing approaches for ATMPs. Recent reforms, including the implementation of the Clinical Trials Regulation and clinical trial information system (CTIS), aim to simplify and harmonize requirements across member states, though challenges remain in achieving full consistency in assessment across national borders [95]. Engaging with regulators early helps developers navigate these complexities and establish manufacturing strategies that comply with EU requirements while maintaining operational feasibility.

Essential Research and Development Toolkit

Successful navigation of regulatory procedures requires both scientific expertise and appropriate technical documentation. The following table outlines key elements of the regulatory strategy toolkit for ATMP developers implementing decentralized manufacturing approaches:

Table: Regulatory Strategy Toolkit for ATMP Developers

Toolkit Component	Function	Application Context
CAT Classification Recommendation	Provides formal determination of ATMP category	Foundation for applicable regulatory requirements and guidance
Scientific Advice Meeting Minutes	Documents regulatory feedback on development plans	Guides study design and evidence generation strategy
Comparative Analysis Framework	Supports demonstration of significant benefit for orphan ATMPs	Protocol assistance for orphan medicines
Risk Management Plan	Outlines strategies for identifying and minimizing product risks	Required for marketing authorization applications
Quality Comparability Protocol	Establishes approach for demonstrating equivalence across manufacturing sites	Critical for decentralized manufacturing models
HTA Parallel Advice Documentation	Records joint regulatory/HTA body feedback on evidence needs	Supports both authorization and reimbursement applications

In addition to these strategic components, developers should maintain comprehensive technical documentation including manufacturing process descriptions, analytical method validation, stability data, and product characterization profiles for each manufacturing site. For decentralized models, special attention should be paid to documenting control strategies that ensure consistent product quality across sites and change management protocols for implementing process improvements while maintaining comparability.

Future Regulatory Developments

The European regulatory landscape for ATMPs continues to evolve. A proposed revision to the EU pharmaceutical legislation would potentially transform the CAT from a permanent committee to a working party and replace the dedicated ATMP classification procedure with a general scientific recommendation on regulatory status covering all medicine types [91]. While this reform remains under discussion, it highlights the dynamic nature of the ATMP regulatory environment.

Concurrently, initiatives like the "Gene Therapies Global Pilot" (CoGenT Global) aim to establish collaborative review processes among international regulators to reduce redundant evaluations across regions [95]. For developers implementing decentralized manufacturing models that may span multiple global regions, such harmonization efforts could significantly simplify regulatory strategy and implementation.

The ongoing implementation of the EU HTA Regulation establishes new requirements for joint clinical assessments of ATMPs, with specific provisions for oncology ATMPs beginning in 2025 and orphan ATMPs in 2028 [94]. These developments underscore the importance of engaging early with regulatory procedures to establish robust development plans that will meet evolving evidence requirements across the product lifecycle.

For developers of ATMPs with decentralized manufacturing approaches, proactively engaging with these regulatory procedures provides not only immediate guidance but also valuable relationships with regulatory authorities that can support efficient navigation of the complex pathway from concept to commercial authorization.

Advanced Therapy Medicinal Products (ATMPs) in the European Union and Cell and Gene Therapies (CGTs) in the United States represent a revolutionary class of biopharmaceuticals with the potential to treat and cure previously intractable diseases. While the core science is global, the regulatory pathways for these therapies differ significantly between these two major jurisdictions. For researchers, scientists, and drug development professionals, particularly those working on innovative decentralized manufacturing models, understanding these differences is not merely an academic exercise—it is a critical prerequisite for successful global development and patient access. This whitepaper provides a comparative analysis of the EU and US regulatory frameworks, highlighting key distinctions in terminology, classification, manufacturing requirements, and approval pathways that directly impact strategic planning for decentralized manufacturing sites.

Terminology, Definitions, and Regulatory Bodies

The foundational difference between the EU and US systems lies in their terminology and the structure of their regulatory authorities.

Terminology and Product Classification

In the European Union, the umbrella term is Advanced Therapy Medicinal Products (ATMPs), which is a legally defined category under Regulation (EC) No 1394/2007 [19]. ATMPs are further classified into four distinct sub-types [96] [19]:

• Gene Therapy Medicinal Products (GTMPs): Contain genes that lead to a therapeutic, prophylactic, or diagnostic effect. They work by inserting 'recombinant' genes into the body.
• Somatic-Cell Therapy Medicinal Products (sCTMPs): Contain cells or tissues that have been manipulated to change their biological characteristics.
• Tissue-Engineered Products (TEPs): Contain cells or tissues that have been modified to repair, regenerate, or replace human tissue.
• Combined ATMPs (cATMPs): Incorporate one or more medical devices as an integral part of the therapy.

In the United States, the formal term "ATMP" is not used. The US Food and Drug Administration (FDA) employs the broader term Cell and Gene Therapies (CGTs), which are regulated as biologics [96] [97]. Nested under this umbrella are human gene therapies and somatic cell therapies, with no separate formal category for tissue-engineered products [96]. A key nuance is that in the EU, a product combining cell and gene therapy, such as CAR-T cells, is always classified as a gene therapy [96].

Regulatory Bodies and Centralized vs. Devolved Processes

The regulatory architecture also varies, influencing engagement strategies for developers.

• European Medicines Agency (EMA): The Committee for Advanced Therapies (CAT) is the multidisciplinary body within the EMA that plays a central role in the scientific assessment of ATMPs. It provides recommendations on ATMP classification, prepares draft opinions on product quality, safety, and efficacy, and contributes to scientific advice [19]. The centralised marketing authorisation procedure provides a single evaluation and authorisation valid across the entire EU [98].
• US Food and Drug Administration (FDA): The Center for Biologics Evaluation and Research (CBER), specifically its Office of Therapeutic Products (OTP), regulates all CGTs [96] [83]. For products where the classification is blurred, sponsors can engage with the OTP or submit a Request for Designation (RFD) to the Office of Combination Products (OCP), which makes a recommendation within 60 days [96].

Table 1: Key Regulatory Bodies and Classifications

Aspect	European Union (EU)	United States (US)
Umbrella Term	Advanced Therapy Medicinal Products (ATMPs)	Cell and Gene Therapies (CGTs)
Governing Regulation	Regulation (EC) No 1394/2007	Public Health Service Act (PHSA) & Federal Food, Drug, and Cosmetic Act (FD&C Act)
Key Regulatory Body	European Medicines Agency (EMA)	US Food and Drug Administration (FDA)
Specialized Committee	Committee for Advanced Therapies (CAT)	Center for Biologics Evaluation and Research (CBER)
Main Product Categories	Gene Therapy (GTMP), Somatic-Cell Therapy (sCTMP), Tissue-Engineered (TEP), Combined (cATMP)	Human Gene Therapy, Somatic Cell Therapy

Regulatory Pathways and Development Support

Both regions have established specific pathways and support mechanisms to guide developers through the complex journey from concept to market.

Pre-Clinical and Clinical Trial Requirements

• EU – Clinical Trial Application (CTA): A CTA must be submitted and approved by the relevant national authorities and ethics committees before each clinical trial can begin [83]. The application is governed by the EU Clinical Trials Regulation.
• US – Investigational New Drug (IND) Application: Sponsors must submit an IND to the FDA prior to initiating clinical studies [83]. For early-stage interactions, the FDA offers Initial targeted engagement for regulatory advice (INTERACT) meetings [96].

Marketing Authorization and Expedited Pathways

• EU – Marketing Authorization Application (MAA): Following successful clinical trials, an MAA is submitted to the EMA via the centralised procedure [83]. To accelerate development, the EU offers several tools:
  • PRIME (PRIority MEdicines) Scheme: Provides early and enhanced dialogue with the EMA, eligibility for accelerated assessment, and appointment of CAT rapporteurs [83]. A 2025 study demonstrated that PRIME designation reduces the median time to marketing authorization by 42.7% (from 669 to 376 days) [99].
  • Orphan Designation: Incentivizes development for rare diseases, offering protocol assistance, market exclusivity, and fee reductions [83]. This designation is associated with a 32.8% reduction in approval time [99].
  • Conditional Marketing Authorization: Allows approval based on less comprehensive data when the benefit of immediate availability outweighs the risk of less complete data [99].
• US – Biologics License Application (BLA): The pathway for market approval is the BLA [83]. The FDA also provides several expedited programs:
  • Regenerative Medicine Advanced Therapy (RMAT) Designation: Specifically for regenerative medicine products, including CGTs, intended to treat serious conditions. It offers intensive FDA guidance and potential for accelerated approval [100] [83].
  • Fast Track and Breakthrough Therapy: Designed to expedite the development and review of therapies for serious conditions with unmet medical needs [83].
  • Accelerated Approval and Priority Review: Speeds up the review process and allows approval based on a surrogate endpoint [83].

Table 2: Key Supportive Regulatory Pathways and Designations

Pathway/Designation	European Union (EU)	United States (US)
Expedited Development	PRIME Scheme	Fast Track
Enhanced Evidence Generation	N/A	Breakthrough Therapy
Advanced Therapy Focus	N/A	Regenerative Medicine Advanced Therapy (RMAT)
Expedited Review	Accelerated Assessment	Priority Review
Approval Based on Surrogate Endpoint	Conditional Marketing Authorization	Accelerated Approval
Orphan/ Rare Disease	Orphan Designation	Orphan Drug Designation

The following diagram illustrates the key stages and major differences in the regulatory pathways from preclinical development to market authorization in the EU and US.

Chemistry, Manufacturing, and Controls (CMC)

Chemistry, Manufacturing, and Controls (CMC) is one of the most challenging areas for developers, with significant nuances between the EU and US.

Starting and Raw Materials

The classification and control of input materials represent a major point of divergence.

• Viral Vectors: In the US, viral vectors used to modify cell therapy products in vitro are classified as a drug substance, necessitating stringent controls and facility licensing [101]. In contrast, the EMA often considers these vectors to be starting materials [101]. While this may suggest less direct oversight, the drug product manufacturer must still ensure the quality of the starting material via a Qualified Person (QP), and GMP-grade manufacturing is required for first-in-human studies [96] [101].
• GMP Requirements: The EMA requires GMP-grade manufacturing of investigational medicinal products for first-in-human studies [96]. The FDA, while allowing a "fit-for-purpose" facility for Phase 1, expects higher quality input materials than for early-phase small molecules and does not allow research-grade excipients or starting materials [96].

Control Strategies and Testing

• Potency Assays: The FDA expects a validated functional potency assay to assess the efficacy of the drug product used in pivotal studies [101]. The EMA's expectations can be slightly more flexible, with infectivity and transgene expression sometimes being sufficient in early phases [101].
• Replication Competent Virus (RCV) Testing: The FDA requires that the final cell-based drug product be tested for RCV [101]. The EMA's position is that once the absence of RCV has been demonstrated on the in vitro vector, the resulting genetically modified cells do not necessarily require further RCV testing [101].
• Alternative Methods: Both regulators have demonstrated openness to alternative analytical methods, such as orthogonal assays (methods using different scientific principles to measure the same attribute), when they are scientifically justified [96]. The FDA has also shown willingness to consider New Approach Methodologies (NAMs), including in silico models, to supplement or replace certain pre-clinical studies [96].

Table 3: Key CMC and Manufacturing Differences

CMC Aspect	European Union (EU)	United States (US)
Viral Vectors (for in vitro use)	Often classified as a Starting Material	Classified as a Drug Substance
RCV Testing for GM Cells	Testing on vector may be sufficient	Required on both vector and final cell-based drug product
Potency Assay Expectation	May accept infectivity/expression assays in early phases	Validated functional potency assay expected for pivotal studies
GMP for First-in-Human	Required	"Fit-for-purpose" facility accepted for Phase 1
Donor Testing (Autologous)	Required by some national authorities	Governed by 21 CFR 1271
Process Validation Batches	Generally 3 consecutive batches	Number not specified; must be statistically adequate

Decentralized Manufacturing and Regulatory Implications

The trend toward decentralized manufacturing for ATMPs/CGTs, particularly for autologous therapies, interacts directly with regulatory frameworks and presents both opportunities and challenges.

Regulatory Alignment and Site Certification

For a decentralized network to operate across the EU and US, each manufacturing site must meet regional regulatory requirements, which are not mutually recognized.

• EU Importation Requirements: A product manufactured in the US and imported into the EU requires EU GMP certification for the manufacturing site. The site must be inspected by EU authorities or recognized under a mutual recognition agreement, and batches must be certified and released by a Qualified Person (QP) within the EU [96]. This is a critical consideration for US companies planning to supply the EU market from a stateside facility.
• US Domestic Push: Recent US policy shifts, including data-security rules and the proposed BIOSECURE Act, are creating a strong impetus for domestic CGT manufacturing. This aims to safeguard American health and genomic data and reduce reliance on foreign supply chains [102].

Harmonization Initiatives and Future Outlook

Recognizing the challenges posed by divergent regulations, authorities are initiating collaborative programs.

• Gene Therapies Global Pilot Program (CoGenT): Launched by the FDA, this pilot initiative explores concurrent, collaborative regulatory reviews of gene therapy applications with international partners like the EMA. Modeled after Project Orbis for oncology, it aims to increase harmonization, improve review efficiency, and accelerate global patient access [100].
• Advanced Manufacturing Technologies (AMT) Designation: The FDA's AMT program encourages the adoption of innovative, scalable manufacturing platforms. It offers expedited review for subsequent products using the designated platform, which is highly relevant for standardized decentralized manufacturing models [102].

The following diagram outlines the core concept of a decentralized manufacturing model and its key regulatory touchpoints.

The Scientist's Toolkit: Key Research Reagents and Materials

Successful navigation of the regulatory landscape begins with robust preclinical and clinical experiments. The table below details essential reagents and materials used in key experiments for ATMP/CGT development, linking them to regulatory requirements for quality and safety.

Table 4: Essential Research Reagents and Materials for ATMP/CGT Development

Reagent/Material	Function in Development	Regulatory Consideration
Viral Vectors (e.g., Lentivirus, AAV)	Gene delivery vehicle for gene therapies and genetically-modified cell therapies (e.g., CAR-T).	EU: Starting material, requires GMP-grade for clinical use [96] [101]. US: Drug substance, requires stringent controls and potency assays [101].
Gene Editing Machinery (e.g., CRISPR-Cas9)	Enables precise genomic modifications for advanced therapies.	EU: Defined as a starting material [96]. Quality and specificity must be thoroughly characterized to assess off-target risk.
Cell Culture Media & Supplements	Supports the expansion and viability of cells during manufacturing.	Must be qualified and, for clinical use, GMP-grade. The absence of animal-derived components (xenogeneic-free) is often required for regulatory approval.
Primary Human Cells (Somatic, Stem Cells)	The active substance or starting material for many cell-based ATMPs/CGTs.	Sourced under strict donor consent and screening protocols per EU Directives (SoHO Regulation) [83] or US 21 CFR 1271 [101].
Critical Raw Materials (e.g., Cytokines, Growth Factors)	Drives cell differentiation, expansion, or activation.	Quality (potency, purity) must be assured via a risk-based control strategy. Use of Drug Master Files (DMFs) is common in the US but has no direct EU equivalent [101].
Functional Potency Assay Reagents	Measures the biological activity of the product, a critical quality attribute.	Required by both agencies. The FDA particularly emphasizes biologically relevant, functional assays over merely quantitative ones [96] [101].

The regulatory pathways for ATMPs in the EU and CGTs in the US, while aligned in their ultimate goals of patient safety and therapeutic efficacy, present a complex tapestry of key differences in classification, CMC requirements, and approval mechanisms. For developers, particularly those pioneering decentralized manufacturing models, a proactive and nuanced understanding of these divergences is non-negotiable. Early engagement with regulators through INTERACT, pre-IND, and CAT classification requests is critical to de-risk development. Furthermore, strategic planning must account for the fact that a manufacturing process and control strategy designed for one region will almost certainly require adaptation for the other. As the field evolves, initiatives like the CoGenT pilot and the adoption of advanced manufacturing technologies offer promise for greater future harmonization. Ultimately, mastering this complex comparative landscape is essential for transforming groundbreaking scientific innovation into accessible, life-changing medicines for patients worldwide.

The transition from centralized to Point-of-Care (POCare) manufacturing for Advanced Therapy Medicinal Products (ATMPs) represents a paradigm shift in regenerative medicine. This review analyzes early implementation frameworks, focusing on the evolving regulatory landscape and emerging technical solutions. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has established the world's first comprehensive regulatory framework for decentralized manufacturing, creating new license types effective July 2025 [4]. Early lessons highlight the critical importance of the Control Site model for maintaining quality oversight, the essential role of closed-system automated technologies in reducing variability, and the persistent challenges in workforce development and demonstrating product comparability across sites [17] [103]. These developments create a foundational model for addressing the unique logistical challenges of autologous ATMPs while ensuring compliance with Good Manufacturing Practice (GMP) standards.

Advanced Therapy Medicinal Products (ATMPs), including cell and gene therapies, embody personalized medicine but face significant manufacturing and logistical challenges. The conventional centralized manufacturing model poses particular difficulties for autologous therapies, where patient-specific starting materials must be transported to a manufacturing facility and the final product shipped back to the treatment center. This process is time-consuming, logistically complex, and may delay treatment for patients with rapidly progressing diseases [17]. The limited shelf life of many fresh cell therapy products further exacerbates these challenges.

Decentralized or POCare manufacturing has emerged as a promising solution, defined as "product manufacturing at multiple sites under central management" [17]. This approach involves manufacturing ATMPs at or near the patient's treatment location, such as hospital laboratories or specialized units close to the bedside. The potential benefits are substantial, including reduced transportation times and costs, elimination of cryopreservation needs, and improved patient access to these innovative therapies. A survey-based study by BioPlan Associates indicates that cell and gene therapy manufacturing is experiencing a serious "capacity crunch," with a manufacturing capacity shortage estimated at 500% [17]. This capacity constraint, coupled with the logistical challenges of centralized manufacturing, has accelerated regulatory and industry interest in POCare models.

Regulatory Evolution and Frameworks

Pioneering Regulatory Frameworks

United Kingdom (MHRA) Framework The UK's MHRA has established the world's first tailored regulatory framework for POCare manufacturing of innovative medicines, with new regulations becoming effective in July 2025 [4]. This framework introduces two novel license types:

• Manufacturer's License (Modular Manufacturing, MM): For manufacturing activities performed away from the classic manufacturing site, potentially at a clinic or hospital laboratory.
• Manufacturer's License (Point of Care, POC): For manufacturing activities performed very close to the patient or at the bedside [4].

A cornerstone of this framework is the Control Site model, where the license holder maintains responsibility for supervising and controlling satellite manufacturing locations through a Master File (MF) system. The Control Site serves as the regulatory nexus, holding the manufacturing license and ensuring consistency across all decentralized sites [17] [4]. This model shifts the product release responsibility from the bedside back to the centralized Control Site, streamlining regulatory oversight while enabling distributed manufacturing.

European Medicines Agency (EMA) Perspective While the EMA has not yet implemented a specific regulatory framework for POCare manufacturing comparable to the MHRA's, it has recognized the potential of decentralized approaches. The EMA and Heads of Medicines Agencies (HMA) included in their Network Strategy 2025 the vision that manufacturing systems could ultimately be combined in "closed, easy-to-operate, tabletop-sized machine[s]" for use in hospital pharmacies or operating theaters [17]. The existing Guideline on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products acknowledges batch release processes in cases of decentralized manufacturing, providing a foundational regulatory context [17].

U.S. Food and Drug Administration (FDA) Perspective The FDA has shown increasing engagement with distributed manufacturing concepts. Through its Emerging Technology Program, the Center for Drug Evaluation and Research (CDER) initiated the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), which includes Distributed Manufacturing as a platform for enabling POCare manufacturing [17]. In draft guidance on CAR-T cell products, the FDA has acknowledged that manufacturing at multiple sites may shorten timelines for autologous products but emphasizes that sponsors must demonstrate a comparable product is manufactured at each location [17].

Table 1: Comparative Overview of Regulatory Approaches to POCare ATMP Manufacturing

Regulatory Agency	Key Frameworks/Positions	Focus Areas	Status/Timeline
MHRA (UK)	Manufacturer's License (MM & POC); Control Site model with Master File system	Regulatory oversight, quality management, supervision of satellite sites	Effective July 2025 [4]
EMA (EU)	GMP specific to ATMPs; Network Strategy 2025	Quality standards, supply chain challenges, medicine accessibility	Under discussion; general guidelines available [17]
FDA (US)	FRAME initiative; Emerging Technology Program	Product comparability across sites, advanced manufacturing technologies	Draft guidance available; ongoing development [17]

The Control Site Model: Centralized Oversight for Decentralized Manufacturing

The Control Site model is a foundational concept in early POCare implementations, designed to maintain regulatory compliance and product quality across distributed manufacturing networks. This model addresses the fundamental challenge of how to ensure consistent quality when manufacturing occurs at multiple locations, potentially including hospitals with varying levels of GMP expertise [17].

The Control Site assumes several critical functions:

• Serves as the single point of contact for regulatory agencies
• Provides overarching quality assurance and oversight systems
• Maintains the POCare Master File for individual GMP manufacturing sites
• Employs the Qualified Person (QP) responsible for batch certification and release [17]

This centralized-decentralized hybrid model enables the regulatory system to maintain oversight through a single validated entity while allowing manufacturing to occur at multiple locations closer to patients. The MHRA's framework specifically mandates that the Control Site holder is responsible for generating the Master File, supervising satellite locations, and ensuring compliance with the registered processes [4].

Technical Implementation and Manufacturing Considerations

Platform Technologies and Automated Systems

Successful POCare implementation relies heavily on technological innovations that minimize variability across manufacturing sites. Closed-system automated technologies have emerged as critical enablers, reducing manual processing steps and the potential for human error [17]. These systems decrease the infrastructure requirements at treatment facilities by integrating multiple processing steps into single, validated units that maintain aseptic conditions throughout manufacturing.

The implementation of standardized GMP manufacturing platforms, potentially deployable as prefabricated units, supports rapid expansion of manufacturing networks while maintaining consistent quality standards [17]. These platforms often incorporate:

• Integrated environmental monitoring systems
• Automated bioreactors for cell expansion
• Closed-system fluid transfer pathways
• In-process analytics for quality control

A key lesson from early implementations is that technological solutions must be designed specifically for the POCare environment, considering the potentially limited cleanroom infrastructure and technical expertise available at satellite sites compared to traditional manufacturing facilities.

Analytical Methods and Comparability Demonstrations

For regulators, a primary concern with decentralized manufacturing is ensuring product comparability across different manufacturing locations. The FDA specifically states that "sponsors should demonstrate that a comparable product is manufactured at each location" and that "analytical methods are comparable across the different sites, if applicable" [17].

This requirement necessitates rigorous analytical development and validation, including:

• Standardized analytical methods across all sites
• Cross-site validation studies
• Robust potency assays capable of detecting site-to-site variations
• Extended analytical characterization for comparability assessments [10]

The comparability exercise becomes particularly challenging for autologous products, where inherent patient-to-patient variability exists. Successful implementations have established comprehensive Critical Quality Attribute (CQA) profiles that define the product characteristics essential for safety and efficacy, then demonstrated consistent control of these CQAs across manufacturing sites [104].

Table 2: Essential Research Reagent Solutions for POCare ATMP Manufacturing

Reagent/Category	Function in POCare Context	GMP & Quality Considerations
Cell Culture Media	Supports cell expansion/ differentiation at point of use	GMP-sourced, qualified for performance, predefined shelf-life and storage conditions [105]
Genetic Vectors (e.g., LV, RV)	Genetic modification of patient cells (ex vivo GTMPs)	Viral safety testing, predefined potency, stored in aliquots to minimize freeze-thaw cycles [105]
Activation Reagents/ Cytokines	Stimulates and differentiates cell populations	Pre-qualified for aseptic processing, concentration verified upon receipt at POC site [105]
Critical Raw Materials	Ancillary materials not intended in final product	Risk-based approach per USP <1043>; supplier quality agreements essential [105]

Process Validation and Quality Control

The validation of POCare manufacturing processes requires innovative approaches to address the unique challenges of decentralized production. Traditional process validation strategies designed for large-scale batch production must be adapted for the small-scale, patient-specific nature of many ATMPs manufactured at the point of care.

Key considerations include:

• Process robustness across multiple operators and sites
• Media fill simulations to validate aseptic processing capabilities
• Shipping validation for starting materials and critical reagents
• Environmental monitoring programs tailored to each site
• Real-time release testing strategies for products with short shelf lives

The implementation of a comprehensive Quality Management System (QMS) specifically designed for decentralized manufacturing is essential. This system must integrate current Good Manufacturing Practice (cGMP) principles while accommodating the operational realities of multiple manufacturing locations [17]. A successful QMS for POCare manufacturing typically includes standardized operating procedures, training programs, change control processes, and deviation management systems that function consistently across the network.

Workforce and Skills Development

The successful implementation of POCare manufacturing requires addressing significant workforce challenges. A recent survey of ATMP professionals revealed that 90% perceive a shortage of personnel with the skills needed for ATMP manufacturing [103]. This skills gap presents a particular challenge for POCare models, where manufacturing may occur at hospital sites with staff who have limited experience in GMP compliance.

The survey identified specific technical skills that are both essential and limited in availability:

• Aseptic-processing techniques (noted by 22 out of 40 respondents)
• Digital and automation skills (18 out of 40 respondents)
• Bioinformatics expertise (15 out of 40 respondents) [103]

These findings highlight the critical need for specialized training programs tailored to the POCare environment. Successful implementations have incorporated:

• Standardized training platforms across all manufacturing sites
• Hands-on simulation exercises for specific technologies
• Cross-training between central and satellite sites
• Competency certification programs for key operations

Beyond technical skills, survey respondents emphasized the importance of "soft skills" including teamwork, communication, problem-solving, and critical thinking [103]. These competencies are particularly valuable in POCare environments where staff must often adapt to unexpected challenges while maintaining strict compliance with quality standards.

Case Studies and Early Implementation Evidence

Clinical Implementation of POCare Manufacturing

Early clinical evidence supports the feasibility of the POCare manufacturing approach. Maschan et al. (2022) reported robust safety and clinical responses in patients with relapsed/refractory B-cell malignancies treated with place-of-care manufactured anti-CD19 CAR-T cells produced at two different locations [17]. In this study, "place-of-care manufacturing" was defined as production near the point of patient treatment, allowing cell products to be manufactured and infused without cryopreservation.

This implementation demonstrated several key advantages:

• Elimination of cryopreservation requirements and associated risks
• Reduced vein-to-vein time for patients
• Comparable product quality across two manufacturing locations
• Acceptable safety profile consistent with centralized manufacturing approaches

The success of this approach provides preliminary validation of the POCare model for autologous cell therapies, particularly for indications where treatment timing is critical.

Organizational Models for POCare Implementation

Early implementations have revealed several organizational models for POCare manufacturing, each with distinct advantages and challenges:

Academic Health Center Model

• Manufacturing occurs within major academic hospitals
• Leverages existing infrastructure and clinical expertise
• Potential challenges in maintaining consistent GMP compliance

Industry-Healthcare Partnership Model

• Pharmaceutical companies partner with hospital networks
• Combines industry GMP expertise with clinical site access
• Requires robust quality agreements and technology transfer

Modular Deployment Model

• Self-contained GMP units deployed to multiple locations
• Maximizes consistency through standardized infrastructure
• Significant upfront investment required

Each model utilizes variations of the Control Site concept to maintain regulatory oversight and quality management across the manufacturing network.

Visualizing the POCare Manufacturing Workflow

The following diagram illustrates the typical workflow and relationships in a POCare manufacturing model, highlighting the central role of the Control Site.

POCare Manufacturing Organizational Structure

The early implementation of POCare ATMP manufacturing demonstrates both feasibility and significant potential to address critical challenges in the field. The establishment of specific regulatory frameworks, particularly the MHRA's pioneering approach, provides a foundation for broader adoption of decentralized manufacturing models. The Control Site concept has emerged as a cornerstone of these frameworks, enabling regulatory oversight while allowing manufacturing to occur at multiple locations closer to patients.

Key lessons from these early implementations include:

• Standardization through technology is essential for maintaining product quality across sites
• Robust comparability protocols must be established early in development
• Workforce development requires specific attention to technical and regulatory competencies
• Flexible regulatory approaches can accommodate innovative manufacturing models without compromising quality standards

Looking forward, the continued evolution of POCare manufacturing will likely be influenced by several emerging trends. Digitalization and Industry 4.0 technologies will enable more comprehensive remote monitoring and control of distributed manufacturing networks. Harmonization of regulatory requirements across regions will facilitate global development of POCare ATMPs. Additionally, increased automation and the development of "plug-and-play" manufacturing platforms will further reduce the infrastructure requirements at POCare sites.

The successful implementation of POCare manufacturing holds the promise of making ATMPs more accessible and affordable while maintaining the rigorous quality standards required for these transformative therapies. As the field continues to evolve, the lessons from these early implementations will provide valuable guidance for developers, manufacturers, and regulators seeking to advance this innovative approach to ATMP manufacturing.

The European Union is undergoing its most significant pharmaceutical legislative overhaul in over two decades, creating a new operational reality for developers of Advanced Therapy Medicinal Products (ATMPs). The simultaneous implementation of the reformed pharmaceutical legislation ("pharma package") and the new Substances of Human Origin (SoHO) Regulation establishes a complex, interconnected framework that demands strategic preparation, especially for innovative decentralized manufacturing models. These changes collectively aim to ensure timely patient access to safe and effective therapies, enhance supply chain security, boost innovation, and address emerging challenges like antimicrobial resistance [106] [107]. For ATMP researchers and developers, understanding the interplay between these legislative streams is crucial for navigating compliance requirements while maintaining competitive advantage. This technical guide provides a comprehensive analysis of the new landscape, offering detailed methodologies and strategic frameworks to future-proof your ATMP development and manufacturing strategies in an evolving regulatory environment.

The New Legislative Framework: Core Components and Interconnections

The EU Pharma Legislation Reform: Key Objectives and Status

The pharma package, proposed by the European Commission in April 2023 and currently under negotiation between the Council and European Parliament, represents the first major revision of EU pharmaceutical laws since 2004 [106] [107]. The Council agreed on its negotiating position on June 4, 2025, moving the legislation closer to final adoption [108]. The reform aims to achieve several interconnected objectives that directly impact ATMP development:

• Ensure timely and equitable patient access to safe, effective, and affordable medicines across all member states [106]
• Enhance security of supply and address systemic medicine shortages through improved monitoring and prevention mechanisms [106] [107]
• Offer an attractive, innovation-friendly environment for research, development, and production in Europe [106]
• Address antimicrobial resistance (AMR) through a One Health approach [106]
• Improve environmental sustainability of pharmaceutical products [107]

A central tension in the proposed legislation involves balancing incentives for innovation with measures to improve access and affordability. The Council's position maintains eight years of regulatory data protection (down from the current standard) with possibilities for extension, while introducing new obligations for companies to ensure adequate supply [108].

The SoHO Regulation: Expanded Scope and Requirements

The new SoHO Regulation (adopted May 27, 2024) replaces the previous Blood Directive and Tissues and Cells Directive, creating a unified framework for substances including blood, tissues, cells, breast milk, and intestinal microbiota [109] [110]. With an application date of August 7, 2027, the regulation significantly expands requirements for entities handling these materials [109]. For ATMP developers, critical changes include:

• Extended activity coverage: The regulation now covers the entire chain from donor registration through collection, testing, storage, distribution, import, export, and release to the ATMP manufacturer [109]
• New governance structure: Establishes an EU-level SoHO Coordination Board (SCB) to support implementation and harmonization [109]
• Enhanced establishment requirements: SoHO entities must undergo authorization and inspection processes, appoint responsible persons, and register in the EU SoHO Platform [109]
• Borderline product classification: Creates a mechanism for harmonizing classification of products that may fall between different regulatory frameworks [109]

Interplay Between Pharma Legislation and SoHO Regulation for ATMPs

The relationship between these legislative frameworks creates both challenges and opportunities for ATMP developers. The SoHO Regulation governs the starting materials (human cells, tissues) while the pharma legislation governs the final medicinal products, creating a regulatory continuum that spans from donation to clinical application [72]. This interplay is particularly critical for decentralized manufacturing models, where the same facility may handle both SoHO activities and ATMP manufacturing steps.

Table: Key Legislative Components Impacting ATMP Development

Legislative Component	Key Provisions	Implementation Timeline	Primary Impact on ATMPs
Pharma Legislation	Revised regulatory data protection (8+ years), shortage prevention measures, environmental risk assessments	Under negotiation; expected 2025-2026	Market exclusivity periods, regulatory pathways, market access requirements
SoHO Regulation	Expanded activity coverage, SoHO Coordination Board, establishment authorization	Applicable from August 7, 2027	Supply chain requirements for starting materials, donor eligibility, border product classification
Revised ATMP Guidelines	Updated quality, non-clinical, clinical requirements for investigational ATMPs	EMA guideline effective July 1, 2025	Clinical trial application requirements, CMC documentation, risk-based approaches

The regulatory landscape is further complicated by what scholarly research has identified as "significant institutional fragmentation" between organizations collecting human biomaterials and those developing ATMPs [72]. This fragmentation presents particular challenges for decentralized manufacturing sites that must navigate both regulatory domains simultaneously.

Strategic Implications for Decentralized ATMP Manufacturing

Supply Chain and Material Traceability Requirements

Decentralized manufacturing models for ATMPs face unique challenges under the converging legislation, particularly regarding supply chain management and material traceability. The expanded scope of the SoHO Regulation means that all parties handling human biological materials - including collection, testing, storage, and distribution - must comply with enhanced requirements as "SoHO entities" [109]. This has profound implications for multi-site manufacturing networks:

• Extended control points: Donor registration through distribution to manufacturing sites now falls under SoHO requirements, necessitating robust quality agreements between all parties in the decentralized network [109] [110]
• Harmonized classification mechanism: The SoHO Regulation establishes a procedure for resolving borderline product classification issues through the SoHO Coordination Board, providing greater regulatory certainty for innovative products [109]
• Enhanced traceability: The requirement for clinical outcome monitoring creates additional data management requirements across decentralized sites [109]

For ATMP developers, this means implementing systems that can maintain chain of identity and chain of custody across geographically dispersed facilities while meeting the documentation requirements of both pharmaceutical and SoHO frameworks.

Regulatory Operations and Compliance Strategy

The new legislation introduces both challenges and opportunities for regulatory operations:

• Streamlined regulatory processes: The pharma legislation aims to reduce administrative burden and accelerate approval times, potentially benefiting decentralized manufacturing models that require nimble regulatory oversight [107]
• SoHO entity compliance: All facilities in a decentralized network handling human biological materials must implement quality systems meeting SoHO requirements, appoint responsible persons, and prepare for inspections [109]
• Borderline product strategy: The mechanism for obtaining classification opinions from the SoHO Coordination Board provides a pathway for resolving regulatory uncertainties that may arise with innovative ATMPs [109]

The European Medicines Agency's "ATMP pilot for academia and non-profit organizations," which provides enhanced regulatory support, represents a complementary initiative that developers of decentralized manufacturing models should consider when planning their regulatory strategy [19].

Essential Toolkit for Implementation and Compliance

Research Reagent Solutions and Essential Materials

Implementing compliant processes requires careful selection of reagents and materials that meet regulatory standards while supporting research and development objectives.

Table: Key Research Reagent Solutions for ATMP Development Under New Framework

Reagent/Material Category	Specific Examples	Function in ATMP Development	Quality/Regulatory Considerations
Cell Culture Media & Supplements	Serum-free media, cytokines, growth factors, antibiotics	Cell expansion, differentiation, maintenance	GMP-grade, documentation of origin, TSE/BSE-free statements, full traceability
Cell Separation/Selection Reagents	Antibody conjugates, magnetic beads, density gradient media	Isolation of specific cell populations from SoHO starting materials	Purity specifications, validation of separation efficiency, documentation for regulatory filings
Cryopreservation Solutions	DMSO, formulation buffers, protein stabilizers	Long-term storage of cell-based products and intermediates	GMP-grade, endotoxin testing, stability data, container compatibility
Gene Editing Tools	CRISPR-Cas9 systems, viral vectors, mRNA, nucleotides	Genetic modification of cells for gene therapies	Purity, activity assays, documentation of sequence verification, absence of contaminants
Quality Control Assays	Sterility tests, mycoplasma detection, potency assays, adventitious agent tests	Ensuring product safety, purity, potency, and identity	Validation to ICH guidelines, reference standards, GMP-compliant execution

Experimental Protocols for Regulatory Compliance

Protocol: Donor Eligibility and Material Traceability Assessment

Purpose: Establish a standardized methodology for assessing donor eligibility and maintaining chain of custody for SoHO-derived materials used in ATMP manufacturing, meeting requirements of both SoHO Regulation and pharmaceutical legislation.

Materials:

• Donor screening questionnaire (aligned with SoHO Regulation Annex requirements)
• Validated infectious disease testing kits (EU-approved)
• Unique identifier system (barcodes/RFID)
• Electronic data capture system with audit trail functionality
• Sample collection kits with temperature monitoring

Methodology:

• Donor Registration Phase: Collect comprehensive donor demographic information and medical history using standardized forms. Assign unique donor identifier that follows material through all processing stages.
• Infectious Disease Testing: Perform required testing for HIV, HBV, HCV, and other relevant pathogens using validated, approved methods. Document all results in traceable format.
• Material Collection and Labeling: Apply unique identifiers to all collection containers using standardized labeling system. Record collection date, time, and relevant parameters.
• Storage and Transport Conditions Monitoring: Implement continuous temperature monitoring with data logging for all storage and transport steps. Establish acceptance criteria for temperature excursions.
• Chain of Custody Documentation: Maintain log of all personnel handling materials, including dates/times of transfers. Document all storage location changes and processing steps.
• Data Management and Reconciliation: Implement periodic reconciliation of physical inventory with electronic records. Establish procedures for investigating and resolving discrepancies.

Validation Parameters:

• Demonstrate maintenance of chain of identity through mock material transfers
• Validate data integrity of electronic systems through audit trail reviews
• Establish sample stability under proposed storage and transport conditions
• Test disaster recovery procedures for electronic data systems

Protocol: Environmental Monitoring for Decentralized Manufacturing Sites

Purpose: Implement comprehensive environmental monitoring program meeting both medicinal product GMP requirements and SoHO establishment standards for decentralized ATMP manufacturing facilities.

Materials:

• Active air samplers with appropriate collection media
• Settle plates (TSA and SDA)
• Surface contact plates
• Particle counters
• Microbial identification system (MALDI-TOF or equivalent)
• Culture media for bacterial and fungal growth

Methodology:

• Risk-Based Sampling Plan Development: Classify manufacturing areas according to criticality (Grade A-D). Determine sampling locations based on process proximity and material exposure risk.
• Active Air Monitoring: Place samplers in critical locations; sample minimum 1m³ air per location. Incubate plates at appropriate temperatures for specified durations.
• Surface Monitoring: Use contact plates on equipment and room surfaces after operations but before cleaning. Include both direct product contact and non-contact surfaces.
• Personnel Monitoring: Implement finger dabs and gown monitoring at frequency based on area classification.
• Data Trend Analysis: Compile results in statistical process control charts. Establish alert and action limits based on historical data and regulatory guidance.
• Corrective Action Implementation: Develop investigation procedures for excursions. Document root cause analyses and effectiveness checks for corrective actions.

Validation Parameters:

• Demonstrate recovery efficiency of sampling methods
• Establish media growth promotion properties
• Validate cleaning and disinfection procedures using environmental isolates
• Correlate particle counts with viable monitoring results

Visualization of Regulatory Pathways and Workflows

SoHO to ATMP Regulatory Pathway

SoHO to ATMP Regulatory Pathway: This diagram illustrates the continuum from donor material collection under the SoHO Regulation through to ATMP manufacturing and marketing authorization, highlighting the borderline classification mechanism between regulatory frameworks.

Decentralized Manufacturing Compliance Framework

Decentralized Manufacturing Compliance Framework: This diagram visualizes the integrated compliance approach required for decentralized ATMP manufacturing sites operating under multiple regulatory frameworks, showing central coordination functions and site-specific compliance obligations.

The converging EU pharmaceutical legislation and SoHO Regulation create both challenges and opportunities for ATMP developers. Organizations implementing decentralized manufacturing models must adopt an integrated compliance strategy that addresses both regulatory streams simultaneously. The most successful organizations will be those that:

• Establish cross-functional regulatory teams with expertise in both pharmaceutical and SoHO requirements
• Implement robust quality systems that can accommodate the expanded scope of regulated activities under the SoHO Regulation
• Develop strategic partnerships with SoHO entities to ensure compliant supply of starting materials
• Leverage available support mechanisms such as the EMA's ATMP pilot for academia and non-profit organizations
• Prepare for the August 2027 implementation of the SoHO Regulation while monitoring the progressing pharma legislation

By taking a proactive, strategic approach to these regulatory changes, ATMP developers can not only ensure compliance but also potentially gain competitive advantage through more efficient regulatory pathways and robust, scalable manufacturing models. The organizations that begin preparation now will be best positioned to navigate this new regulatory landscape successfully.

Conclusion

The regulatory pathway for decentralized manufacturing of ATMPs is rapidly maturing, offering a viable solution to enhance patient access to personalized, cutting-edge therapies. Success hinges on the robust implementation of a Control Site model, a comprehensive QMS, and a steadfast commitment to demonstrating product comparability across all production sites. As evidenced by the UK's pioneering MHRA framework and ongoing EU initiatives, regulators are actively creating adaptive pathways for these innovative models. Future directions will see greater integration of AI, digital tools, and platform technologies, further optimized through collaborative projects like the Horizon Europe HLTH-2025-01-IND-01 call. For researchers and developers, proactive and early engagement with regulatory bodies, coupled with strategic planning for scaling out rather than up, will be paramount to navigating this complex landscape and bringing transformative treatments from the bench to the bedside efficiently and safely.

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