Navigating ATMP Manufacturing License: A Comprehensive Guide to National Competent Authority Requirements

Abstract

This article provides researchers, scientists, and drug development professionals with a comprehensive guide to obtaining manufacturing authorization for Advanced Therapy Medicinal Products (ATMPs) from National Competent Authorities (NCAs) in the European Union. Covering the foundational regulatory framework, step-by-step application methodology, solutions to common manufacturing challenges, and international regulatory comparisons, it serves as an essential resource for navigating the complex ATMP licensing landscape. The content synthesizes current EU regulations, Good Manufacturing Practice (GMP) requirements specific to ATMPs, and emerging trends to support successful regulatory strategy and compliance.

Understanding the Regulatory Foundation: ATMPs and National Competent Authorities

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking category of biological medicinal products that utilize genes, cells, or tissues to treat, diagnose, or prevent diseases [1]. Under the European Union regulatory framework, ATMPs are defined by Regulation (EC) No 1394/2007, which established the specific legal provisions for these innovative therapies [2] [3]. These products are characterized by their high degree of complexity and their potential to address unmet medical needs for serious or rare conditions through novel mechanisms of action, often involving substantial manipulation of biological materials or non-homologous use [4] [1].

The development and authorization of ATMPs fall under the oversight of the European Medicines Agency (EMA), which operates a centralized authorization procedure for all ATMPs intended for the EU market [4]. A specialized committee within EMA, the Committee for Advanced Therapies (CAT), plays a pivotal role in the scientific assessment, classification, and regulatory guidance for these products [2] [3]. The classification of a product as an ATMP carries significant regulatory implications, determining the applicable development pathway, data requirements, and marketing authorization procedures that developers must follow [5].

The Core Legal Framework for ATMPs

The regulatory foundation for ATMPs in the European Union is built upon a structured hierarchy of legal documents that define their status, requirements, and authorization pathways. The principal legislative act governing ATMPs is Regulation (EC) No 1394/2007, which amended Directive 2001/83/EC and Regulation (EC) No 726/2004 specifically for advanced therapies [2] [6]. This regulation serves as the cornerstone of ATMP regulation, establishing precise definitions for different ATMP categories and creating the Committee for Advanced Therapies (CAT) as the central scientific committee responsible for their evaluation [2].

Complementing this framework, Commission Directive 2009/120/EC further refined the technical definitions and provided detailed scientific requirements for gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products [2] [6]. This directive operationalizes the broader definitions established in the main regulation by specifying the methodological standards and quality benchmarks that ATMPs must meet throughout their development lifecycle. Additionally, ATMPs must comply with horizontal pharmaceutical legislation, including Good Manufacturing Practice (GMP) requirements outlined in Commission Directive 2003/94/EC, Good Clinical Practice (GCP) principles under Directive 2001/20/EC and Regulation EU No 536/2014, and pharmacovigilance obligations under Directive 2010/84/EU and Regulation (EU) No 1235/2010 [2].

For ATMPs incorporating human tissues or cells, the European Tissues and Cells Directive (2004/23/EC) and its implementing directives establish standards for donation, procurement, testing, processing, preservation, storage, and distribution [2]. This framework is soon to be replaced by the Substances of Human Origin Regulation (SoHO-R), creating a unified regulatory approach for human-derived materials [7]. Furthermore, ATMPs containing genetically modified organisms (GMOs) must comply with Directive 2001/18/EC on deliberate release into the environment [2] [7]. The table below summarizes the core legislative instruments constituting the EU ATMP framework.

Table 1: Core EU Legislative Framework for ATMPs

Legislative Instrument	Legal Nature	Key Provisions	Amendments/Related Acts
Regulation (EC) No 1394/2007	Regulation (directly applicable)	Principal ATMP definitions; Establishes CAT; Centralized authorization procedure	Amends Directive 2001/83/EC and Regulation (EC) No 726/2004
Directive 2009/120/EC	Directive (requires transposition)	Detailed technical definitions for GTMPs, SCTMPs, TEPs; Scientific requirements	Amends Directive 2001/83/EC
Directive 2001/83/EC	Directive (requires transposition)	Community code on medicinal products; Definitions of medicinal products	Amended by Regulation 1394/2007 and Directive 2009/120/EC
Regulation (EC) No 726/2004	Regulation (directly applicable)	Establishes EMA; Centralized authorization procedure	Amended by Regulation 1394/2007
Directive 2004/23/EC	Directive (requires transposition)	Quality and safety standards for human tissues and cells	Implementing Directives: 2006/17/EC, 2006/86/EC

ATMP Classification and Definitions

Gene Therapy Medicinal Products (GTMPs)

Gene Therapy Medicinal Products (GTMPs) are defined as biological medicinal products consisting of recombinant nucleic acids or genetically modified microorganisms or viruses administered to humans with the primary objective of regulating, repairing, replacing, adding, or deleting genetic sequences [4] [5]. The therapeutic, prophylactic, or diagnostic effects of GTMPs must directly relate to the recombinant nucleic acid sequence they contain or to the product of genetic expression of this sequence [3] [5]. A critical distinction in the classification of GTMPs is the exclusion of vaccines against infectious diseases, even when these contain genetic material as an active substance, as they fall under a different regulatory category [5].

GTMPs function by introducing "recombinant" genes into the body—stretches of DNA created in the laboratory that bring together genetic material from different sources [4]. These products are being developed to treat a diverse range of conditions, including genetic disorders, various forms of cancer, and long-term chronic diseases [4]. The regulatory framework for GTMPs requires that they undergo rigorous assessment to ensure their quality, safety, and efficacy, with particular attention to aspects such as vector design, transduction efficiency, and long-term genetic stability [3].

Somatic Cell Therapy Medicinal Products (SCTMPs)

Somatic Cell Therapy Medicinal Products (SCTMPs) contain or consist of human cells or tissues that have been subjected to substantial manipulation or are intended for non-homologous use [2] [1]. The regulatory definition specifies two primary conditions that classify a product as an SCTMP: first, when the cells or tissues have been subject to substantial manipulation that alters their biological characteristics, physiological functions, or structural properties relevant for the intended clinical use; and second, when the cells or tissues are not intended to be used for the same essential functions in the recipient and the donor (non-homologous use) [5].

These products are used to cure, diagnose, or prevent diseases through the pharmacological, immunological, or metabolic action of their cells or tissues [4]. The concept of "substantial manipulation" is central to the classification of SCTMPs and refers to processing that alters the biological characteristics, physiological functions, or structural properties of cells or tissues in ways relevant to the intended clinical use [1]. Examples of substantial manipulation include cell activation, genetic modification, extended ex vivo culture, and differentiation protocols that change the original characteristics of the cells [3]. In contrast, minimal manipulations such as cutting, grinding, shaping, centrifugation, or cryopreservation typically do not qualify as substantial manipulation unless they significantly alter the function of the cells.

Tissue-Engineered Products (TEPs)

Tissue-Engineered Products (TEPs) contain or consist of engineered cells or tissues of human or animal origin that are presented as having properties for, or are used in or administered to human beings to repair, regenerate, or replace human tissue [4] [5]. The key distinguishing factor for TEPs is the requirement that the cells or tissues must be "engineered," meaning they have been substantially manipulated or modified to exhibit properties necessary for tissue repair or regeneration [3]. This engineering component typically involves ex vivo culture processes, scaffold-based tissue development, or biomaterial-cell combinations that create a functional tissue construct.

TEPs are characterized by their ability to restore, maintain, or improve tissue function through the action of the engineered cellular components [1]. The regulatory framework recognizes that TEPs often represent complex biological systems that may combine cellular elements with supportive matrices or signaling molecules to achieve their therapeutic effect. The classification as a TEP depends on both the engineering process applied to the cells or tissues and the intended tissue-regenerative function claimed for the product [3].

Combined Advanced Therapy Medicinal Products (cATMPs)

Combined Advanced Therapy Medicinal Products (cATMPs) constitute a distinct category defined as ATMPs that incorporate one or more medical devices as an integral part of the product [4] [6]. The medical device component must be physically combined with the biological element in a way that their separation would compromise the product's safety or efficacy [3]. Common examples include cells embedded in biodegradable matrices, tissue constructs incorporating supportive scaffolds, or delivery systems specifically designed for administering advanced therapies [4].

The regulation of cATMPs requires collaborative assessment between the CAT and national competent authorities responsible for medical devices (notified bodies) [3] [6]. This integrated evaluation ensures that both the biological and device components meet their respective regulatory standards for safety, performance, and quality. With the implementation of the European Medical Device Regulation (EU MDR 2017/745), the requirements for the device component of cATMPs have become more stringent, necessitating comprehensive clinical evidence and enhanced post-market surveillance [8]. The assessment of cATMPs focuses on the interaction between components, the integrity of the combined product, and the overall benefit-risk profile of the integrated therapeutic approach.

Table 2: ATMP Classification Criteria and Examples

ATMP Category	Definitional Criteria	Key Concepts	Product Examples
Gene Therapy Medicinal Product (GTMP)	Contains recombinant nucleic acids; Effect relates directly to genetic sequence	Genetic sequence alteration; Recombinant nucleic acids; Excludes vaccines against infectious diseases	CAR-T cell therapies; Viral vector-based gene therapies
Somatic Cell Therapy Medicinal Product (SCTMP)	Contains cells/tissues that are substantially manipulated OR for non-homologous use	Substantial manipulation; Non-homologous use; Pharmacological/immunological/metabolic action	Expanded mesenchymal stem cells (Alofisel); Dendritic cell therapies
Tissue-Engineered Product (TEP)	Contains engineered cells/tissues to repair, regenerate or replace human tissue	Engineered cells/tissues; Tissue repair/regeneration/replacement	Cartilage repair products (ChondroCelect)
Combined ATMP (cATMP)	ATMP combined with medical device as integral part	Medical device integral to product; Combined technological approach	Cells embedded in biodegradable matrix/scaffold

Regulatory Procedures and Classification Mechanisms

The Committee for Advanced Therapies (CAT) and Its Role

The Committee for Advanced Therapies (CAT) is a multidisciplinary expert body established under Regulation (EC) No 1394/2007 with primary responsibility for the scientific assessment of ATMPs within the European regulatory framework [2] [3]. The CAT comprises members with expertise in diverse scientific domains relevant to advanced therapies, including molecular biology, cell biology, tissue engineering, gene therapy, and clinical applications of these technologies [4]. The committee's composition ensures comprehensive evaluation of the complex scientific and technical aspects unique to ATMPs.

The CAT performs several critical functions in the ATMP regulatory landscape. Firstly, it provides scientific recommendations on ATMP classification through a formal procedure that allows developers to seek regulatory guidance on whether their product meets the criteria for classification as an ATMP [2] [3]. This classification procedure typically concludes within 60 days of application receipt and provides developers with certainty regarding the regulatory pathway for their product [3] [5]. Secondly, during the marketing authorization application process, the CAT prepares a draft opinion on the quality, safety, and efficacy of ATMPs, which forms the basis for the Committee for Medicinal Products for Human Use (CHMP) final opinion on authorization [4]. Additionally, the CAT evaluates applications for certification of quality and non-clinical data submitted by small and medium-sized enterprises (SMEs), contributes to scientific advice procedures for ATMPs under development, and monitors scientific developments in the field of advanced therapies [2] [4].

ATMP Classification Procedure

The ATMP classification procedure is a formal mechanism through which developers can obtain a binding scientific recommendation from the CAT on whether their product meets the criteria to be classified as an ATMP and, if so, which specific category it belongs to [2] [3]. This procedure is particularly valuable when the classification of a product is not straightforward based on the regulatory definitions alone. Developers submit a detailed application to the CAT containing scientific documentation describing the product's characteristics, manufacturing process, mechanism of action, and intended use [3].

The CAT assesses this information against the established definitions for GTMPs, SCTMPs, TEPs, and cATMPs, with particular attention to key classification criteria such as the presence of substantial manipulation, the distinction between homologous versus non-homologous use, and the integration of medical device components [3] [5]. For borderline cases, such as products that might alternatively be regulated as medical devices, transplantation products, or blood components, the CAT provides clarification on the applicable regulatory framework [6]. The resulting classification opinion, published by EMA, provides regulatory certainty to developers and ensures consistent application of ATMP definitions across the European Union.

Substantial Manipulation and Non-Homologous Use

The concepts of "substantial manipulation" and "non-homologous use" represent critical determinants in the classification of cell-based products as ATMPs [1] [6]. Substantial manipulation refers to processing that alters the biological characteristics, physiological functions, or structural properties of cells or tissues in ways that are relevant to the intended clinical use [1]. The regulatory framework provides guidance on processing activities that are generally considered substantial manipulation, including genetic modification of cells, extended ex vivo expansion under specific culture conditions, activation through exposure to biochemical signals, and differentiation along specific lineages [3].

Conversely, minimal manipulation typically includes processes such as cutting, grinding, shaping, centrifugation, cryopreservation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, and cell separation or concentration that do not alter the original relevant characteristics of the cells or tissues [1]. Non-homologous use occurs when the cells or tissues are intended for use in the recipient for different essential functions than those they performed in the donor [1] [5]. For example, using adipose-derived cells for their immunomodulatory properties rather than their structural function would constitute non-homologous use. The determination of whether manipulation is substantial or use is non-homologous requires careful assessment of both the processing methods and the intended biological function of the final product.

Diagram 1: ATMP Classification Decision Pathway

Borderline Products and Classification Challenges

The classification of certain products as ATMPs presents significant regulatory challenges due to the existence of borderline cases that share characteristics with multiple regulatory categories. The European framework addresses these complexities through specific exclusion criteria and demarcation lines between ATMPs and other product classes such as medical devices, transplantation products, and blood components [6]. Products that consist of non-viable human tissues or employ minimal manipulation techniques typically fall outside the ATMP classification and are regulated under alternative frameworks such as the Tissues and Cells Directive [2].

One particularly challenging area involves combined products that incorporate both biological and device components. The classification as a cATMP requires that the medical device be an "integral part" of the product, meaning that the biological and device components are physically combined in a way that their separation would compromise safety or efficacy [3] [6]. Products where the device is merely used for administration of the biological component generally do not qualify as cATMPs. Another complex border exists between GTMPs and certain biological medicines that incorporate genetic elements but do not primarily function through genetic modification, such as some vaccines [5].

The CAT has developed specific approaches to address these borderline cases, including the provision of scientific recommendations on classification and the publication of guidance documents clarifying the application of classification criteria [3]. Additionally, the CAT may consult with other regulatory bodies, such as notified bodies responsible for medical device assessment, when evaluating products that span multiple regulatory domains [3] [6]. This collaborative approach ensures consistent classification decisions across the European regulatory landscape.

ATMP Development and Authorization Pathway

The development pathway for ATMPs follows a structured regulatory process with specific requirements at each stage from preclinical development through marketing authorization. All ATMPs intended for the EU market must undergo the centralized authorization procedure, resulting in a single marketing authorization valid across all member states [4] [3]. This pathway requires submission of a comprehensive Marketing Authorization Application (MAA) to the EMA, which is subsequently evaluated by the CAT and CHMP [4].

The regulatory framework provides several adaptation mechanisms to address the unique challenges in ATMP development. The conditional marketing authorization pathway allows for approval based on less comprehensive data than normally required when the product addresses unmet medical needs and the benefit-risk balance is positive [2]. This is particularly relevant for ATMPs targeting serious conditions with limited treatment options. Additionally, the hospital exemption provision allows for the use of non-routine ATMPs manufactured and used within a single member state under the exclusive professional responsibility of a medical practitioner [3]. This pathway enables patient access to customized ATMPs while maintaining appropriate regulatory oversight at the national level.

For certain ATMPs targeting rare diseases, the orphan medicinal product designation provides incentives including protocol assistance, market exclusivity, and fee reductions [2] [5]. The Priority Medicines (PRIME) scheme offers enhanced support for ATMPs that address unmet medical needs, providing early and interactive regulatory guidance [7]. Furthermore, the certification procedure for SMEs allows small developers to obtain EMA certification of their quality and non-clinical data, potentially facilitating investment and partnerships for further development [2].

Diagram 2: ATMP Development and Authorization Pathway

Essential Research Reagents and Materials

The development and characterization of ATMPs require specialized research reagents and materials that ensure product quality, safety, and consistency. The following table details essential components of the "Scientist's Toolkit" for ATMP research and development, with particular emphasis on reagents that support regulatory compliance and product characterization.

Table 3: Essential Research Reagent Solutions for ATMP Development

Reagent/Material Category	Specific Examples	Function in ATMP Development	Quality/Regulatory Considerations
Cell Culture Media	Serum-free media, Xeno-free supplements, Defined growth factors	Supports cell expansion and maintenance while minimizing variability	GMP-grade; Documentation of origin and composition; Animal-component free where possible
Cell Separation Reagents	Immunomagnetic beads, Density gradient media, Fluorescence-activated cell sorting reagents	Isolation and purification of specific cell populations from source material	Validation of separation efficiency and cell viability; Demonstration of reagent removal
Genetic Modification Tools	Viral vectors (lentiviral, retroviral, AAV), Transposon systems, CRISPR-Cas9 components	Introduction of genetic modifications for GTMPs and engineered cell therapies	Vector characterization; Transduction efficiency; Integration site analysis; GMP-grade vector production
Cell Characterization Reagents	Flow cytometry antibodies, PCR assays, Immunocytochemistry reagents, Metabolic assay kits	Assessment of cell identity, purity, potency, and viability	Validation for specific cell type; Standardization across batches; Stability-indicating properties
Biomaterial Scaffolds	Biodegradable polymers, Hydrogels, Decellularized matrices, Ceramic-based materials	Provides structural support for TEPs and cATMPs	Biocompatibility testing; Degradation profile; Mechanical properties; Sterilization validation
Cryopreservation Solutions	Defined cryoprotectants, Controlled-rate freezing media, Cell storage containers	Maintains cell viability and functionality during storage and transport	Validation of post-thaw recovery and functionality; Container integrity testing

Methodologies for ATMP Characterization and Testing

The regulatory characterization of ATMPs requires implementation of comprehensive testing strategies that address the unique challenges posed by these living products. A robust analytical framework must be established to demonstrate product quality, consistency, and stability throughout development and manufacturing. The following methodologies represent essential approaches for ATMP characterization as required by the regulatory framework.

Identity, Purity, and Potency Assays

Identity testing for ATMPs must confirm that the product contains the correct cellular or genetic components and should include multiple complementary methods. For cell-based ATMPs, flow cytometry using specific surface markers provides quantitative assessment of cell population composition, while PCR-based methods can verify genetic identity and detect specific modifications [1]. Purity assessment encompasses both cellular impurities (unwanted cell types) and process-related impurities (residual reagents, vectors, or materials), requiring orthogonal methods such as microscopy, enzyme assays, and chromatographic techniques [1]. Potency assays present particular challenges for ATMPs and must demonstrate the biological activity relevant to the proposed mechanism of action through in vitro functional assays, cytokine secretion profiles, or target cell engagement assays [1]. These assays must be quantitatively validated and shown to be stability-indicating for product release.

Vector Characterization for GTMPs

Gene Therapy Medicinal Products require extensive vector characterization to ensure safety and consistency. For viral vector-based GTMPs, key analyses include vector titer determination through physical (genome copies) and functional (transducing units) methods, vector identity through restriction mapping or sequencing, and purity assessment through evaluation of empty capsids and process-related impurities [3]. Vector potency must be demonstrated through in vitro transduction assays measuring transgene expression and function, while safety testing includes evaluations of replication-competent viruses, vector integration patterns, and innate immune responses [3]. Non-viral GTMPs require characterization of the nucleic acid integrity, delivery system composition, and functional delivery efficiency to target cells.

Stability Study Methodologies

Stability assessment for ATMPs must address both quantitative stability (cell viability, vector potency, biochemical properties) and functional stability (biological activity, differentiation potential, therapeutic effect) [5]. Stability study protocols should incorporate real-time testing under recommended storage conditions and may include accelerated or stress conditions to identify potential degradation pathways. For cell-based ATMPs, stability studies must demonstrate maintenance of critical quality attributes throughout the proposed shelf life, including cell viability, phenotype stability, functional potency, and sterility [1]. The complex nature of ATMPs often necessitates customized stability protocols that reflect the specific product characteristics and storage conditions.

The European regulatory framework for Advanced Therapy Medicinal Products establishes a comprehensive classification system that categorizes these innovative therapies into four distinct groups: Gene Therapy Medicinal Products, Somatic Cell Therapy Medicinal Products, Tissue-Engineered Products, and Combined ATMPs [2] [4]. The definitions for each category, anchored in Regulation (EC) No 1394/2007 and further elaborated in Directive 2009/120/EC, provide clear criteria for determining whether a product qualifies as an ATMP, with key concepts such as "substantial manipulation" and "non-homologous use" serving as critical determinants for cell-based products [1] [5].

The regulatory classification of a product as an ATMP carries significant implications for its development pathway and marketing authorization process, requiring adherence to the centralized procedure and engagement with the Committee for Advanced Therapies [4] [3]. As the field of advanced therapies continues to evolve, the regulatory framework maintains necessary flexibility through mechanisms such as the classification procedure, scientific advice, and adaptive pathways that accommodate the unique challenges posed by these complex biological medicines [3] [7]. A thorough understanding of ATMP definitions and classification criteria provides developers with the foundation needed to successfully navigate the regulatory requirements and advance these innovative therapies to patients.

The European Union's regulatory framework for Advanced Therapy Medicinal Products (ATMPs) represents a specialized legal adaptation designed to address the unique challenges posed by innovative biological therapies. The foundational legislation consists of Directive 2001/83/EC, which establishes the Community code relating to medicinal products for human use, and Regulation (EC) No 1394/2007, which serves as a lex specialis (special law) specifically for ATMPs [9] [10]. This regulatory tandem was developed in response to scientific progress in cellular and molecular biotechnology that enabled novel treatments for diseases and dysfunctions of the human body [9]. The essential aim of this legislation is to safeguard public health while simultaneously promoting the free movement of these innovative products within the EU market and encouraging advances in the biotechnology sector [11] [10].

For researchers, scientists, and drug development professionals working in the field of advanced therapies, understanding this regulatory framework is critical for successful navigation of the authorization process for ATMPs. The framework acknowledges the complexity and technical specificity of these products, which include gene therapies, somatic cell therapies, and tissue-engineered products, and establishes specially tailored rules that build upon the existing pharmaceutical legislation [10]. This guide provides an in-depth technical analysis of these core legal instruments, with particular focus on their implications for manufacturing authorization within the context of national competent authority oversight.

Core Definitions and Product Classification

Advanced Therapy Medicinal Products: Legal Definitions

Regulation (EC) No 1394/2007 provides precise legal definitions for ATMPs, recognizing four distinct categories of these innovative medicines [2]:

• Gene Therapy Medicinal Products: Biological medicinal products that contain an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence [2]. Their therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

• Somatic Cell Therapy Medicinal Products: Biological medicinal products containing or consisting of cells or tissues that have been substantially manipulated or are not intended to be used for the same essential function(s) in the recipient and the donor. These products are used for treating, preventing or diagnosing diseases through substantial pharmacological, immunological or metabolic action [2].

• Tissue-Engineered Products: Products that contain or consist of engineered cells or tissues and are presented as having properties for treating or preventing disease in human beings. These products may contain cells or tissues of human or animal origin, or both, and the cells or tissues may be viable or non-viable. Additionally, they may incorporate additional substances like cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or matrices [2].

• Combined ATMPs: Advanced therapy medicinal products that incorporate, as an integral part of the product, one or more medical devices within the meaning of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Directive 90/385/EEC [2].

Table 1: Classification of Advanced Therapy Medicinal Products

ATMP Category	Key Characteristics	Principal Mode of Action
Gene Therapy Medicinal Products	Contains recombinant nucleic acid	Genetic modification through insertion and expression of nucleic acid sequences
Somatic Cell Therapy Medicinal Products	Contains manipulated human cells/tissues	Pharmacological, immunological, or metabolic action through cellular activity
Tissue-Engineered Products	Contains engineered cells/tissues with scaffolds/matrices	Regeneration, repair, or replacement of human tissues through combined action
Combined ATMPs	Incorporates medical device as integral component	Combined pharmacological, immunological, or metabolic action with structural support

The definition of ATMPs within Directive 2001/83/EC explicitly references Regulation (EC) No 1394/2007, creating a direct linkage between the general pharmaceutical legislation and the specific provisions for advanced therapies [12]. This interconnection ensures that ATMPs are regulated as biological medicinal products while accounting for their distinctive characteristics.

The Committee for Advanced Therapies and Product Classification

A cornerstone of Regulation (EC) No 1394/2007 was the establishment of the Committee for Advanced Therapies (CAT) within the European Medicines Agency (EMA) [9] [10]. This multidisciplinary committee brings together expertise spanning gene therapy, cell therapy, tissue engineering, medical devices, pharmacovigilance, and ethics [9] [2]. The CAT plays several crucial roles in the regulatory framework:

• Preparing draft opinions on the quality, safety, and efficacy of ATMPs for final approval by the Committee for Medicinal Products for Human Use (CHMP) [9]
• Providing scientific recommendations on ATMP classification [2]
• Following scientific developments in the field of advanced therapies [2]

Since June 2009, the CAT has issued scientific recommendations on ATMP classification based on the definitions laid down in EU legislative texts [2]. This procedure is particularly valuable for developers seeking regulatory clarity early in the product development process. The CAT's classification recommendations are based on the definitions provided in Regulation (EC) No 1394/2007 for tissue-engineered products and combined ATMPs, and Part IV of Annex I to Directive 2001/83/EC for gene therapy and somatic cell therapy medicinal products [2].

Diagram 1: ATMP Classification Decision Pathway

The Centralized Authorization Procedure and Manufacturing Requirements

Mandatory Centralized Authorization

Regulation (EC) No 1394/2007 made the centralized authorization procedure compulsory for all ATMPs intended to be placed on the market in Member States [9] [10]. This requirement was instituted to overcome the scarcity of specialized expertise across the Community, ensure a high level of scientific evaluation, preserve confidence among patients and medical professionals, and facilitate market access for these innovative technologies [10]. The centralized procedure involves:

• A single scientific evaluation of the quality, safety, and efficacy of the product conducted by the EMA [10]
• Preparation of a draft opinion by the Committee for Advanced Therapies (CAT) [9]
• Final approval by the Committee for Medicinal Products for Human Use (CHMP) [9]
• Coordination between various committees to ensure scientific consistency and system efficiency [9]

The centralized marketing authorization applies to ATMPs that are "intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process" [10]. This requirement aligns with the general scope of Community pharmaceutical legislation established in Title II of Directive 2001/83/EC.

Manufacturing Authorization Requirements

The manufacturing of ATMPs within the European Union is subject to stringent authorization requirements under Directive 2001/83/EC [13]. Any legal entity wishing to manufacture a medicinal product must hold a manufacturing authorization issued by the national competent authority of the Member State where the manufacturing activities occur [13]. The key requirements for ATMP manufacturers include:

• Good Manufacturing Practice (GMP) Compliance: All ATMPs intended for the EU market must be produced in accordance with EU quality standards, specifically GMP principles and guidelines, and the European Pharmacopoeia [13]. The European Commission has published detailed guidelines on GMP specific to ATMPs in accordance with Article 5 of Regulation (EC) No 1394/2007 [13].

• Qualified Person (QP) Oversight: Manufacturers must designate a qualified person responsible for ensuring that the requirements for the manufacturing authorization and applicable legislation are respected [13]. This includes batch certification and release.

• Quality Documentation: The manufacturing authorization application must include Module 3 of the Marketing Authorisation Application dossier, "Chemical, pharmaceutical, and biological documentation" (Chemistry, Manufacturing and Controls - CMC) that determines the specifications capable of guaranteeing the reproducibility of the medicine's composition [13].

Table 2: Key Challenges in ATMP Manufacturing and Regulatory Solutions

Manufacturing Challenge	Impact on Authorization Process	Regulatory Consideration
High production & development costs	Substantial financial investment required; barrier for smaller entities	SME incentives; certification procedure for quality and non-clinical data [2]
Use of substances of human origin with short shelf life	Complex logistics and limited stability testing window	Flexible validation approaches; real-time quality control
Autologous nature and small batch sizes	Limited number of analytical tests for process validation	Risk-based approaches; comparability protocols
Extreme logistical complexity	Chain of identity maintenance; cold chain validation	Detailed tracking systems; validation of transport conditions
Need for specialized facilities and equipment	Significant capital investment	Clear GMP guidelines for ATMP-specific facilities [13]
Degree of product variability	Challenge in demonstrating consistency	Process validation; definition of critical quality attributes

Hospital Exemption and Non-Routine Preparation

A significant exemption to the centralized authorization requirement exists for ATMPs "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" [10]. This provision, commonly referred to as the "hospital exemption," allows for the non-routine manufacture and use of ATMPs within a specific hospital setting without going through the centralized authorization procedure.

The hospital exemption is intended to balance regulatory oversight with patient access to innovative therapies, particularly in cases where industrial-scale manufacturing may not be feasible or appropriate. However, the exemption still requires that relevant Community rules related to quality and safety are not undermined [10]. Member States have incorporated provisions for these special ATMPs into their national laws, as referenced in the German implementation of the Regulation [14].

Technical Requirements and Quality Standards

Good Manufacturing Practice for ATMPs

The manufacturing of ATMPs must comply with Good Manufacturing Practice (GMP) standards, which are defined as "the part of the quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use" [13]. For ATMPs, GMP compliance presents unique challenges due to:

• The use of substances of human origin composed of live cells with short shelf lives [13]
• The need to maintain sterility throughout complex manufacturing processes [13]
• Variable biological materials that introduce inherent product variability [13]
• Complex logistics involving collection of patient cells, transportation to manufacturing facilities, and supply of finished ATMPs to healthcare providers [13]

The European Commission has issued detailed guidelines on GMP specific to ATMPs in accordance with Article 5 of Regulation (EC) No 1394/2007 [13]. These guidelines address the particular characteristics of ATMPs while maintaining the fundamental quality standards required for all medicinal products.

Additional Technical Requirements

Beyond general GMP requirements, ATMPs are subject to additional technical standards that reflect their biological complexity and novel characteristics:

• Starting Materials Requirements: When tissues and cells are used as starting materials, applicants must comply with Directive 2004/23/EC (the European Tissues and Cells Directive) and its technical implementing directives, which cover standards for donation, procurement, testing, processing, preservation, storage, and distribution [2]. For ATMPs containing human cells or tissues, Directive 2004/23/EC applies to donation, procurement, and testing, while further aspects are covered by Regulation (EC) No 1394/2007 [10].

• Environmental Risk Assessment: ATMPs containing genetically modified organisms must follow relevant legislation on the deliberate release of genetically modified organisms into the environment, particularly Directive 2001/18/EC [2].

• Traceability Requirements: Directive 2006/86/EC establishes standards for traceability, notification of serious adverse reactions and events, and requirements for coding, processing, preservation, storage, and distribution of human tissues and cells [2].

Diagram 2: ATMP Manufacturing and Control Workflow

Interactions with National Competent Authorities

The Role of National Competent Authorities in ATMP Manufacturing Authorization

National competent authorities play a crucial role in the implementation and enforcement of the EU regulatory framework for ATMPs. Their responsibilities encompass multiple aspects of the manufacturing authorization process:

• Assessment of Applications: National competent authorities register, review, and assess applications for manufacturing authorisations of medicinal products intended for use within the EU [13].

• GMP Inspections: Manufacturers within the EU/European Economic Area (EEA) are under national supervision of Member State inspection agencies, which conduct regular and repeated on-site inspections to verify compliance with marketing authorization and EU GMP requirements [13].

• Batch Release: For ATMPs (as with other biological medicinal products), the national competent authority is responsible for the official release of batches by the control authorities [13].

• Regulatory Guidance: National competent authorities provide regulatory and scientific advice and guidance to manufacturers, serving as the primary entry point for manufacturing authorization applicants [13].

The EudraGMDP database, maintained and operated by the EMA with content provided by national competent authorities, contains manufacturing and import authorisations, registration of active substance manufacturers, GMP certificates, and non-compliance statements issued after inspections [13]. This database enhances transparency and information sharing among regulatory authorities across the EU.

Multi-Site Manufacturing and Regulatory Coordination

The manufacturing of ATMPs often involves complex arrangements across multiple sites, particularly for autologous products where manufacturing may need to occur close to the patient. Regulation (EC) No 1394/2007 and Directive 2001/83/EC establish requirements for these scenarios:

• Authorization for All Sites: Under current EU law requirements, each production site must hold a manufacturing authorization and comply with ATMP-specific GMP [13].

• Decentralized Manufacturing: Recent legislative proposals address the challenges of decentralized production sites potentially near to the patient. The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions that would allow derogation whereby "the manufacturing authorisation shall not be required for the decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site" [13].

• Harmonization Efforts: The Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG), chaired by the EMA and composed of senior GMP inspectors from the EEA, works to harmonize and coordinate GMP activities at the European level to ensure a common interpretation of requirements [13].

Table 3: Essential Regulatory Tools for ATMP Development

Tool/Procedure	Legal Basis	Purpose	Relevance to Manufacturing
CAT Classification	Article 17, Regulation 1394/2007 [2]	Scientific recommendation on ATMP classification	Clarifies regulatory pathway and requirements
SME Certification	Article 18, Regulation 1394/2007 [2]	Certification of quality and non-clinical data for SMEs	Supports manufacturing development before MAA submission
Scientific Advice	EMA Procedures [13]	Regulatory guidance on development strategy	Provides manufacturing and testing strategy input
GMP Inspections	Directive 2001/83/EC [13]	Verification of compliance with quality standards	Mandatory for manufacturing authorization
Variations Regulation	Regulation (EC) No 1234/2008 [2]	Examination of changes to marketing authorisations	Required for manufacturing process changes

The legal framework established by Directive 2001/83/EC and Regulation (EC) No 1394/2007 creates a comprehensive regulatory pathway for Advanced Therapy Medicinal Products that balances innovation with patient safety. For researchers, scientists, and drug development professionals, understanding the interplay between these legal instruments is essential for successful navigation of the ATMP manufacturing authorization process.

The framework acknowledges the unique challenges posed by ATMPs while maintaining the fundamental principles of pharmaceutical regulation that have evolved over 50 years of EU pharmaceutical legislation [15] [16]. As the field of advanced therapies continues to evolve, this regulatory foundation provides both the structure for ensuring product quality and safety and the flexibility to accommodate new scientific developments.

For manufacturers seeking authorization from national competent authorities, successful navigation of this framework requires early engagement with regulatory bodies, careful attention to the specific technical requirements for ATMPs, and robust quality systems capable of addressing the unique challenges of these innovative biological therapies. The continued harmonization of regulatory approaches across Member States, facilitated by bodies such as the EMA's Committee for Advanced Therapies and the GMP/GDP Inspectors Working Group, promises to further streamline the authorization process while maintaining the high standards of quality and safety that protect European patients.

The development and manufacture of Advanced Therapy Medicinal Products (ATMPs) represent one of the most innovative yet complex areas in modern medicine. These gene-based, cell-based, and tissue-engineered therapies require a sophisticated regulatory framework to ensure patient safety while fostering innovation. The European regulatory network for ATMPs is a collaborative system comprising the European Medicines Agency (EMA), its specialized Committee for Advanced Therapies (CAT), and the National Competent Authorities (NCAs) of EU Member States. These bodies perform distinct yet interconnected functions throughout the product lifecycle, from initial classification and clinical development to manufacturing authorization and post-market surveillance. For researchers and developers, understanding the precise roles, responsibilities, and interaction points among these regulatory entities is fundamental to successfully navigating the pathway from concept to authorized therapy. This guide provides a technical examination of this framework, with particular emphasis on the critical role of NCAs in the manufacturing authorization process.

Defining Advanced Therapy Medicinal Products (ATMPs)

ATMPs are innovative biological medicines for human use that are based on genes, cells, or tissues. The European regulatory framework classifies them into three main categories, with a fourth distinct category for combined products [4]:

• Gene Therapy Medicinal Products: These contain genes that lead to a therapeutic, prophylactic, or diagnostic effect. They function by inserting 'recombinant' genes into the body, typically created in the laboratory by bringing together DNA from different sources. They are used to treat a variety of diseases, including genetic disorders, cancer, or long-term diseases [4].

• Somatic-Cell Therapy Medicinal Products: These contain cells or tissues that have been manipulated to change their biological characteristics, or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose, or prevent diseases [4].

• Tissue-Engineered Medicines: These contain cells or tissues that have been modified so they can be used to repair, regenerate, or replace human tissue [4].

• Combined ATMPs: Some ATMPs contain one or more medical devices as an integral part of the medicine. A typical example is cells embedded in a biodegradable matrix or scaffold [4].

A product's classification as an ATMP triggers specific regulatory pathways and requirements. The CAT provides free-of-charge scientific recommendations on classification to help developers determine if their product qualifies as an ATMP and which category it belongs to, a procedure strongly recommended for developers to utilize [17].

The European Medicines Agency (EMA)

Core Mission and Function

The European Medicines Agency (EMA) is an agency of the European Union with a mission to protect and promote public and animal health across the EU and European Economic Area (EEA), serving a population of around 450 million people [18]. The Agency's primary function is the scientific evaluation, supervision, and safety monitoring of medicines. For human medicines, including ATMPs, it operates the centralized authorization procedure, which results in a single marketing authorization that is valid across all EU Member States [19] [20].

Specific Roles in the ATMP Sector

The EMA's role in the ATMP ecosystem extends beyond standard medicine evaluation and encompasses several specific functions [4]:

• Scientific Assessment: EMA is responsible for the scientific assessment of all advanced therapy medicines submitted via the centralized procedure. This involves a single evaluation and authorization process for the entire EU market [4].

• Supporting Development: EMA provides scientific support and regulatory guidance to ATMP developers, including small and medium-sized enterprises (SMEs) and academia. Mechanisms include the Innovation Task Force for early dialogue and fee reductions for SMEs and academic developers [4] [19].

• Pharmacovigilance: EMA, in cooperation with NCAs, continuously monitors the safety of authorized ATMPs throughout their lifecycle to ensure their benefits continue to outweigh their risks [19].

• Guideline Development: The Agency develops scientific guidelines on requirements for the quality, safety, and efficacy testing of ATMPs, helping developers meet regulatory standards [19].

• Good Manufacturing Practice (GMP) Coordination: EMA plays a key role in coordinating and harmonizing GMP activities at the European level. It chairs the Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG) and maintains the EudraGMDP database, which contains manufacturing authorizations, GMP certificates, and non-compliance statements [21].

It is crucial to note that EMA's remit has specific boundaries. The Agency does not issue manufacturing authorizations, authorize clinical trials, decide on medicine pricing or reimbursement, or control pharmaceutical patents. These responsibilities fall to the NCAs or other EU bodies [19].

Committee for Advanced Therapies (CAT)

Composition and Expertise

The Committee for Advanced Therapies (CAT) is a multidisciplinary committee established under Regulation (EC) No 1394/2007, gathering some of the best available experts in Europe in the field of advanced therapies [22]. It operates within the EMA framework but possesses specific expertise for evaluating ATMPs. The CAT's composition reflects the unique scientific and technical challenges posed by these complex products, encompassing specialists in cell and gene therapy, tissue engineering, molecular biology, and related fields.

Key Responsibilities and Activities

The CAT's responsibilities are central to the regulatory oversight of ATMPs and can be categorized into four core areas [22]:

• Marketing Authorization Evaluation: The CAT's main responsibility is to prepare a draft opinion on each ATMP application submitted to EMA. This opinion on the product's quality, safety, and efficacy is then sent to the Committee for Medicinal Products for Human Use (CHMP), which adopts a final opinion recommending (or not) authorization to the European Commission [22].

• Classification and Certification:

  • It provides scientific recommendations on whether a medicine under development qualifies as an ATMP [22] [17].
  • It participates in certifying quality and non-clinical data for SMEs developing ATMPs [22].

• Scientific Advice and Guidance: The CAT contributes to scientific advice for ATMP developers, in cooperation with the Scientific Advice Working Party (SAWP). It also assists in developing scientific and regulatory guidance documents relating to ATMPs [22].

• Regulatory Support: The committee advises the CHMP on any medicinal product requiring ATMP expertise and provides scientific input for EU initiatives related to innovative medicines and therapies [22].

Table 1: Key Outputs and Procedures of the Committee for Advanced Therapies (CAT)

Procedure/Output	Purpose	Legal Basis/Context
Draft Opinion on ATMPs	Scientific assessment for marketing authorization	Regulation (EC) No 1394/2007 [22]
Scientific Recommendation on Classification	Determines if a product is an ATMP and its type	Article 17 of Regulation (EC) No 1394/2007 [17]
ATMP Certification	Certifies quality and non-clinical data for SMEs	Incentive for small and medium-sized enterprises [22]
Scientific Advice	Provides guidance on development plans to developers	Cooperation with Scientific Advice Working Party [22]

A significant future consideration for the CAT is the proposed EU pharmaceutical legislation reform. This reform suggests integrating the CAT's functions into other committees and working parties, a change that stakeholders have warned could challenge innovation in the ATMP sector by risking the loss of specialized knowledge [23].

National Competent Authorities (NCAs)

Fundamental Role in National Regulation

National Competent Authorities (NCAs) are the national regulatory bodies of individual EU Member States (e.g., BfArM in Germany, ANSM in France, AIFA in Italy). They form, together with the EMA and the European Commission, the European medicines regulatory network. While the EMA oversees the centralized authorization, NCAs are responsible for a multitude of critical regulatory activities at the national level. Their functions are particularly crucial for the practical aspects of ATMP development and manufacture, especially before a marketing authorization is even sought.

Core Functions in the ATMP Landscape

The responsibilities of NCAs are extensive and directly impact ATMP developers on the ground [19] [21]:

• Authorization and Oversight of Clinical Trials: EMA does not authorize clinical trials. Sponsors must submit applications to the NCAs of the countries where the trial will be conducted. NCAs are responsible for assessing these applications and ensuring compliance with regulatory standards [19].

• Manufacturing Authorization: This is a critical function of NCAs. Any company wishing to manufacture an ATMP (or any medicine) in the EU must hold a manufacturing authorization issued by the NCA of the Member State where the manufacturing activities take place [21].

• GMP Inspection and Enforcement: NCAs conduct regular and repeated on-site GMP inspections of manufacturing sites to verify compliance with EU quality standards. After each inspection, they issue a GMP certificate (for a positive outcome) or a statement of non-compliance (for a negative outcome), which is recorded in the EudraGMDP database [21].

• Market Supervision and Pharmacovigilance: NCAs monitor the safety of medicines once they are on the market in their territory and are involved in the management of medicine shortages [19] [20].

• National Authorization Procedures: For medicines not approved via the centralized procedure, NCAs manage national authorization procedures, including the mutual recognition and decentralized procedures.

Interplay of Regulatory Bodies in ATMP Manufacturing Authorization

The process of obtaining and maintaining a manufacturing authorization for an ATMP illustrates the essential collaboration between a developer, the relevant NCA, and the EMA. The following diagram maps the logical relationships and workflow in this core regulatory pathway.

Diagram 1: ATMP Manufacturing Authorization and Supervision Pathway. This workflow highlights the primary role of the National Competent Authority (NCA) in authorizing and supervising manufacturing activities, with the EMA providing system-level coordination via the EudraGMDP database.

The manufacturing of ATMPs, including investigational products for clinical trials, must comply with EU Good Manufacturing Practice (GMP) principles and the specific GMP guidelines for ATMPs issued by the European Commission [21]. The NCA's role is one of direct oversight and enforcement, while the EMA's role is one of coordination and harmonization. The EMA, through the GMP/GDP Inspectors Working Group, works to ensure a common interpretation of GMP rules across the EU and maintains the EudraGMDP database, which is a key tool for transparency and information sharing among regulators [21].

The Developer's Toolkit: Regulatory Pathway Essentials

For researchers and developers navigating the ATMP regulatory pathway, several key procedures and documents are essential. Understanding and utilizing these tools from the early stages of development can significantly streamline the process and mitigate regulatory risks.

Table 2: Essential Regulatory Tools and Procedures for ATMP Developers

Tool/Procedure	Function/Purpose	Key Actor	Developer Consideration
CAT Scientific Recommendation on Classification	Provides a formal opinion on whether a product is an ATMP and its type [17].	CAT/EMA	Free of charge. Highly recommended in case of doubt to clarify the applicable regulatory pathway early on [17].
Manufacturing Authorisation	Legally permits the commercial manufacture of an ATMP within an EU Member State [21].	National Competent Authority (NCA)	Must be obtained from the NCA of the country where the manufacturing site is located. Requires GMP compliance.
GMP for ATMPs	Ensures products are consistently produced and controlled according to quality standards [21].	Manufacturer (Oversight by NCA)	The European Commission has published detailed GMP guidelines specific to ATMPs. Compliance is mandatory.
EudraGMDP Database	Public database of manufacturing authorisations and GMP compliance status [21].	EMA (Maintained) / NCAs (Data Providers)	A resource for verifying the compliance status of manufacturing sites, including potential partners or contractors.
Centralised Marketing Authorisation	Grants a single approval valid across the entire EU/EEA market [4].	EMA (Assessment) / European Commission (Decision)	Mandatory for all ATMPs. EMA's CAT performs the initial scientific assessment [4] [22].
Scientific Advice & Protocol Assistance	Allows developers to get regulatory feedback on their development plan [19].	EMA (CHMP/CAT/SAWP)	Invaluable for aligning the development strategy with regulatory expectations, especially for innovative products.

The successful navigation of the European regulatory landscape for ATMPs demands a clear understanding of the distinct yet complementary roles played by the EMA, the CAT, and the National Competent Authorities. The EMA serves as the central hub for the scientific evaluation of marketing authorizations and the coordination of EU-wide regulatory efforts. The CAT provides the indispensable, specialized scientific expertise required for evaluating these complex products and offers critical classification and certification procedures. Finally, the National Competent Authorities are the foundational pillars for on-the-ground regulation, responsible for authorizing and inspecting clinical trials and, most importantly for manufacturers, granting and overseeing the manufacturing authorization that is a prerequisite for producing ATMPs within the EU.

For researchers and drug development professionals, engaging with these bodies proactively—through CAT classification procedures, scientific advice, and early dialogue with NCAs on GMP and manufacturing requirements—is not merely a regulatory formality but a strategic imperative. As the field of advanced therapies continues to evolve, this collaborative regulatory framework, despite facing potential reforms, remains essential for balancing the urgent need for innovative treatments with the unwavering commitment to patient safety and product quality.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of biological medicines that utilize genes, cells, or tissues to treat, diagnose, or prevent diseases. These innovative therapies offer potential solutions for complex conditions by targeting root causes rather than merely alleviating symptoms. Within the European Union regulatory framework, ATMPs are classified into three main categories—gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines—with an additional category for combined ATMPs that incorporate medical devices as integral components [4]. The development and authorization of these therapies follow a centralized procedure through the European Medicines Agency (EMA), ensuring consistent evaluation standards across member states [4].

The regulation of ATMPs is governed primarily by Regulation (EC) No 1394/2007, which established specific definitions and requirements for these sophisticated products [2]. This regulatory framework created the Committee for Advanced Therapies (CAT), a multidisciplinary committee responsible for assessing the quality, safety, and efficacy of ATMPs [2]. For researchers and drug development professionals working with national competent authorities, understanding this classification system is fundamental to navigating the manufacturing license application process, as each ATMP category presents distinct technical and regulatory considerations throughout the product lifecycle.

Comprehensive ATMP Classification Framework

Core Categories and Definitions

Table 1: Fundamental Classification of Advanced Therapy Medicinal Products (ATMPs)

ATMP Category	Core Definition	Primary Mechanism of Action	Examples of Medical Applications
Gene Therapy Medicines	Contain genes that lead to a therapeutic, prophylactic or diagnostic effect [4].	Insertion of recombinant genes into the body to correct or compensate for disease-causing genetic alterations [4].	Treatment of genetic disorders (e.g., RPE65-mutated Leber Congenital Amaurosis), cancer, or long-term diseases [4] [24] [25].
Somatic-Cell Therapy Medicines	Contain cells or tissues that have been manipulated to change their biological characteristics or are not intended for the same essential function in the body [4].	Administration of manipulated cells to cure, diagnose, or prevent diseases through mechanisms such as immune modulation or tissue repair [4].	Chimeric Antigen Receptor (CAR) T-cell immunotherapies for cancer, stem cell-based therapies [4] [26].
Tissue-Engineered Medicines	Contain cells or tissues that have been modified to repair, regenerate, or replace human tissue [4].	Use of engineered constructs combining cells and scaffolds to restore tissue structure and function at damaged sites [4].	Repair of bone, cartilage, skin defects, or corneal repair using recombinant collagen scaffolds [4] [27].
Combined ATMPs	Incorporate one or more medical devices as an integral part of the medicine [4].	Combined action of the cellular component and the medical device to achieve the intended therapeutic effect.	Cells embedded in a biodegradable matrix or scaffold for enhanced tissue regeneration [4].

The classification of ATMPs is based on rigorous scientific definitions laid down in EU legislative texts, specifically Regulation (EC) No 1394/2007 for tissue-engineered products and combined ATMPs, and Directive 2001/83/EC for gene therapy and somatic cell therapy medicinal products [2]. The Committee for Advanced Therapies (CAT) provides scientific recommendations on ATMP classification, which is a critical first step for developers seeking manufacturing authorization from national competent authorities [4] [2]. This classification determines the specific regulatory pathway, data requirements, and good practice standards that must be followed throughout product development and commercialization.

Regulatory Classification Workflow

The following diagram illustrates the logical decision process that the Committee for Advanced Therapies (CAT) follows when classifying an Advanced Therapy Medicinal Product.

Technical Specifications and Methodologies

Gene Therapy Medicinal Products: Experimental Workflow

Gene therapy medicines involve the delivery of recombinant genes to target cells to achieve a therapeutic effect. The following diagram outlines a generalized experimental workflow for the development and testing of an in vivo gene therapy, such as for inherited retinal diseases.

Gene Therapy Experimental Protocol:

• Vector Engineering and Production: Select and engineer a suitable viral vector (e.g., Adeno-associated virus - AAV) for gene delivery. The AAV vector is chosen for its tropism for specific retinal cells and safety profile. The recombinant vector is produced in a helper virus-free system, typically using HEK293 cells, and purified via ultracentrifugation or chromatography [24] [25].

• Therapeutic Gene Cloning: Clone the therapeutic cDNA (e.g., the correct version of the RPE65 or ABCA4 gene) into the expression cassette of the vector. The cassette must include a tissue-specific promoter (e.g., a photoreceptor-specific promoter like GRK1) to direct expression to the target cells and ensure stable, long-term expression [24] [25].

• In Vitro Validation: Transfert the construct into relevant cell lines (e.g., patient-derived iPSCs differentiated into retinal pigment epithelium) to confirm successful transduction, gene expression, and functional correction of the pathological phenotype (e.g., restoration of the visual cycle) [24].

• In Vivo Efficacy Testing: Administer the final vector product via subretinal injection into animal models of the disease (e.g., Rpe65-/- or Abca4-/- mice). Monitor animals for restoration of visual function using electroretinography (ERG), improvement in behavioral visual tests (e.g., optomotor response), and histological confirmation of photoreceptor survival [24] [25].

• Safety and Biodistribution: Conduct comprehensive toxicology studies in relevant animal models. Assess local and systemic toxicity, immune responses to the vector or transgene, and vector biodistribution to non-target tissues. This is critical for defining the safety profile for clinical trial applications [4] [28].

Somatic-Cell Therapy Medicines: Manufacturing and Testing

Table 2: Key Reagents and Materials for Somatic-Cell Therapy Manufacturing

Research Reagent / Material	Function in ATMP Development	Application Example
Cell Separation Media (e.g., Ficoll)	Density gradient centrifugation to isolate peripheral blood mononuclear cells (PBMCs) from leukapheresis product.	Initial step in CAR-T cell manufacturing to isolate T-cells from patient blood [26].
Activation Beads/CD3+CD28 Antibodies	To activate the T-cell receptor complex and co-stimulatory signals, initiating T-cell proliferation.	Critical step for ex vivo T-cell expansion prior to genetic modification [26].
Viral Vector (e.g., Lentivirus, Retrovirus)	Stable delivery and integration of the genetic construct (e.g., CAR gene) into the target cell genome.	Genetic modification of patient T-cells to express a Chimeric Antigen Receptor (CAR) [26].
Cell Culture Media and Cytokines (e.g., IL-2)	Provides nutrients and growth signals for the expansion of modified cells to the required therapeutic dose.	Large-scale ex vivo expansion of CAR-T cells in bioreactors [28].
Cryopreservation Medium (e.g., with DMSO)	Allows for long-term storage of the final cell product at ultra-low temperatures while maintaining cell viability.	Final formulation of the ATMP product for transportation and administration [28].

Somatic-cell therapy products, such as CAR-T cells, undergo a complex, multi-stage manufacturing process. The critical quality attributes (CQAs) of the final product, including identity, purity, potency, and viability, must be rigorously controlled. The process involves cell collection, activation, genetic modification, expansion, and formulation [28]. A key regulatory focus for national authorities is the demonstration of a consistent and controlled manufacturing process under Good Manufacturing Practice (GMP) conditions, which is essential for ensuring product safety and efficacy [4] [28].

Critical Quality and Safety Assessments for All ATMPs

All ATMP categories share common, critical safety assessments that must be addressed during non-clinical development. A primary concern is the risk of tumorigenicity, especially for products involving stem cells or integrating vectors [28]. This is typically assessed using in vivo studies in immunocompromised models (e.g., NOG/NSG mice) to detect any unwanted cell growth [28]. For gene therapies, off-target editing is a major risk; for CRISPR-Cas-based therapies, this requires careful assessment of potential off-target sites through in silico prediction and next-generation sequencing [24].

Genetic stability of cell-based products is assessed by performing tests like karyotyping to detect chromosomal abnormalities that may arise during extended culture [28]. Furthermore, all ATMPs must undergo stringent sterility testing. Because traditional sterilization methods are not applicable to living cells and tissues, the entire manufacturing process must be conducted under validated aseptic conditions. Process validation includes simulation tests known as "media fills" to demonstrate that the aseptic processing conditions are effective at preventing microbial contamination [28].

Regulatory Pathways and Good Practice Standards

The regulatory journey of an ATMP, from research to market, is governed by a comprehensive legal framework. Applicants must be aware of the relevant legislation, which includes directives on clinical trials (Directive 2001/20/EC, Regulation EU No 536/2014), good clinical and manufacturing practices (Directive 2005/28/EC, Directive 2003/94/EC), and pharmacovigilance (Directive 2010/84/EU) [2]. Furthermore, specific regulations apply when ATMPs contain medical devices, are based on tissues and cells (Directive 2004/23/EC), or involve genetically modified organisms (Directive 2001/18/EC) [2].

Table 3: Overview of Key EU Regulatory Frameworks Applicable to ATMPs

Legislative Area	Key Document	Relevance to ATMP Manufacturing License
Core ATMP Regulation	Regulation (EC) No 1394/2007 [2]	Provides the overarching legal definitions and establishes the Committee for Advanced Therapies (CAT).
Medicinal Products	Directive 2001/83/EC [2]	Defines general requirements for medicinal products for human use, including GMP and safety standards.
Authorization Procedure	Regulation (EC) No 726/2004 [2]	Establishes the centralized marketing authorization procedure, which is mandatory for ATMPs.
Clinical Trials	Regulation EU No 536/2014 [2]	Sets rules for the conduct of clinical trials on medicinal products for human use within the EU.
Tissues and Cells	Directive 2004/23/EC [2]	Sets standards for the quality and safety of human tissues and cells used as starting materials.
Good Manufacturing Practice	Directive 2003/94/EC [2]	Lays down the principles and guidelines of GMP for medicines for human use.

A significant challenge in ATMP development is the transition from non-clinical research under Good Laboratory Practice (GLP) to GMP-compliant manufacturing. GLP ensures the quality and integrity of non-clinical safety data, while GMP ensures that products are consistently produced and controlled according to quality standards [28]. This transition requires securing a reliable supply of GMP-grade raw materials, developing scalable and reproducible cell expansion processes in closed-system bioreactors, and implementing robust quality control systems and process validation [28]. For developers from academia and small companies, the EMA offers support through initiatives like the ATMP pilot program, which provides regulatory guidance and fee reductions [4].

The precise classification of an ATMP into one of the four categories—gene therapy, somatic-cell therapy, tissue-engineered, or combined ATMP—is a critical first step that defines its developmental and regulatory pathway. For researchers and manufacturers engaging with national competent authorities, a deep understanding of the technical specifications, experimental methodologies, and the extensive regulatory framework is non-negotiable. While the field presents challenges in manufacturing, scalability, and safety assessment, the evolving regulatory guidelines and support mechanisms are facilitating the translation of these advanced therapies from the laboratory to the clinic. As the ATMP landscape continues to advance, maintaining a rigorous focus on quality by design, comprehensive safety assessments, and adherence to good practice standards will be paramount for successfully obtaining a manufacturing license and delivering transformative treatments to patients.

Within the European Union's regulatory framework, the centralized authorization procedure serves as the mandatory pathway for all Advanced Therapy Medicinal Products (ATMPs) seeking market approval [29]. This mechanism requires ATMP manufacturers to submit a single Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA), which conducts a comprehensive scientific assessment leading to a European Commission decision that is valid across all Member States [30]. The procedure establishes a streamlined regulatory pathway that ensures consistent evaluation standards while facilitating simultaneous market access throughout the European Economic Area.

The mandatory nature of this pathway for ATMPs stems from Regulation (EC) No 1394/2007, which classified these innovative therapies as biological medicinal products requiring specialized regulatory oversight [31]. This legislation recognized that ATMPs—encompassing gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines—represent a distinct category of therapeutics with unique characteristics and potential risks [4]. The centralized procedure addresses these specialized requirements through the involvement of specific scientific committees with expertise in advanced therapy evaluation, particularly the Committee for Advanced Therapies (CAT) [4].

Regulatory Framework and Key Institutions

The Centralized Authorization Workflow

The ATMP authorization process follows a defined sequence with multiple regulatory bodies fulfilling specific roles. The diagram below illustrates the complete pathway from application submission to final decision.

Key Regulatory Bodies and Their Functions

The centralized authorization procedure involves multiple European regulatory entities, each with distinct responsibilities in the evaluation and approval process for ATMPs.

Table 1: Key Regulatory Bodies in the ATMP Authorization Procedure

Institution	Primary Role in ATMP Authorization	Composition
Committee for Advanced Therapies (CAT)	Prepares draft opinion on quality, safety, and efficacy of ATMPs; provides classification recommendations [30] [4]	Members from CHMP, EU Member States, clinicians, and patient associations [30]
Committee for Medicinal Products for Human Use (CHMP)	Adopts final opinion on marketing authorization based on CAT's assessment; recommends authorization to European Commission [30]	One member from each EU Member State and EEA country [30]
Pharmacovigilance Risk Assessment Committee (PRAC)	Assesses and monitors ATMP safety; evaluates risk management plans [30]	Members from EU Member States, healthcare professionals, and patient organizations [30]
European Commission	Grants legally binding marketing authorization valid throughout EU based on scientific assessment [30]	European Union's executive body [30]

The European Medicines Agency (EMA) serves as the central coordinating body for this procedure, managing the scientific assessment process and facilitating communication between applicants and regulatory committees [29] [30]. The EMA provides multiple support mechanisms for ATMP developers, including the ATMP pilot for academia and non-profit organizations that offers dedicated regulatory guidance and fee reductions [4].

Marketing Authorisation Application Process

Application Requirements and Documentation

The Marketing Authorisation Application for an ATMP must comply with specific documentation requirements organized according to the Common Technical Document (CTD) structure [30]. This standardized format ensures comprehensive assessment of all product aspects by regulatory authorities.

Table 2: Marketing Authorisation Application Dossier Structure

CTD Module	Content Requirements	Key Considerations for ATMPs
Module 1: Administrative Information	Regional administrative information and prescribing information [30]	Specific requirements for ATMP classification [30]
Module 2: CTD Summaries	Overview of quality, non-clinical, and clinical data [30]	Integrated summaries highlighting novel aspects [30]
Module 3: Quality Documentation	Chemical, pharmaceutical, and biological data [30]	Comprehensive characterization of complex biological materials [13]
Module 4: Non-Clinical Study Reports	Toxicological and pharmacological data [30]	Specific biodistribution and tumorigenicity studies [32]
Module 5: Clinical Study Reports	Efficacy and safety data from clinical trials [30]	Long-term follow-up data for potential delayed risks [32]

The electronic Common Technical Document (eCTD) format represents the mandatory submission standard, facilitating streamlined review through the EMA's online portals [30]. Applicants must provide comprehensive data demonstrating a favorable risk-benefit balance, sufficient therapeutic efficacy, and appropriate qualitative and quantitative composition [30].

Assessment Timeline and Procedures

The formal evaluation process follows a structured timeline with designated checkpoints and opportunities for applicant feedback:

• Validation Phase: The EMA verifies application completeness before initiating scientific assessment [30].

• Day 120 Assessment: CHMP and CAT reviewers complete initial evaluation and issue list of questions to applicants addressing deficiencies [30].

• Clock Stop Period: Applicants prepare comprehensive responses to regulatory questions; this period varies based on response complexity [30].

• Day 150 Assessment: Regulatory committees review applicant responses and may request additional clarification [30].

• Day 180 Assessment: CHMP adopts final opinion recommending authorization or refusal [30].

• European Commission Decision: Within 67 days of receiving CHMP opinion, the European Commission issues binding marketing authorization valid throughout the EU [30].

The entire procedure typically spans approximately 12-15 months from submission to decision, though accelerated assessment pathways may reduce this timeline for promising therapies addressing unmet medical needs [31].

Interface with National Manufacturing Authorization

The Manufacturing Authorization Framework

While marketing authorization occurs at the European level, manufacturing authorization remains a national competency, creating a complementary regulatory interface [13]. Any legal entity manufacturing ATMPs must obtain authorization from the national competent authority of the Member State where manufacturing activities occur [13] [21]. This decentralized approach allows for tailored oversight of production facilities while maintaining consistent quality standards through harmonized Good Manufacturing Practice (GMP) requirements.

The manufacturing authorization process requires demonstrated compliance with EU GMP standards, which include specific guidelines for ATMPs addressing their unique characteristics [13] [21]. These guidelines account for the complexities of working with biological materials, including the use of substances of human origin, limited shelf life, and specialized manipulation processes [13]. The table below outlines key requirements for ATMP manufacturing authorization.

Table 3: Manufacturing Authorization Requirements for ATMPs

Requirement Category	Specific Obligations	Relevant Guidelines
Quality Standards	Adherence to Good Manufacturing Practice (GMP); European Pharmacopoeia standards [13]	Guidelines on GMP specific to ATMPs [13]
Personnel Requirements	Employment of Qualified Person (QP) responsible for regulatory compliance [13]	GMP guidance on personnel qualifications [21]
Quality System	Pharmaceutical Quality System ensuring consistent product quality [21]	ICH Q10 Pharmaceutical Quality System [32]
Facility Standards	Specialized premises and equipment for biological manufacturing [13]	GMP guidelines for biological medicinal products [21]
Ongoing Compliance	Regular inspections and batch control by national authorities [13]	Compilation of GMP inspection procedures [13]

Integration Between Marketing and Manufacturing Authorization

The regulatory framework establishes a crucial interface between the centralized marketing authorization and national manufacturing oversight. The marketing authorisation holder bears responsibility for ensuring that all manufacturing sites, processes, and quality controls comply with GMP requirements, necessitating close cooperation with manufacturing authorization holders [13]. This integration manifests through several mechanisms:

• Shared Documentation: Module 3 of the MAA contains detailed quality information that must align with manufacturing processes [13]

• Regulatory Coordination: National competent authorities participate in GMP inspections and batch release while the EMA coordinates harmonized standards [13]

• Ongoing Monitoring: Regular and repeated on-site inspections by national authorities verify continued GMP compliance [13]

This integrated model enables comprehensive oversight of ATMPs from production through patient administration, addressing the unique challenges posed by these complex therapies while maintaining consistent quality standards across the European Economic Area.

Challenges and Regulatory Support Mechanisms

ATMP-Specific Development Challenges

ATMP developers face several unique challenges throughout the authorization process, many stemming from the complex nature of these biological therapeutics:

• Manufacturing Complexity: The use of biological materials with limited shelf lives creates extreme logistical challenges, requiring tightly coordinated collection, transportation, and delivery systems [13]

• Characterization Difficulties: Demonstrating consistent quality presents technical hurdles due to product variability and limited sample sizes for analytical testing [13]

• Clinical Development Constraints: Generating robust efficacy and safety data proves challenging, particularly for rare diseases with small patient populations [33] [32]

• Economic Pressures: High development and manufacturing costs, coupled with specialized facility requirements, create financial barriers for developers [13] [34]

These challenges contribute to relatively low success rates in achieving reimbursement despite significant therapeutic promise, highlighting the need for specialized regulatory support throughout the development process [33].

Regulatory Support and Expedited Pathways

The EMA provides multiple support mechanisms to address ATMP-specific challenges and facilitate efficient development:

• Early Dialogue Opportunities: Applicants can seek regulatory feedback through scientific advice and protocol assistance during development [4]

• ATMP Classification Procedure: Developers can obtain formal confirmation of ATMP classification before submitting marketing authorization applications [29]

• PRIME (PRIority Medicines) Scheme: Provides enhanced support for promising therapies targeting unmet medical needs, including early dialogue and accelerated assessment [31]

• Conditional Marketing Authorisation: Allows approval based on less comprehensive data when benefit-risk balance is positive and unmet medical needs exist [30] [31]

Additionally, the CAT certification procedure for small and medium-sized enterprises offers evaluation of quality and non-clinical data during development, helping to optimize resource allocation and strengthen evidence generation before initiating clinical trials [4].

Experimental Protocols and Methodologies

Key Experimental Approaches in ATMP Development

The development of ATMPs requires specialized experimental methodologies to address their unique characteristics and regulatory requirements. The table below outlines critical experimental protocols referenced in regulatory guidelines.

Table 4: Essential Experimental Protocols for ATMP Development

Experimental Domain	Standard Methodologies	Regulatory References
Potency Testing	Cell-based bioassays measuring biological activity; surrogate marker analysis [32]	Guideline on potency testing of cell based immunotherapy medicinal products [32]
Non-Clinical Safety Assessment	Tumorigenicity studies; biodistribution analysis; germline transmission assessment [32]	ICH S6 (R1) Preclinical safety evaluation; Guideline on non-clinical testing for inadvertent germline transmission [32]
Quality Characterization	Identity, purity, and potency assays; process comparability studies [32]	ICH Q5E Comparability of biotechnological/biological products; ICH Q6B Specifications [32]
Environmental Risk Assessment	Evaluation of genetically modified organisms; vector shedding studies [32]	Guideline on environmental risk assessments for medicinal products containing GMOs [32]
Long-Term Follow-Up	Monitoring for delayed adverse events; insertional mutagenesis surveillance [32]	Guideline on follow-up of patients administered with gene therapy medicinal products [32]

The Scientist's Toolkit: Essential Research Reagents

ATMP development relies on specialized reagents and materials to ensure product quality, safety, and efficacy. The following table details critical components referenced in regulatory guidelines.

Table 5: Essential Research Reagents for ATMP Development

Reagent Category	Specific Examples	Function and Regulatory Considerations
Cell Culture Supplements	Bovine serum, porcine trypsin, specific growth factors [32]	Support cell growth and differentiation; require careful sourcing and testing for adventitious agents [32]
Gene Transfer Vectors	Lentiviral vectors, recombinant adeno-associated viral vectors [32]	Facilitate genetic modification; require comprehensive characterization and safety testing [32]
Cell Substrates	Master cell banks, working cell banks, pluripotent stem cells [32]	Serve as starting materials for ATMP manufacturing; require extensive qualification and stability testing [32]
Scaffolds and Matrices	Biodegradable matrices, medical devices for combined ATMPs [4]	Provide structural support for tissue-engineered products; require separate device regulation [4]
Critical Reagents	Antibodies, enzymes, cytokines, selection markers [32]	Used in manufacturing and quality control; require qualification and stability testing [32]

These research reagents must comply with stringent quality standards outlined in various regulatory guidelines, including the European Pharmacopoeia and specific EMA guidelines on biological medicinal products [32]. Their selection and qualification form an essential component of the Chemistry, Manufacturing, and Controls (CMC) section of the marketing authorization application [13].

The centralized authorization procedure represents a specialized regulatory pathway designed to address the unique challenges posed by ATMPs while ensuring consistent evaluation standards across the European Union. This mandatory process requires close coordination between European regulatory bodies and national competent authorities, particularly regarding manufacturing oversight. The framework continues to evolve through initiatives like the joint action plan on ATMPs and the PRIME scheme, reflecting the dynamic nature of this innovative therapeutic field [4] [31]. As the ATMP sector progresses through 2025, the centralized procedure will continue to balance therapeutic innovation with appropriate regulatory oversight, ultimately determining how effectively these groundbreaking therapies reach eligible patient populations [34].

The Practical Pathway: Securing Your ATMP Manufacturing Authorization

Step-by-Step Guide to the Manufacturing Authorization Application Process

The manufacturing authorization for Advanced Therapy Medicinal Products (ATMPs) represents a critical regulatory milestone that ensures therapeutic products meet stringent quality, safety, and efficacy standards before clinical application. In the European Union, including Germany, ATMPs encompass gene therapies, somatic cell therapies, tissue-engineered products, and combination products integrating medical devices with biological components [35]. The regulatory framework for ATMP manufacturing requires adherence to both pan-European standards established by the European Medicines Agency (EMA) and country-specific requirements implemented by national competent authorities.

The manufacturing authorization process intersects with multiple regulatory domains, including the EU's centralized authorization procedures, Good Manufacturing Practice (GMP) standards specific to ATMPs, and national implementation guidelines. For manufacturers seeking authorization in Germany, this involves meticulous coordination with both the Paul-Ehrlich-Institut (PEI) as the federal agency responsible for vaccines and biomedicines, and the Federal Institute for Drugs and Medical Devices (BfArM), alongside compliance with EMA guidelines that took effect in July 2025 [35]. This guide provides a comprehensive, technical roadmap for navigating this complex authorization landscape, with specific emphasis on the German regulatory context.

Regulatory Framework and Governing Bodies

European and National Regulatory Structure

The ATMP manufacturing authorization ecosystem operates at two primary levels: the European level coordinated by the European Medicines Agency (EMA) and the national level governed by member state competent authorities. The EMA establishes overarching guidelines and procedures for ATMPs across the European Union, while national authorities like Germany's PEI and BfArM implement these standards with country-specific requirements [36] [35].

The EMA's updated regulatory guidelines for ATMPs, effective July 2025, emphasize a risk-based approach to evaluating product quality, non-clinical data, and clinical evidence [35]. These guidelines specifically incorporate ICH E11 guidelines for pediatric clinical research and clarify definitions for device-drug combination ATMPs. Furthermore, the EMA has announced plans to develop specialized guidance for gene editing products, reflecting the rapidly evolving nature of advanced therapies [35].

Key Regulatory Documents and Standards

ATMP manufacturers must demonstrate compliance with multiple regulatory frameworks, including:

• EU Directive 2001/83/EC on Community code relating to medicinal products for human use
• German Medicinal Products Act (AMG) and German Gene Technology Act
• EU GMP Annex 4 specific to ATMP manufacturing requirements
• EMA Guidelines on ATMPs regarding quality, non-clinical, and clinical aspects
• ISO 14644 standards for cleanroom classification and monitoring

Table: Key Regulatory Bodies and Their Responsibilities in ATMP Manufacturing Authorization

Regulatory Body	Key Responsibilities	Jurisdiction
European Medicines Agency (EMA)	Centralized authorization procedure, EU-wide guidelines, clinical data assessment	European Union
Paul-Ehrlich-Institut (PEI)	Evaluation of ATMPs, clinical trial oversight, lot release procedures	Germany
Federal Institute for Drugs and Medical Devices (BfArM)	Medicinal product authorization, GMP inspections	Germany
National Ethics Committees	Ethical review of clinical trial protocols	Regional (Germany)

Pre-Application Preparation Phase

Facility Planning and Design

The manufacturing facility design constitutes a foundational element of ATMP authorization. Regulatory requirements mandate strict adherence to EU GMP Annex 4 standards, which specify detailed requirements for ATMP production environments. A case study from Mainz illustrates that establishing a 300-square-meter Grade C cleanroom involves construction costs ranging from €70,000 to €120,000, with validation services (Installation, Operational, and Performance Qualification) consuming approximately 15% of the total facility investment [36].

Facility planning must incorporate comprehensive environmental monitoring systems aligned with EN ISO 14644-1 standards for particle counting. One German stem cell manufacturer experienced an 11-month certification delay due to improper placement of air handling system monitoring points [36]. The ongoing compliance costs for maintaining certified facilities include annual environmental monitoring (approximately €20,000) and regular calibration of automated cultivation equipment (approximately €15,000 per device annually) [36].

Quality Management System Development

Establishing a robust Quality Management System (QMS) is prerequisite to authorization application. The QMS must encompass all aspects of manufacturing operations, including:

• Documentation control for standard operating procedures and batch records
• Personnel qualification and training programs compliant with German Pharmaceutical Operations Regulation (ApBetrO)
• Supplier qualification and materials management systems
• Quality control testing methodologies and specifications
• Deviation, change control, and corrective action processes
• Validation master plans for processes, equipment, and analytical methods

According to industry reports from Germany, developing and implementing a comprehensive QMS typically requires 6-9 months before application submission. Companies should anticipate allocating significant resources to staff training, with one Dresden-based firm reporting 6-week GMP training modules per employee and annual training expenditures exceeding €40,000 [36].

Technical Documentation Preparation

The authorization application requires extensive technical documentation demonstrating product understanding and process control. As referenced in the search results, a typical Market Authorization Application (MAA) for a stem cell product can exceed 10,000 pages of technical documentation [36]. Critical components include:

Manufacturing Process Description

A comprehensive description of the manufacturing process typically requires approximately 3 months to compile. This section must detail all steps from donor screening and cell collection through processing, manipulation, cryopreservation, and final product packaging. The description should include process flow diagrams, in-process controls, and critical process parameters with their associated acceptance criteria.

Quality Studies

Quality documentation requires 6-8 months to prepare and must characterize critical quality attributes including cell identity, purity, potency, and viability. This section incorporates data from method validation studies demonstrating the suitability of all analytical procedures. Companies often engage third-party testing organizations like Eurofins for specialized characterization studies, with individual analyses costing €30,000-50,000 [36].

Non-Clinical Studies

Non-clinical documentation typically demands 9-12 months of preparation and should provide pharmacological and toxicological assessment of the product. This includes studies demonstrating proof-of-concept, dose-ranging, and safety profiles in relevant models. Particular emphasis is placed on evaluations of tumorigenicity, especially for pluripotent stem cell-derived products.

The following diagram illustrates the sequential and parallel activities in the pre-application preparation phase:

Core Application Components and Documentation

Quality Module

The Quality Module forms the foundation of the manufacturing authorization application, providing comprehensive evidence of product quality and manufacturing control. This module must include:

Active Substance Documentation

Detailed information on the biological starting materials and raw materials, including:

• Cell Source Characterization: Donor eligibility criteria, testing, and cell line derivation methodology
• Raw Materials Qualification: Documentation supporting the quality and suitability of all reagents, cytokines, growth factors, and culture media, including evidence of absence of transmissible spongiform encephalopathy (TSE) and animal-derived component traceability
• Container Closure Systems: Qualification data for primary packaging materials directly contacting the product

Manufacturing Process Development and Validation

Comprehensive process description and validation data, including:

• Process Flow Diagrams with identified critical process parameters (CPPs) and in-process controls
• Process Validation Protocols and Reports demonstrating consistent production of material meeting predetermined quality attributes
• Process-Related Impurity Clearance studies validating removal of reagents, cytokines, or other process residuals

Product Characterization and Specification

Analytical data supporting the product profile, including:

• Identity, Purity, and Potency Assays with appropriate validation data
• Reference Standard Qualification where applicable
• Stability Data supporting the proposed shelf life and storage conditions
• Product Specification File defining acceptance criteria for product release

Non-Clinical and Clinical Module

The authorization application must include comprehensive non-clinical and clinical data packages demonstrating product safety and biological activity:

Pharmacology Studies

Documentation of pharmacodynamic properties including:

• Proof-of-Concept Studies demonstrating biological activity in relevant models
• Mechanism of Action data supporting the proposed therapeutic approach
• Dose-Response Relationships informing initial clinical dosing strategies

Toxicology Studies

Safety assessment documentation including:

• Repeat-Dose Toxicity Studies with appropriate observation periods
• Tumorigenicity Assessments for cell-based products, particularly those with proliferative capacity
• Local Tolerance Studies evaluating effects at the administration site
• Safety Pharmacology evaluating potential unintended pharmacological effects

Clinical Data

For products with previous human experience, the application should include:

• Clinical Trial Protocols and Reports from all completed studies
• Safety Database comprising all adverse events from clinical experience
• Proof-of-Concept Clinical Data where available

Table: Technical Documentation Requirements and Preparation Timelines

Documentation Section	Key Components	Estimated Preparation Time	Common Deficiencies
Manufacturing Process Description	Process flow diagrams, critical process parameters, in-process controls	3 months	Insufficient definition of critical parameters, inadequate process validation
Quality Studies	Analytical method validation, product characterization, stability data	6-8 months	Incomplete method validation, insufficient stability data package
Non-Clinical Studies	Proof-of-concept, toxicity, tumorigenicity assessment	9-12 months	Inadequate tumorigenicity assessment, unsuitable animal models
Environmental Control Data	Cleanroom classification, monitoring data, aseptic process validation	2-4 months	Inadequate environmental monitoring program, poor aseptic process simulation

Submission and Evaluation Process

Application Submission and Validation Phase

The formal submission of the manufacturing authorization application initiates a structured review process. Upon receipt, the competent authority (PEI or BfArM in Germany) conducts an initial administrative review to verify application completeness. This validation phase typically requires 14-30 calendar days, during which the authority may request missing elements or clarifications before accepting the application for substantive review.

Applicants should note that submission timelines may be affected by regulatory calendar considerations, including holiday periods and agency meeting schedules. Following successful validation, the application proceeds to the comprehensive scientific assessment phase, which typically spans 110-150 days for standard review timelines, though ATMP applications often require extended evaluation periods [36].

Scientific Assessment and Questions

During the scientific assessment phase, multidisciplinary review teams evaluate each technical module (quality, non-clinical, clinical). The assessment teams typically include specialists in:

• Cell Biology and Characterization
• Manufacturing Science and Process Engineering
• Toxicology and Safety Assessment
• Clinical Development and Trial Design

A critical milestone in this phase is the issuance of assessment reports with requests for clarification or additional data. Industry data indicates that approximately 78% of stem cell companies receive questions related to supply chain documentation deficiencies during review [36]. Companies should establish a dedicated cross-functional team prepared to respond to questions within designated timelines, typically 7-14 days for minor queries and 30-60 days for major requests requiring additional studies or data generation.

On-Site Inspection Phase

The manufacturing authorization process includes a mandatory Good Manufacturing Practice (GMP) inspection of the production facilities. This typically occurs after the initial scientific assessment but before final authorization approval. The inspection team examines:

• Facility Design and Environmental Controls
• Quality Management System Implementation
• Personnel Training and Competency
• Documentation Practices (batch records, testing documentation)
• Equipment Qualification and Maintenance
• Computerized System Validation

One Leipzig-based corneal stem cell product manufacturer experienced a significant authorization delay after inspectors identified non-conformances with ISO 14644 cleanroom standards, requiring additional data submission and re-inspection [36]. Preparation for GMP inspection should include at least one internal mock audit and resolution of any identified deficiencies prior to the regulatory inspection.

The following workflow diagram illustrates the submission, evaluation, and authorization process:

Post-Authorization Obligations

Pharmacovigilance and Safety Monitoring

Manufacturing authorization holders must implement comprehensive pharmacovigilance systems to monitor product safety throughout the lifecycle. EMA guidelines specifically emphasize robust post-authorization safety monitoring for ATMPs [35]. Key requirements include:

• Establishment of a Quality Management System for Pharmacovigilance with defined procedures for adverse reaction detection, assessment, and reporting
• Appointment of a Qualified Person Responsible for Pharmacovigilance (QPPV) residing in the EU
• Development of a Risk Management Plan (RMP) identifying known risks, potential risks, and missing information
• Maintenance of a Pharmacovigilance System Master File documenting the pharmacovigilance system

For ATMPs with limited clinical experience prior to authorization, post-authorization safety studies are often mandated as specific obligations. These studies typically require annual progress reporting and final study reports upon completion.

Change Control and Process Improvements

After authorization, any modifications to the manufacturing process, quality control methods, or equipment must be managed through a formal change control system. Changes are categorized based on potential impact on product quality, with major changes requiring prior approval from competent authorities. The change management process includes:

• Change Classification (minor, major, significant) based on potential impact
• Documentation Requirements supporting the change justification
• Comparative Studies demonstrating equivalence or superiority of changed processes
• Regulatory Submission timelines aligned with change classification

Industry experience demonstrates that companies should anticipate 3-5 major process changes annually during the initial years following authorization as manufacturing experience accumulates and process optimization opportunities are identified.

License Maintenance and Renewal

Manufacturing authorizations are typically valid for five years from the date of issue, after which they must be renewed based on demonstrated compliance with regulatory requirements. The renewal process requires submission of:

• Comprehensive Benefit-Risk Assessment based on accumulated post-authorization experience
• Updated Quality, Non-Clinical, and Clinical Overviews summarizing product experience
• Pharmacovigilance System Performance Reports
• Summary of Product Changes implemented since initial authorization or last renewal

The renewal application should be submitted no later than nine months before the authorization expiration date to ensure continuous manufacturing authority.

Essential Research Reagents and Materials

The following table details critical reagents and materials essential for ATMP manufacturing and characterization, with particular emphasis on quality considerations for regulatory submissions:

Table: Essential Research Reagents and Materials for ATMP Manufacturing

Reagent/Material Category	Specific Examples	Function in ATMP Manufacturing	Quality Documentation Requirements
Cell Culture Media	Serum-free media formulations, defined supplements	Provides nutrients and signaling molecules supporting cell growth and maintenance	Certificate of Analysis with full composition, endotoxin testing, sterility testing, performance qualification
Growth Factors and Cytokines	Recombinant G-CSF, SCF, FGF, EPO, TPO	Directs cell differentiation, expansion, and functional maturation	Recombinant source documentation, purity assessment, bioactivity testing, carrier protein documentation
Cell Separation Reagents	Antibody-labeled magnetic beads, density gradient media	Isolation and purification of target cell populations from source material	Specificity validation, functional testing, endotoxin levels, leachable/extractable profiles
Critical Process Materials	Cryopreservation solutions, cell dissociation enzymes, transduction enhancers	Enables specific manufacturing process steps	Animal-origin documentation, viral safety data (for animal-derived materials), validation of absence of adventitious agents
Quality Control Reagents	Flow cytometry antibodies, ELISA kits, PCR master mixes	Characterization of critical quality attributes	Validation certificates, specificity documentation, reference standard qualification

The manufacturing authorization pathway for Advanced Therapy Medicinal Products represents a rigorous scientific and regulatory journey requiring meticulous planning, substantial resources, and interdisciplinary expertise. Successful navigation of this process demands integration of quality-by-design principles, comprehensive risk management, and proactive regulatory engagement throughout development.

The evolving regulatory landscape for ATMPs, including recent EMA guideline updates effective July 2025, emphasizes a risk-based approach to manufacturing authorization while maintaining rigorous standards for product quality and patient safety [35]. Companies pursuing ATMP manufacturing authorization should anticipate timelines of 18-28 months from application preparation through approval, with total costs ranging from €200,000 to over €1,000,000 depending on facility requirements and product complexity [36].

As reflected by the experience of successful German ATMP manufacturers, the most effective authorization strategies incorporate regulatory considerations from earliest development stages, implement modular facility design approaches to accommodate process evolution, and maintain proactive communication with national competent authorities throughout the application process. This systematic approach positions companies to successfully navigate the complex authorization landscape and bring innovative therapies to patients in need.

Good Manufacturing Practice (GMP) Requirements Specific to ATMPs

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking category of medicines for human use based on genes, cells, or tissues. The European Medicines Agency (EMA) classifies ATMPs into three main types: gene therapy medicines, which contain genes for therapeutic, prophylactic, or diagnostic effects; somatic-cell therapy medicines, which contain manipulated cells or tissues; and tissue-engineered medicines, containing cells or tissues modified to repair, regenerate, or replace human tissue [4]. Some ATMPs may incorporate one or more medical devices as integral components, classified as combined ATMPs [4]. These therapies differ fundamentally from traditional synthetic compounds, often requiring customized manufacturing approaches, particularly for autologous therapies (derived from and returned to a single patient) and allogeneic products (derived from multiple donors to treat many patients) [37].

In the European Union, the regulatory framework for ATMP manufacturing is primarily established under EudraLex Volume 4, Part IV, which contains "Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products" adopted in November 2017 [37] [13] [21]. These guidelines were issued in accordance with Article 5 of Regulation (EC) No 1394/2007 on ATMPs and apply to both products granted marketing authorization and those used in clinical trials [21]. The European Commission defines GMP as "the part of the quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use" [21]. As of July 2025, a new EMA Guideline on clinical-stage ATMPs has come into effect, providing multidisciplinary requirements for investigational ATMPs in clinical trials [38].

Table: Advanced Therapy Medicinal Product Classification

ATMP Category	Key Characteristics	Examples
Gene Therapy Medicines	Contain recombinant genes for therapeutic, prophylactic or diagnostic effects	Products for genetic disorders, cancer, long-term diseases
Somatic-Cell Therapy Medicines	Contain cells or tissues manipulated to change biological characteristics	CAR-T cells, manipulated cell therapies
Tissue-Engineered Medicines	Contain cells or tissues modified to repair, regenerate or replace tissue	Cells embedded in biodegradable matrices/scaffolds
Combined ATMPs	Incorporate one or more medical devices as integral part of the medicine	Cells embedded in biodegradable matrix or scaffold

Core GMP Principles for ATMP Manufacturing

Pharmaceutical Quality System

ATMP manufacturers must establish, implement, and maintain a comprehensive Pharmaceutical Quality System (PQS), defined as "the total sum of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use" [21]. The PQS should incorporate principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System), promoting a systematic approach to quality risk management throughout the product lifecycle [39]. The upcoming revisions to Part IV GMP guidelines emphasize the development and implementation of a comprehensive Contamination Control Strategy (CCS), aligning with the updated Annex 1 requirements for sterile medicinal products [39]. This risk-based approach is particularly critical for ATMPs due to their complex nature and use of biological materials with inherent variability.

Personnel and Premises

Manufacturers must ensure that personnel possess appropriate qualifications, training, and experience specific to ATMP technologies [40]. The facility design must accommodate the unique requirements of ATMP manufacturing, including heightened segregation between different products and process steps [37]. For cell therapies that cannot be sterile-filtered due to cell size, cleanroom classifications and barrier systems such as isolators and Restricted Access Barrier Systems (RABS) become critical, though the guidelines maintain provisions for biosafety cabinets to accommodate manual manipulations associated with individualized ATMP batches [39]. The revised guidelines will provide further clarifications on expectations for cleanroom classifications and the use of these barrier systems [39].

Documentation and Production Controls

Comprehensive documentation must demonstrate that all manufacturing operations are clearly defined, systematically reviewed, and produce ATMPs of consistent quality [40]. Production controls must address the unique challenges of ATMPs, including the short shelf life of living cells, need for temperature-controlled logistics, and traceability requirements for autologous products [13] [21]. The documentation system must ensure full traceability from the starting and raw materials, through all production steps, to the finished product distribution [40] [21].

Quality Control

Quality Control units must operate independently from production and have the authority to approve or reject materials and products [40]. Given the biological nature of ATMPs, control strategies must include validated analytical methods for assessing identity, purity, potency, and safety [21]. The industry is increasingly adopting rapid microbiological testing methods to accommodate the short shelf lives of many ATMPs [39]. For cell-based immunotherapy medicinal products, specific potency testing guidelines have been established to ensure biological activity [32].

Unique ATMP Manufacturing Challenges and GMP Adaptation

Starting Materials of Human Origin

ATMPs frequently use substances of human origin such as blood, tissues, and cells as starting materials, introducing significant complexity to GMP compliance [13] [21]. These materials exhibit inherent biological variability and require rigorous testing for infectious agents [13]. The upcoming revision of Part IV GMP guidelines will update legal references and definitions related to starting materials of human origin, reflecting new regulations on quality and safety standards for these substances [39]. For allogeneic products, donor eligibility determination must comply with EU and member state-specific legal requirements for infectious disease screening [38].

Contamination Control Strategy

Given that many ATMPs cannot be terminally sterilized or sterile-filtered, a robust Contamination Control Strategy is fundamental [37] [39]. The revised Annex 1, effective since August 2023, introduces modifications specifically relevant to ATMP manufacturing, and the upcoming Part IV revisions will harmonize ATMP-specific GMP requirements with these changes [39]. The strategy should encompass all aspects of manufacturing, from starting materials and personnel procedures to process systems and environmental monitoring [39].

Process Validation and Comparability

Validating the consistency of ATMP production processes presents unique challenges, particularly for autologous products where small batch sizes and product variability limit traditional statistical approaches to process validation [13]. Manufacturers must demonstrate comparability after process changes, which is complicated by the biological complexity of ATMPs and limitations in analytical methods [13] [38]. The EMA has published specific questions and answers on comparability considerations for ATMPs to guide manufacturers through these challenges [32].

Table: Key Challenges in ATMP Manufacturing and GMP Solutions

Challenge Category	Specific Challenges	GMP Adaptation Strategies
Starting Materials	Biological variability, short shelf life, infectious agent risk	Rigorous donor screening, validated testing methods, traceability systems
Process Controls	Inability to sterile filter, manual processing steps, automation limitations	Barrier systems, aseptic processing validation, environmental monitoring
Product Characterization	Complex molecular structure, limited shelf life for testing	Platform assays, rapid testing methods, real-time release testing
Facility Design	Multiple product handling, segregation requirements, scale-out vs scale-up	Modular facilities, single-use systems, closed processing
Logistics	Cryogenic storage requirements, chain of identity maintenance, autologous scheduling	Validated shipping systems, electronic tracking, coordinated scheduling

Regulatory Framework and Manufacturing Authorization

Manufacturing Authorization Requirements

Any legal entity manufacturing ATMPs in the European Union must hold a manufacturing authorization issued by the national competent authority of the Member State where the activities are carried out [13] [21]. To obtain this authorization, manufacturers must demonstrate compliance with EU GMP standards, including the specific guidelines for ATMPs [13]. The authorization process involves assessment of facilities, equipment, personnel qualifications, quality systems, and manufacturing processes [13]. Regular and repeated on-site inspections by national authorities verify ongoing compliance with GMP requirements [21].

Key Regulatory Bodies

Multiple regulatory bodies oversee ATMP manufacturing in the EU:

• National Competent Authorities: Assess manufacturing authorization applications, conduct GMP inspections, and provide regulatory and scientific advice [13] [21].
• European Medicines Agency (EMA): Coordinates and harmonizes GMP activities across the EU, maintains compilation of inspection procedures, and provides scientific guidelines [13].
• Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG): Chaired by EMA with senior GMP inspectors from EEA countries, provides guidance on harmonization of GMP matters [13] [21].
• Committee for Advanced Therapies (CAT): Provides scientific expertise on ATMP evaluation and classification [4].

Regulatory Oversight of ATMP Manufacturing

EudraGMDP Database

The EudraGMDP database serves as the central repository for GMP compliance information across the EU [13] [21]. Maintained by EMA, this publicly accessible database contains manufacturing and import authorizations, GMP certificates, non-compliance statements, and inspection reports [21]. National authorities upload inspection outcomes, enabling information sharing between member states and facilitating a coordinated approach to GMP enforcement [21].

Recent Developments and Future Directions

Proposed Revisions to Part IV GMP Guidelines

In May 2025, EMA released a concept paper proposing significant revisions to Part IV of the EU GMP guidelines specific to ATMPs [39]. Key proposed changes include:

• Alignment with Revised Annex 1: Harmonizing ATMP-specific requirements with the updated Annex 1 on sterile medicinal products, with emphasis on comprehensive Contamination Control Strategies [39].
• Integration of ICH Concepts: Incorporating principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) [39].
• Adaptation to Technological Advancements: Providing clarifications on qualifying and controlling new technologies such as automated systems, closed single-use systems, and rapid microbiological testing methods [39].
• Updates on Cleanroom and Barrier Systems: Refining expectations for cleanroom classifications and biosafety cabinets [39].
• Legal References Update: Updating references related to starting materials of human origin [39].

The public consultation period for these revisions was open from May 8 to July 8, 2025 [39].

Point of Care Manufacturing

The regulatory framework is evolving to address decentralized manufacturing approaches, particularly relevant for autologous ATMPs with limited shelf life [37] [13]. The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has developed a regulatory framework for drugs manufactured at or near the point of care, which became law in July 2025 [37]. In the EU, the 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions on decentralized production sites, potentially allowing derogation from individual manufacturing authorization requirements for sites operating under the responsibility of a central qualified person [13].

International Regulatory Convergence

There are ongoing efforts toward international regulatory convergence for ATMPs, particularly alignment between EMA and U.S. FDA requirements [38]. While significant convergence has occurred in Chemistry, Manufacturing, and Controls (CMC) requirements, differences remain in areas such as allogeneic donor eligibility determination and GMP compliance expectations [38]. The EMA's new guideline on clinical-stage ATMPs, effective July 2025, represents a step toward consolidated regulatory expectations, though regional variations persist [38].

Essential Research and Manufacturing Toolkit

Table: Key Reagent Solutions for ATMP Research and Manufacturing

Reagent Category	Specific Examples	Function in ATMP Development
Cell Culture Media	Serum-free media, defined growth factors, cytokines	Support cell expansion and maintenance while reducing variability and contamination risk
Gene Transfer Vectors	Lentiviral vectors, adeno-associated viral vectors, plasmids	Facilitate genetic modification of cells for gene therapies and genetically-modified cell therapies
Cell Separation Reagents	Antibody cocktails, magnetic beads, density gradient media	Isolate specific cell populations from heterogeneous starting materials
Cryopreservation Solutions	Defined cryoprotectants, controlled rate freezing media	Maintain cell viability and function during frozen storage and transport
Quality Control Assays	Potency assays, sterility tests, mycoplasma detection	Ensure product safety, identity, purity, and strength throughout shelf life

Compliance Strategy for National Authority Applications

Preparation for Manufacturing Authorization

Successful applications to national competent authorities for ATMP manufacturing authorization require comprehensive preparation in several key areas:

• Pharmaceutical Quality System: Establish a robust PQS that incorporates ICH Q9 and Q10 principles, with documented procedures covering all manufacturing and control activities [39] [21].
• Facility and Equipment Qualification: Design facilities with appropriate segregation and environmental controls, validated for intended use [37] [39].
• Personnel Training: Implement training programs specific to ATMP technologies and GMP requirements [40] [21].
• Documentation System: Create comprehensive documentation covering specifications, manufacturing formulas, processing instructions, and testing protocols [40].
• Quality Control Procedures: Establish validated analytical methods for in-process, release, and stability testing [40] [32].

Contamination Control Strategy Implementation

Develop a science-based Contamination Control Strategy that addresses the unique vulnerabilities of ATMP manufacturing [39]. This should include:

• Environmental Monitoring Programs: Comprehensive monitoring of cleanrooms and critical processing areas [39].
• Aseptic Process Validation: Media fills and process simulations that challenge the aseptic manufacturing process [40] [39].
• Supplier Qualification: Rigorous qualification of starting material and critical component suppliers [40] [21].
• Container-Closure Integrity: Validation of container-closure systems for finished products [40].

Managing Regulatory Interactions

Proactively engage with regulatory authorities throughout the development process:

• Scientific Advice: Seek early regulatory feedback through national competent authorities or EMA scientific advice procedures [4] [13].
• Inspections Preparedness: Maintain continuous inspection readiness with regular self-inspections and quality system reviews [21].
• Variation Management: Establish robust procedures for managing and submitting variations to authorized manufacturing processes [13].

Successful navigation of the ATMP GMP landscape requires understanding both the general GMP principles and the specific adaptations necessary for these complex, biologically-derived therapies. As the regulatory framework continues to evolve, manufacturers must maintain flexibility and implement robust quality systems capable of addressing both current requirements and emerging expectations.

Within the European Union's pharmaceutical regulatory framework, the Qualified Person (QP) is a legally defined professional pivotal to ensuring that every batch of medicinal product is manufactured and tested in compliance with relevant laws and marketing authorizations. The role is a cornerstone of public health protection, explicitly mandated by Directive 2001/83/EC [13]. For Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic-cell therapies, and tissue-engineered medicines, the QP's responsibilities are exercised within a context of exceptional complexity, dealing with highly variable starting materials and sophisticated manufacturing processes [4] [13]. The QP provides the ultimate assurance to patients and regulatory authorities that each batch of a medicine, including ATMPs, is of the requisite quality before it is released to the market.

Legal Basis and Regulatory Framework

The role and responsibilities of the QP are established in Article 48 of Directive 2001/83/EC [13]. This directive mandates that no medicinal product can be placed on the market in the EEA unless a QP has certified that the batch complies with the requirements of the marketing authorisation and Good Manufacturing Practice (GMP) [13]. The legal obligation extends to all stages of manufacture, and for ATMPs, this includes the control of unique materials like substances of human origin, which must also comply with specific directives on their procurement and testing [41].

The regulatory framework for ATMPs is further detailed in several key documents:

• Regulation (EC) No 1394/2007 for Advanced Therapy Medicinal Products.
• EU Guidelines on GMP specific to ATMPs, which adapt standard GMP to the specific characteristics of these products [41] [13].
• The Compilation of GMP inspection-related procedures maintained by the European Medicines Agency (EMA), which harmonises the interpretation of requirements across Member States [13].

Core Responsibilities of the Qualified Person

The duties of a QP are comprehensive and integral to the pharmaceutical quality system. The primary responsibilities are summarised in the table below and elaborated in the subsequent sections.

Table 1: Key Responsibilities of the Qualified Person

Responsibility Area	Specific Actions and Accountabilities
Batch Certification & Release	Certify each batch for compliance with MA and GMP before release; ensure oversight of outsourced activities [42] [13].
GMP Compliance Assurance	Ensure manufacturing complies with GMP; have a thorough understanding of the products and processes [13].
Audit & Supply Chain Oversight	Audit and approve contractors; verify supply chains for active substances [42].
Quality System & Documentation	Ensure robust pharmaceutical quality system; verify complete and accurate manufacturing documentation [43] [13].
Regulatory Interaction	Serve as a key contact for regulatory authorities; manage communications regarding batch quality [13].

Batch Certification and Release

The most definitive responsibility of the QP is the certification and release of every batch of medicinal product. This is not a mere administrative task but a legal certification based on objective evidence. Before release, the QP must ensure that [13]:

• Each batch has been manufactured and checked in compliance with the Marketing Authorisation (MA) and GMP principles.
• For ATMPs, the principles and guidelines of GMP specific to these complex products have been followed.
• All necessary manufacturing, testing, and quality control documentation has been reviewed and found satisfactory.

GMP Compliance Assurance

The QP is responsible for ensuring that Good Manufacturing Practice is adhered to throughout the manufacturing process. This requires a deep understanding of the manufacturing operations and the associated quality risks. For ATMPs, this is particularly challenging due to the use of biological materials with inherent variability, complex manufacturing manipulations, and stringent sterility requirements [13]. The QP must be intimately familiar with the specialised GMP guidelines for ATMPs to effectively exercise this oversight.

Management of Outsourced Activities

Modern pharmaceutical manufacturing often involves a network of contractors. The QP must ensure that all outsourced activities are controlled. According to EU GMP, a direct written contract should be in place between the Marketing Authorisation Holder (MAH) and the Manufacturing Importation Authorisation (MIA) holder responsible for QP certification, as well as between the MIA holder and any contract manufacturers [42]. The QP is responsible for ensuring that these contracts are in place and that the contracted sites are audited and perform to the required standards.

Knowledge Management and Continuous Improvement

The QP plays a critical role in the Pharmaceutical Quality System (PQS), a model defined in ICH Q10 [43] [44]. Within this system, knowledge management—the systematic collection, analysis, and dissemination of product and process knowledge—is a key enabler. The QP uses this knowledge for informed, science-based decision-making. Furthermore, the QP is involved in the management review of process performance and product quality, contributing to the continuous improvement of the PQS [43] [45].

Requirements to Become a Qualified Person

The requirements to become a QP are stringent, ensuring that only professionals with the appropriate knowledge and experience undertake this critical role.

Table 2: Minimum Requirements for Qualified Person Status

Requirement Category	Description and Key Criteria
Educational Background	University degree in medicine, pharmacy, chemistry, biology, or other approved sciences [13].
Practical Experience	Minimum of two years of practical experience in qualified roles within pharmaceutical manufacturing [13].
Knowledge Demonstration	Pass formal examinations proving mastery of theoretical knowledge [13].
Legal Status & Registration	Formal recognition and registration by the National Competent Authority of an EU Member State [13].

The following diagram illustrates the pathway to becoming a QP and their primary responsibilities in the ATMP context.

The QP in the ATMP Manufacturing and Licensing Context

For a National Competent Authority (NCA) assessing an application for an ATMP manufacturing license, the qualification, experience, and operational integration of the QP are subjects of intense scrutiny. The relationship between the QP and other key actors in the ATMP ecosystem is critical.

Interaction with National Competent Authorities

The QP is a central figure in the interactions between the manufacturing authorization holder and the NCA. The NCA is responsible for assessing the suitability of the QP during the licensing process and for conducting regular inspections to ensure ongoing compliance. During these inspections, the QP's adherence to responsibilities, particularly in managing the unique challenges of ATMPs, is a key focus [13]. The QP must ensure robust communication with the NCA, especially regarding any potential quality issues that could impact patient safety.

Specific ATMP Challenges for the QP

The QP's role in ATMP manufacturing involves navigating a set of distinct challenges that go beyond conventional pharmaceuticals. The following table outlines the critical challenges and the associated GMP considerations that a QP must manage.

Table 3: ATMP-Specific Challenges and QP Considerations

ATMP Challenge	Impact on QP Responsibilities & GMP Considerations
Variable Biological Starting Materials	Ensure rigorous testing and qualification of donors; manage inherent variability in cell lines and tissues; implement robust identity testing throughout the process [13].
Complex and Manipulated Processes	Validate manufacturing processes despite small batch sizes (especially for autologous products); ensure aseptic processing throughout complex manipulations [13].
Limited Shelf Life and Logistical Complexity	Establish and verify a controlled, timely chain of identity and chain of custody from patient to facility and back [13].
Decentralised Manufacturing	Navigate the evolving regulatory landscape for multi-site or point-of-care manufacturing, ensuring GMP compliance across all sites under the QP's responsibility [13].

The QP Declaration and Regulatory Submissions

A critical document reflecting the QP's responsibilities is the QP Declaration. For marketing authorisation applications, a template provided by the EMA guides the content of this declaration, which must confirm that the active substance has been manufactured in accordance with GMP [46]. This declaration provides regulatory authorities with the QP's formal assurance regarding the quality of the product's components.

Experimental and Operational Protocols for QP Oversight

The QP's certification relies on evidence generated from a framework of controlled protocols and systems. The following section details key methodologies and tools underpinning effective QP oversight.

Protocol for Supply Chain Verification

Purpose: To periodically verify the integrity of the supply chain for an active substance back to the manufacturer of the starting materials, as required by EU GMP [42]. Methodology:

• Define Frequency: Establish a risk-based frequency for verification (e.g., annually, or per a defined number of batches).
• Documentation Review: Obtain and audit documentation from direct suppliers, including batch records, quality control certificates, and audit reports.
• Transaction Tracing: Trace a specific batch of active substance through shipping documents, purchase orders, and invoices to confirm its origin.
• On-Site Audit: Conduct periodic audits of the active substance manufacturer and, based on risk assessment, critical starting material suppliers.
• Report and CAPA: Document the verification outcome. Any discrepancies or failures must trigger the Corrective and Preventive Action (CAPA) system [43] [42].

Protocol for Management of Outsourced Activities

Purpose: To ensure quality and compliance are maintained for activities performed by contract acceptors (e.g., Contract Manufacturing Organisations). Methodology:

• Direct Contracting: Preferable to have a direct written contract (or technical agreement) between the MIA holder (contract giver) and the contract acceptor, clearly defining activities and responsibilities [42].
• Supplier Qualification: Conduct a formal audit of the contract acceptor before initiation of work.
• Defined Responsibilities: The contract must explicitly state who is responsible for each GMP-related activity, including testing, release, and quality investigations.
• Communication Plan: Establish procedures for the timely communication of quality issues, changes, and batch documentation.
• QP Oversight: The QP of the MIA holder must have access to all records and data necessary to certify the batch, irrespective of where the manufacturing steps occurred [42].

The Scientist's Toolkit: Essential Systems for QP Effectiveness

The effectiveness of a QP is dependent on the proper functioning of several key systems within the Pharmaceutical Quality System. The table below lists these critical "tools" and their functions.

Table 4: Essential Systems Supporting the QP Role

System or Tool	Function in Supporting QP Responsibilities
Pharmaceutical Quality System (PQS)	The overarching framework (per ICH Q10) that integrates all quality-related activities, from management oversight to continuous improvement [43] [44] [45].
Electronic Quality Management System (eQMS)	A software platform to manage and track quality processes like CAPA, change control, and documentation, providing auditable trails and data integrity [45].
Corrective and Preventive Action (CAPA) System	A formal process for investigating discrepancies, identifying root causes, and implementing actions to prevent recurrence, which is vital for maintaining a state of control [43] [44].
Change Management System	A controlled process for evaluating, approving, and implementing changes to materials, processes, or equipment to ensure they do not adversely affect product quality [43] [44].
Knowledge Management System	The systematic approach to collecting, analysing, and storing product and process knowledge, which forms the basis for the QP's science-based decisions [43] [44].
Data Governance Framework	Policies and procedures that ensure data is complete, consistent, and accurate (ALCOA+ principles) across both paper and electronic systems, which is fundamental to reliable certification [43] [47].

The role of the Qualified Person is a unique and indispensable element of the EU's pharmaceutical regulatory structure. For Advanced Therapy Medicinal Products, the QP's responsibilities are magnified by the complex nature of the products and processes. The QP serves as the ultimate guarantor of quality, bridging the scientific complexities of manufacturing with the legal and regulatory requirements for patient safety. A thorough understanding of the QP's defined responsibilities, stringent qualification requirements, and the specific challenges of the ATMP field is essential for all stakeholders involved in the research, development, and licensing of these innovative medicines.

Chemistry, Manufacturing, and Controls (CMC) Documentation Requirements

For researchers and drug development professionals, robust Chemistry, Manufacturing, and Controls (CMC) documentation is a critical pillar for obtaining a manufacturing license from any national competent authority, especially for Advanced Therapy Medicinal Products (ATMPs). CMC documentation provides the comprehensive data that demonstrates a product's identity, quality, purity, and potency. For ATMPs—which include gene therapies, somatic cell therapies, and tissue-engineered products—the complexity of the starting materials (often human cells and tissues) and manufacturing processes makes the CMC section particularly vital. It is the primary evidence that a sponsor can consistently produce a product that is safe for use in clinical trials and, eventually, for commercial supply. Recent guidelines, such as the European Medicines Agency's (EMA) 2025 Guideline on clinical-stage ATMPs, emphasize that immature quality development can compromise the use of clinical trial data to support a marketing authorization, and a weak quality system could even prevent a clinical trial from being authorized [38].

Core CMC Documentation Requirements

The core CMC dossier must provide a complete narrative of the product's journey from starting material to finished drug. Regulatory requirements are phase-appropriate, but the foundational elements remain consistent.

Drug Substance and Drug Product Information

The documentation must clearly distinguish between, and describe in detail, the Drug Substance (DS) and the Drug Product (DP).

• Description and Characterization: This includes the molecular structure, amino acid sequence (for proteins), and any modifications for the DS, and a comprehensive description of the DP's formulation, including all excipients and their justified concentrations [48].
• Manufacturing Process: A stepwise description of the manufacturing process is required. For the DS, this covers cell line development, fermentation or bioreactor conditions, and purification. For the DP, it includes formulation, filling, and packaging. The description should include a flow diagram, equipment used, and in-process controls [48].

Control Strategies and Analytical Methods

A control strategy is a planned set of controls, derived from current product and process understanding, that ensures process performance and product quality.

• Control of Materials: This involves documenting the source, quality control, and traceability for all raw materials, cell banks, and viral vectors [48].
• Analytical Procedures and Validation: Sponsors must provide Standard Operating Procedure (SOP) summaries for identity, purity, potency, and safety testing. The level of method validation should be appropriate to the phase of investigation, with critical assays requiring at least qualification in early phases [49] [48]. The FDA and EMA emphasize the use of orthogonal analytical methods to fully define complex biologic attributes [48].
• Specifications: The document must establish justified acceptance criteria for the DS and DP [48].

Stability and Product Lifecycle

Stability data supports the proposed storage conditions and shelf life of the product.

• Stability Data: Sponsors should provide available real-time and accelerated stability data. Even in early development, data must support the proposed storage conditions for the planned clinical trial [48].
• Ongoing Stability Program: A plan for continued stability monitoring throughout the clinical trial program is mandatory to ensure product quality over time [48].
• Comparability Protocols: With the 2025 trend of stronger emphasis on comparability, regulators expect early plans for handling anticipated manufacturing changes. A comparability protocol outlines the studies and analytical analyses that will be performed to demonstrate that a process change does not adversely affect the product [49] [48].

CMC requirements by Clinical Trial Phase

Regulatory expectations for CMC data are phase-appropriate, meaning the depth and completeness of information should align with the stage of clinical development. The following table summarizes the key focus areas for each phase.

Table 1: Phase-Appropriate CMC Requirements for Clinical Trials

Trial Phase	CMC Focus Areas	Key Documentation
Phase I	Ensure patient safety; basic product characterization.	Minimal stability data, GMP compliance letters, basic manufacturing process description [50].
Phase II	Refine process and establish preliminary consistency.	Full batch records, validated process parameters, early control strategy [50].
Phase III	Confirm commercial process and product quality.	Full-scale manufacturing plan, validated analytical methods, long-term stability, packaging specs [50].
Marketing Application	Comprehensive data for licensure.	Complete Module 3 of the Common Technical Document (CTD) [50].

Regulatory Landscape and Authority-Specific Nuances

While the core principles of CMC are globally harmonized, national competent authorities have specific nuances that sponsors must navigate.

United States Food and Drug Administration (FDA) Framework

The FDA's Center for Biologics Evaluation and Research (CBER) regulates ATMPs. The primary guidance is provided in the "Chemistry, Manufacturing, and Controls (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)." Key initiatives in 2025 include:

• CMC Development and Readiness Pilot (CDRP): This program is designed to facilitate CMC development for products with expedited clinical development timeframes. Sponsors accepted into the pilot gain opportunities for increased communication with FDA review staff through designated meetings, aiming to support earlier patient access [51].
• Expedited Programs: The FDA has released draft guidance on expedited programs for regenerative medicine therapies, detailing how to utilize the Regenerative Medicine Advanced Therapy (RMAT) designation and accelerated approval pathways [52].

European Medicines Agency (EMA) Framework

The EMA's regulatory framework for ATMPs is detailed in several guidelines, most notably the "Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials," which came into effect in July 2025 [38].

• Multidisciplinary Document: This guideline consolidates information from over 40 separate guidelines and reflection papers, serving as a primary reference for ATMPs in both early and late-stage trials [38].
• Key Nuances vs. FDA:
  • GMP Compliance: The EU emphasizes mandatory self-inspections and documented evidence of an effective quality system as a prerequisite for clinical trials. In contrast, the U.S. employs a phase-appropriate approach with attestation in early phases, with full GMP compliance verified later during a pre-license inspection [38].
  • Allogeneic Donor Eligibility: The EMA guideline provides general guidance but reminds sponsors to comply with relevant EU and member state-specific legal requirements. The FDA is more prescriptive, with detailed requirements for donor screening, testing, and restrictions on pooling donor cells [38].

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) Framework

Japan has established a progressive, conditional approval system for regenerative medicine products, overseen by the PMDA.

• Conditional/Time-Limited Approval: This system allows products to reach patients faster based on preliminary data, with the requirement that sponsors collect and submit post-market data to confirm safety and efficacy [53].
• Strategic Importance: Japan's regenerative medicine market is projected to grow significantly, from $1.34 billion in 2024 to $3.09 billion by 2030, making it a strategically important region for ATMP developers [53].

Common CMC Deficiencies and Best Practices

Understanding common pitfalls can help sponsors avoid costly delays. Over 30% of IND application delays in biotech-led submissions are due to CMC deficiencies [50].

Frequent Pitfalls

• Incomplete Stability Data: Submitting insufficient real-time stability data or omitting the ongoing stability plan [48].
• Inadequate Method Validation: Especially for critical potency assays, which are essential for demonstrating biological activity [48].
• Unjustified Formulation: Failure to provide adequate justification for excipient choices or container closure system compatibility [48].
• Inconsistent Process Descriptions: Manufacturing process descriptions that are inconsistent between different sections of the CMC dossier [48].

Best Practices for Success

• Start CMC Documentation Early: Begin CMC activities at least 6 months before IND submission, in parallel with protocol design [50] [48].
• Engage Regulators Proactively: Schedule pre-IND meetings with agencies like the FDA and PMDA to confirm CMC expectations, especially for novel modalities [38] [50] [48].
• Adopt a Risk-Based Approach: Implement Quality by Design (QbD) principles to identify Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) early in development [48].
• Plan for Scale-Up: Consider commercial scalability even during Phase 1 process development to avoid major changes later [48].
• Ensure Data Integrity: Use validated electronic systems with robust audit trails for all CMC records [48].

Experimental Protocols for Key CMC Activities

Protocol for Process Performance Qualification (PPQ)

Objective: To demonstrate with a high degree of assurance that a manufacturing process is capable of consistently producing a drug product that meets its predetermined quality attributes.

Methodology:

• Process Design: Establish the process based on knowledge gained through development and scale-up activities.
• Process Qualification: Design and execute a PPQ protocol using the commercial-scale equipment and process. This typically involves producing a minimum of three consecutive commercial-scale batches that are successful.
• Monitoring and Testing: Subject the PPQ batches to intensive monitoring and testing against the predefined CQAs and specifications.
• Data Analysis and Report: Statistically analyze the data to confirm process consistency and prepare a final report. Successful PPQ is a prerequisite for licensure (BLA/MAA) [49].

Protocol for Analytical Method Validation

Objective: To demonstrate that an analytical procedure is suitable for its intended use, ensuring the reliability of test results used to assess product quality.

Methodology: For a potency assay, key validation parameters are assessed:

• Accuracy: Measure the closeness of agreement between the value accepted as a true value and the value found.
• Precision: Includes repeatability (same analyst, same day) and intermediate precision (different days, different analysts).
• Specificity: Ability to assess the analyte unequivocally in the presence of other components.
• Linearity and Range: Establish that the test result is directly proportional to the concentration of the analyte over a specified range.
• Robustness: Measure the capacity of the method to remain unaffected by small, deliberate variations in method parameters.

The level of validation (e.g., full validation vs. qualification) is phase-appropriate [49] [48].

The Scientist's Toolkit: Essential Research Reagent Solutions

The development and control of ATMPs rely on a suite of critical biological and analytical reagents.

Table 2: Key Research Reagent Solutions for ATMP CMC Development

Reagent/Material	Function in CMC
Reference Standards	Qualified standards used to calibrate instruments and validate analytical methods; essential for demonstrating assay performance and product comparability [48].
Cell Banks (MCB/WCB)	Master and Working Cell Banks serve as the defined source of living production cells; fully characterized for identity, purity, and stability to ensure manufacturing consistency [48].
Critical Reagents	Includes antibodies, enzymes, and cell lines used in analytical testing (e.g., for identity, potency, and impurity assays). Their quality and qualification are vital for data integrity [48].
Vector Standards	For gene therapies, well-characterized viral vector reference materials are crucial for quantifying vector concentration, infectious titer, and potency [48].

Workflow and Pathway Visualizations

CMC Documentation Development Workflow

The following diagram illustrates the interconnected stages of CMC development, from early planning through to regulatory submission and lifecycle management.

Diagram 1: CMC Documentation Development Workflow

Analytical Method Validation Pathway

This pathway outlines the logical sequence of experiments required to validate an analytical method for use in a CMC control strategy.

Diagram 2: Analytical Method Validation Pathway

For any researcher or developer aiming to secure a manufacturing license from a national competent authority for an ATMP, a deep and proactive approach to CMC documentation is non-negotiable. The requirements are dynamic, with regulatory agencies like the FDA, EMA, and PMDA continuously updating their guidelines to reflect the unique challenges of these complex products. Success hinges on starting CMC activities early, engaging in frequent communication with regulators, and building a comprehensive data package that proves mastery over the product and its process. By treating CMC not as a last-minute regulatory hurdle but as a strategic pillar of product development, sponsors can navigate the path to licensure more efficiently, ensuring that transformative therapies can reach patients in need without undue delay.

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), understanding the intricate relationship with National Competent Authorities (NCAs) is fundamental to successful product development and compliance. Within the European Union regulatory framework, NCAs serve as the national regulatory bodies in each Member State responsible for implementing EU pharmaceutical legislation at the country level [21]. For ATMPs—which encompass gene therapies, somatic cell therapies, and tissue-engineered products—these authorities play critical roles throughout the product lifecycle, from initial development through post-authorization compliance [4].

The regulatory pathway for ATMPs operates under a dual-layer oversight system where the European Medicines Agency (EMA) manages the centralized authorization procedure, while NCAs maintain jurisdiction over numerous critical aspects at the national level [4] [54]. This includes manufacturing authorizations, clinical trial approvals, and oversight of the Hospital Exemption pathway [55]. For ATMP developers, establishing and maintaining effective communication with relevant NCAs is not merely regulatory compliance but a strategic necessity that can significantly influence development timelines and success rates.

Pre-Submission Phase: Early Interactions

Strategic Regulatory Advice Mechanisms

Early engagement with NCAs during the pre-submission phase provides invaluable opportunities to align development strategies with regulatory expectations before significant resources are invested. The European regulatory network offers multiple formal mechanisms for these early interactions:

• Simultaneous National Scientific Advice (SNSA): This pilot program, coordinated through the EU Innovation Network, allows developers to obtain harmonized scientific advice from multiple NCAs simultaneously through a unified application process with predictable timelines [56]. This mechanism is particularly valuable for clinical trials spanning multiple Member States or early-stage development of innovative ATMPs.

• National Scientific Advice: Individual NCAs provide advice on national-specific requirements and interpretation of EU-level guidelines. This is especially important for aspects falling under national competence, such as requirements for hospital exemption ATMPs or national reimbursement considerations [56].

• Pre-submission Meetings: Most NCAs offer opportunities for direct dialogue before formal submission of manufacturing authorization applications or clinical trial applications. These meetings help clarify technical requirements, anticipated timelines, and potential submission deficiencies [54].

Preparation for Effective Pre-Submission Interactions

To maximize the value of early interactions with NCAs, developers should approach these exchanges with comprehensive preparation and clear objectives. The following table outlines key preparation elements:

Preparation Element	Description	Strategic Importance
Specific Questions	Develop focused, technically precise questions regarding areas of regulatory uncertainty	Enables efficient use of limited meeting time and directs discussion to critical development challenges
Development Strategy Summary	Concise overview of product characteristics, manufacturing approach, and clinical development plan	Provides context for regulators to understand the product stage and specific challenges being faced
Preliminary Data Package	Summary of available quality, non-clinical, or early clinical data	Supports evidence-based discussions and demonstrates commitment to rigorous scientific development
Regulatory Background	Information about previous interactions with other NCAs or EMA committees	Ensures awareness of broader regulatory context and previous feedback

The proof of establishment documentation must demonstrate that the company has a permanent legal structure formed in accordance with the law of an EEA Member State, allowing the holder to assume the duties and responsibilities required by Union law [57]. For manufacturing authorization applications, early discussions with NCAs should address Good Manufacturing Practice (GMP) compliance strategies, including facility design, quality systems, and control strategies appropriate to the product's development stage [21] [42].

Application and Assessment Phase

Manufacturing Authorization Process

Any company manufacturing ATMPs within the European Union must hold a manufacturing authorization issued by the NCA of the Member State where the manufacturing activities occur [21]. The application process involves comprehensive assessment of technical, quality, and facility-related documentation, followed by on-site inspections to verify compliance with EU GMP standards.

The relationship between different regulatory authorizations and oversight bodies for ATMPs can be visualized as follows:

The manufacturing authorization process requires demonstration of comprehensive GMP compliance across all aspects of production, including starting materials, premises, equipment, personnel, and procedures [21]. For ATMPs, specific GMP guidelines account for their unique characteristics, particularly the use of substances of human origin such as blood, tissues, and cells [21]. The NCA assesses the application and conducts regular on-site inspections to verify ongoing compliance with GMP requirements [21].

Clinical Trial Applications

For clinical trials involving investigational ATMPs, the Clinical Trials Information System (CTIS) under the Clinical Trials Regulation provides the centralized application platform, while NCAs maintain responsibility for assessment and oversight within their territories [56]. Since January 2025, all clinical trials in the EU must comply with the Clinical Trials Regulation and be managed through CTIS [56].

The EMA's guideline on quality, non-clinical, and clinical requirements for investigational ATMPs in clinical trials, which came into effect July 1, 2025, provides comprehensive guidance for clinical trial applications [38]. This multidisciplinary document addresses development, manufacturing, quality control, and clinical development of investigational ATMPs for both exploratory and confirmatory trials [38] [56].

Ongoing Compliance and Post-Authorization Interactions

GMP Compliance and Inspection Framework

Once manufacturing authorization is granted, companies enter a phase of continuous regulatory interaction with NCAs focused on maintaining compliance. The GMP inspection framework involves:

• Regular On-site Inspections: NCAs conduct periodic inspections to verify ongoing adherence to GMP standards and marketing authorization requirements [21].
• Pharmaceutical Quality System Reviews: Manufacturers must establish and maintain a pharmaceutical quality system with annual product quality reviews as required by EU GMP Chapter 1 [42].
• Documentation and Traceability: Robust documentation systems must ensure full traceability of materials and processes, with particular attention to batch numbering systems that maintain clear connections between bulk and finished product batches [42].

After each inspection, the NCA issues a GMP certificate for positive outcomes or a statement of non-compliance for negative outcomes, with records maintained in the centralized EudraGMDP database [21]. This database, operated by EMA, provides transparency and enables information sharing between regulatory authorities across the EU [21].

Variation Management and Change Control

Throughout the product lifecycle, ATMP manufacturers inevitably need to implement changes to manufacturing processes, controls, or facilities. The variation management process requires careful coordination with NCAs:

• Regulatory Classification: Changes must be classified according to their potential impact on product quality, safety, or efficacy, determining the required regulatory pathway (Type IA, IB, or II variations) [57].
• Documentation Requirements: Variation applications must include comprehensive documentation demonstrating that the change does not adversely affect product quality, safety, or efficacy [57].
• Prior Approval: For major changes, manufacturers must obtain approval from the relevant NCA before implementation, requiring detailed scientific and technical justification [42].

Pharmacovigilance and Safety Monitoring

For authorized ATMPs, ongoing safety monitoring represents a critical compliance area requiring continuous interaction with NCAs. Marketing authorization holders must implement comprehensive pharmacovigilance systems to monitor, record, and report adverse reactions [57]. The specific requirements for ATMPs include enhanced safety monitoring plans and long-term follow-up strategies to address potential delayed adverse events [4].

Special Considerations for ATMPs

Hospital Exemption Pathway

The hospital exemption (HE) pathway under Article 3(7) of Regulation (EC) No 1394/2007 allows ATMPs to be prepared and used within a single Member State under specific conditions without centralized marketing authorization [55]. This pathway involves direct oversight by NCAs and requires:

• Non-routine Preparation: ATMPs must be prepared on a non-routine basis according to specific quality standards [55].
• Hospital-based Manufacturing: Preparation must occur in a hospital setting for individual patients following a medical prescription [55].
• Member State Specific Authorization: Each HE product requires approval from the NCA of the Member State where it will be used [55].

Recent regulatory developments have brought increased attention to the HE pathway, with the European Blood Alliance advocating for its expansion as a harmonized regular approach for producing ATMPs, particularly those targeting unmet medical needs or rare diseases [55].

SME-Specific Support Mechanisms

Small and medium-sized enterprises (SMEs) developing ATMPs can access specialized support mechanisms through both EMA and NCAs:

• Fee Reductions: SMEs qualify for significant fee reductions (90% for scientific advice, scientific services, and inspections) and fee deferrals for marketing authorization applications [57].
• Administrative Assistance: Dedicated SME offices at EMA and some NCAs provide procedural guidance and support [57].
• Translation Support: EMA provides translation assistance for product information documents, representing considerable financial relief for SMEs [57].

To access these incentives, companies must obtain official SME status from EMA by submitting a declaration of SME status form, which requires demonstrating compliance with EU size criteria (micro, small, or medium-sized enterprises) [57].

Regulatory Tools and Documentation Systems

Key Electronic Systems

Effective interaction with NCAs requires familiarity with the electronic systems that facilitate regulatory processes:

System Name	Function	Relevance to NCA Interactions
EudraGMDP	Union database containing manufacturing authorizations, GMP certificates, and non-compliance statements	Primary source for verifying GMP compliance status; publicly accessible [21]
CTIS	Clinical Trials Information System for application submission and management under Clinical Trials Regulation	Central platform for clinical trial applications, assessments, and oversight [56]
eSubmission	EMA's online portal for electronic Common Technical Document (eCTD) submissions	Required format for marketing authorization applications [54]

Essential Documentation Framework

The following table outlines critical documentation requirements for various stages of NCA interaction:

Document Type	Purpose	Regulatory Reference
Manufacturing Authorization Application	Request permission to manufacture ATMPs	National legislation implementing Directive 2001/83/EC [21]
GMP Documentation	Demonstrate quality system implementation and manufacturing process control	EU Guidelines on Good Manufacturing Practice specific to ATMPs [21]
Product Quality Review	Annual assessment of process performance and product quality	EU GMP Chapter 1 [42]
Quality Risk Management Documentation	Systematic risk assessment and control strategy	ICH Q9 incorporated into EU GMP [42]

Navigating interactions with National Competent Authorities throughout the ATMP lifecycle requires strategic planning, meticulous documentation, and proactive engagement. From pre-submission meetings discussing development strategies to ongoing compliance activities post-authorization, maintaining effective communication with NCAs is essential for successful ATMP development and commercialization.

The regulatory landscape for ATMPs continues to evolve, with recent developments including the implementation of new clinical trial requirements, updated guidelines for investigational ATMPs, and ongoing discussions regarding the hospital exemption pathway [38] [56] [55]. By understanding the roles, responsibilities, and expectations of NCAs at each stage of the product lifecycle, ATMP developers can build more efficient regulatory strategies, mitigate compliance risks, and ultimately accelerate patient access to these innovative therapies.

Overcoming ATMP Manufacturing Hurdles: Quality Control and Complex Production Challenges

Addressing Logistical Complexities in Autologous vs. Allogeneic Therapies

The development of Advanced Therapy Medicicnal Products (ATMPs) represents a paradigm shift in modern medicine, offering groundbreaking treatments for conditions ranging from cancer to genetic disorders. For researchers, scientists, and drug development professionals navigating the regulatory landscape for ATMP manufacturing licenses, understanding the distinct logistical frameworks for autologous (patient-specific) and allogeneic (donor-derived) therapies is fundamental. These two approaches necessitate completely different supply chain models, manufacturing strategies, and quality control processes that directly impact regulatory submissions to national competent authorities.

Cell therapies involve the use of living cells as therapeutic agents, with autologous therapies utilizing a patient's own cells and allogeneic therapies employing cells from healthy donors [58]. The strategic choice between these approaches affects every aspect of product development—from manufacturing scalability and cost structures to compliance with good manufacturing practice (GMP) requirements enforced by regulatory bodies like the European Medicines Agency (EMA) [41] [39]. This technical guide examines the core logistical differentiators between these models within the context of ATMP manufacturing license applications, providing a framework for addressing regulatory requirements specific to each modality.

Core Technical Differences and Logistical Implications

The fundamental distinction between autologous and allogeneic therapies creates divergent logistical pathways that regulatory authorities carefully scrutinize during manufacturing license reviews. Understanding these differences is essential for designing compliant manufacturing and distribution systems.

• Autologous Therapies: These treatments follow a patient-specific model where cells are collected from an individual patient, transported to a manufacturing facility, processed and expanded, then returned to the same patient [58] [59]. This creates a complex circular supply chain with stringent chain-of-identity requirements and extremely limited product stability windows—sometimes as short as a few hours ex vivo [58]. Each patient's batch is essentially a unique product, requiring individualized quality control testing and documentation.

• Allogeneic Therapies: This approach utilizes a donor-derived model where cells from healthy donors are processed into "off-the-shelf" products that can be administered to multiple patients [58] [59]. This enables a more traditional linear supply chain with opportunities for batch production, bulk storage, and standardized quality control processes. While this model offers better scalability, it introduces different challenges related to donor screening, cell bank characterization, and managing immune compatibility between donor and recipient [58] [59].

The following diagram illustrates the fundamental logistical workflows for both therapy types, highlighting critical control points that must be addressed in manufacturing license applications:

Quantitative Comparison of Logistical Parameters

For ATMP manufacturing license applications, national competent authorities require detailed quantitative data demonstrating understanding of these logistical challenges. The following tables summarize key comparative metrics that must be addressed in regulatory submissions.

Table 1: Manufacturing and Supply Chain Comparison

Parameter	Autologous Therapies	Allogeneic Therapies
Production Model	Patient-specific, custom manufacturing	Batch production, "off-the-shelf"
Supply Chain Structure	Circular, complex coordination	Linear, more traditional
Manufacturing Strategy	Scale-out (multiple parallel lines)	Scale-up (larger batch sizes)
Batch Consistency	High variability between patients	Standardized processes
Vein-to-Vein Time	Several weeks typically [58]	Immediate availability
Production Cost per Dose	$200,000–800,000 [60]	Potentially lower due to mass production [58]

Table 2: Materials and Quality Control Comparison

Parameter	Autologous Therapies	Allogeneic Therapies
Starting Material	Patient cells (often compromised)	Healthy donor cells
Cell Source Challenges	Cellular aging/senescence, disease state	Donor variability, screening
Quality Control Focus	Individual patient tracking, chain of identity	Donor eligibility, batch consistency
Release Testing	Tight turnaround, minimal sample volume	More flexible timing and volume [59]
Immunological Concerns	Reduced rejection risk, possible immune responses to modified cells	Graft-versus-host disease, host rejection [58]
Regulatory Emphasis	Personalized product safety, cross-contamination prevention	Donor screening, characterization, immunogenicity management

Advanced Logistics and Supply Chain Solutions

Temperature-Controlled Shipping and Monitoring

Maintaining product integrity during transport requires sophisticated temperature control systems. Cryopreserved shipments typically require liquid nitrogen (LN2) or dry ice solutions that maintain temperatures below -150°C, while some products may require refrigerated conditions (2-8°C) [61] [60]. The EMA's GMP guidelines for ATMPs emphasize the importance of maintaining these temperature ranges throughout the supply chain, with recent proposed revisions strengthening requirements for comprehensive control strategies [39].

Advanced monitoring systems now provide real-time tracking of location, temperature, shock, and orientation using GPS and IoT technology [60] [62]. These systems can trigger automated alerts when predefined parameters are breached, enabling immediate intervention. For manufacturing license applications, demonstrating robust monitoring capabilities and contingency plans for temperature excursions is essential for regulatory approval.

Supply Chain Integration Technologies

Modern ATMP logistics require sophisticated digital integration platforms that coordinate between clinical sites, manufacturing facilities, and transportation networks. These systems automate scheduling by aligning patient apheresis appointments with manufacturing capacity and transportation availability [60]. The implementation of Manufacturing Execution Systems (MES) and radio-frequency identification (RFID) tags enables seamless data flow and process automation, moving the industry toward Bioprocessing 4.0 standards [63].

For autologous therapies specifically, specialized software orchestrates the entire cell therapy supply chain, allowing clinicians to view therapy progress through each stage via integrated systems [60]. When applying for manufacturing licenses, demonstrating these technological capabilities shows national competent authorities that applicants can maintain the chain of identity and custody required for patient-specific products.

Regulatory Framework and GMP Considerations

The European Medicines Agency has established specific GMP requirements for ATMPs under Part IV of the EU GMP Guidelines, with recent proposals to update these guidelines to reflect technological advancements [39]. Key considerations for manufacturing license applications include:

• Quality Risk Management: Implementation of ICH Q9 principles throughout the supply chain [39]
• Pharmaceutical Quality System: Establishment of ICH Q10-compliant systems tailored to ATMP-specific needs [39]
• Cleanroom Classifications: Clear definitions for cleanroom requirements and barrier systems [39]
• Starting Materials Compliance: Adherence to regulations on substances of human origin [41]

The EMA offers significant fee reductions for ATMP developers—65% for scientific advice requests (90% for SMEs) and 90% for the certification procedure [41]. These incentives aim to encourage ATMP development while ensuring rigorous regulatory oversight.

Essential Research Reagent Solutions and Materials

The following table outlines critical materials and technologies required for addressing logistical challenges in cell therapy development, particularly relevant for preclinical studies supporting manufacturing license applications.

Table 3: Essential Research Reagent Solutions for Cell Therapy Logistics

Reagent/Material	Function	Application in Logistics Research
Serum-Free Cell Culture Media	Defined composition for cell expansion	Reduces variability in manufacturing; eliminates serum sourcing challenges [64]
Cryopreservation Solutions	Maintain cell viability during frozen storage	Protocol development for product storage and transport [61]
Leukapheresis Collection Kits	Standardized white blood cell collection	Starting material procurement for allogeneic therapies [64]
GMP-Grade Cell Separation Reagents	Isolation of specific cell populations	Process development for manufacturing [64]
Single-Use Bioprocess Containers	Sterile fluid containment and storage	Prevents cross-contamination; enables closed system processing [63]
Temperature Monitoring Devices	Shipment condition tracking	Validation of transport conditions for regulatory submissions [60]
Automated Fill-Drain Systems	Precise fluid transfer operations	Standardization of manufacturing processes [63]

Navigating the logistical complexities of autologous versus allogeneic therapies requires deep understanding of their fundamentally different supply chain models, manufacturing strategies, and regulatory requirements. For researchers and drug development professionals preparing ATMP manufacturing license applications, demonstrating comprehensive control over these parameters is essential for successful regulatory review. As the field evolves with emerging technologies like automation, IoT monitoring, and advanced analytics, the regulatory framework continues to adapt. By addressing the distinct challenges of each approach through robust logistical strategies and quality systems, developers can accelerate the delivery of these transformative therapies to patients while meeting the stringent requirements of national competent authorities.

Maintaining Product Sterility and Chain of Identity Throughout Manufacturing

For researchers and developers of Advanced Therapy Medicinal Products (ATMPs), maintaining product sterility and ensuring a verifiable chain of identity (CoI) throughout manufacturing are not just technical challenges—they are fundamental regulatory requirements for obtaining a manufacturing license from national competent authorities. The European Medicines Agency (EMA) categorizes ATMPs as gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs that incorporate medical devices [4]. These products, based on genes, cells, or tissues rather than traditional chemical compounds, present unique manufacturing challenges due to their biological complexity, limited shelf life, and often patient-specific nature [65] [66].

The regulatory landscape for ATMPs is evolving rapidly. The European Commission and EMA have established a dedicated framework under Regulation (EC) 1394/2007, with the Committee for Advanced Therapies (CAT) providing scientific expertise for evaluation [4] [65]. Current Good Manufacturing Practice (GMP) requirements for ATMPs are detailed in EudraLex Volume 4, Part IV, which was recently proposed for revision to align with the updated Annex 1 on sterile medicinal products and incorporate modern quality risk management principles [67] [40] [39]. For personalized ATMPs involving patient-specific batches, the inability to use terminal sterilization and the need for extensive manual operations further complicate sterility assurance [66]. Simultaneously, the Chain of Identity must be maintained through robust electronic systems that prevent misidentification of starting materials and final products throughout complex manufacturing workflows [68].

Current Regulatory Landscape and Expectations

Evolving GMP Standards for ATMPs

The regulatory framework for ATMP manufacturing is in a significant transition phase. The EMA's GMP/GDP Inspection Working Group published a concept paper in May 2025 proposing important revisions to the ATMP-specific GMP guidelines (Part IV of Eudralex Volume 4) [67] [39]. These revisions aim to harmonize the ATMP guidelines with the revised Annex 1 for sterile medicinal products, which became effective in August 2023, while maintaining appropriate flexibility for ATMP-specific manufacturing challenges [67].

Key regulatory updates impacting sterility and CoI include:

• Integration of Contamination Control Strategy (CCS): The revised guidelines will emphasize the development and implementation of a comprehensive CCS as outlined in the updated Annex 1, requiring manufacturers to adopt a holistic approach to contamination prevention throughout the manufacturing process [39].

• Incorporation of ICH Guidelines: The revision plans to integrate principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System), promoting a systematic approach to quality risk management and establishing robust pharmaceutical quality systems [39].

• Clarification on Technologies and Systems: The updated guidelines will provide clearer expectations for cleanroom classifications, barrier systems (isolators and RABS), and acknowledge the continued appropriateness of biosafety cabinets for manual operations in personalized ATMP batches [67] [39].

• Updated Definitions for Human-derived Materials: With the publication of the new Substances of Human Origin (SoHO) Regulation (EU 2024/1938), the revision will update legal references and definitions related to starting materials of human origin, directly impacting traceability requirements [67] [65].

Table 1: Key Regulatory Documents for ATMP Sterility and Chain of Identity

Regulatory Document	Key Focus Areas	Relevance to Sterility/CoI	Current Status
EudraLex Vol. 4, Part IV	GMP principles specific to ATMPs	Foundation for sterility assurance & traceability systems	In force (2017), under revision [40]
Annex 1 (Sterile Medicinals)	Manufacture of sterile medicinal products	Contamination control strategy, environmental monitoring	Effective Aug 2023 [39]
PIC/S Annex 2A	Manufacture of ATMPs for human use	Reference for sterile filtration alternatives	In force [66]
Annex 11 (Computerized Systems)	Data integrity for GxP systems	Chain of identity electronic records, audit trails	In force [68]
SoHO Regulation (EU 2024/1938)	Quality & safety standards for human-origin substances	Donor eligibility, starting material traceability	Applicable from 2027 [65]

Regulatory Timelines and Implementation

The implementation timeline for updated ATMP regulations follows a structured approach. The concept paper consultation period concluded in July 2025, with a draft revised guideline expected in September 2026, final adoption by the GMDP workshop in March 2027 [67]. Manufacturers should note that the SoHO Regulation will fully apply from 2027, replacing existing directives on blood, cells, and tissues [65]. This regulation expands oversight to all human-origin substances (excluding solid organs) and establishes SoHO national authorities with authorization, oversight, and control functions, significantly impacting donor eligibility verification and material traceability [65].

Methodologies for Maintaining Product Sterility

Contamination Control Strategy (CCS)

A comprehensive Contamination Control Strategy must be implemented as a proactive, scientifically-driven approach to sterility assurance. The CCS should be documented and cover all aspects of manufacturing that could impact product sterility, from raw materials to final product administration [39]. The strategy should be built on a foundation of quality risk management (QRM) principles as defined in ICH Q9, with risk assessments conducted for all process steps vulnerable to microbial, endotoxin, or particulate contamination [39].

Essential components of an effective CCS for ATMPs include:

• Facility and Equipment Design: Controlled environments with appropriate cleanroom classifications (Grade A-D) based on process criticality, with qualified HVAC systems maintaining proper pressure cascades, temperature, and humidity [67]. Manufacturers should implement barrier technologies such as isolators or Restricted Access Barrier Systems (RABS) for open processing steps, though the guidelines remain open to biosafety cabinets for manual operations in personalized batches [67] [39].

• Environmental Monitoring Program: A robust program including viable and non-viable particle monitoring at critical locations, with clearly defined alert and action limits. Monitoring should cover air, surfaces, and personnel, with frequency based on risk assessment [39].

• Process Controls: Implementation of closed systems where possible, with demonstrated integrity through testing. For open processes, strict control of interventions and aseptic techniques is required [66]. Processes should be designed to minimize manipulations and exposure, with defined maximum hold times for intermediate products [66].

• Utilities and Raw Materials: Control and monitoring of water systems, process gases, and other utilities. Comprehensive testing and qualification of raw materials, especially human-derived starting materials with inherent contamination risks [65].

Aseptic Processing and Process Validation

For most ATMPs, terminal sterilization is not feasible due to product sensitivity, making aseptic processing the primary method for sterility assurance [66]. Manufacturers must validate their aseptic processes using media fills that simulate the entire manufacturing process, including worst-case scenarios and interventions. The 2023 revision of Annex 1 emphasizes a holistic approach to aseptic processing, requiring contamination control strategies that address all potential sources of contamination [39].

Key considerations for ATMP aseptic processing include:

• Personnel Training and Qualification: Aseptic technique training with regular assessment and requalification. Strict gowning procedures and personnel monitoring [39].

• Process Validation Approach: For autologous products with limited batch sizes, process validation should demonstrate consistency across multiple batches and operators. For allogeneic products, traditional validation approaches with larger batch numbers may be applicable [66].

• Single-Use Systems: Implementation of closed, pre-sterilized single-use systems can significantly reduce contamination risk. These systems require appropriate qualification, including extractables and leachables studies where there is product contact [67] [39].

• Rapid Microbiological Methods: Adoption of novel microbiological methods that provide faster results than traditional culture methods, enabling more timely decision-making [67] [39].

Diagram 1: Holistic Contamination Control Strategy Workflow

Methodologies for Maintaining Chain of Identity

Electronic Systems and Data Integrity

Maintaining an unambiguous Chain of Identity is particularly critical for autologous ATMPs where the product is specific to an individual patient and mix-ups could have fatal consequences. Robust electronic systems are essential for maintaining CoI throughout complex manufacturing processes [68]. Annex 11 of EudraLex Volume 4 establishes requirements for computerized systems, emphasizing data integrity principles aligned with ALCOA+ (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, Available) [68].

Key elements of electronic CoI systems include:

• Unique Identifier Systems: Implementation of robust labeling with unique identifiers (such as 2D barcodes or RFID) that remain with the product throughout manufacturing. These identifiers should be machine-readable and resistant to environmental stresses [68].

• Access Controls: Role-based access control systems ensuring only authorized personnel can perform specific functions. The principle of least privilege should be applied, with no single individual able to complete all steps in a process without oversight [68].

• Audit Trails: Automated, secure audit trails that record all GxP-relevant actions without modification. Audit trails must capture the "who, what, when, and why" of all actions, including previous and new values for data changes [68].

• Electronic Batch Records: Implementation of electronic batch records (eBR) that enforce process steps in the correct sequence and prevent progression unless quality checks are satisfied. These systems should integrate with laboratory information management systems (LIMS) and other manufacturing systems [68].

Process Controls for Identity Preservation

Beyond electronic systems, procedural controls are essential for maintaining CoI throughout the ATMP manufacturing process:

• Double-Verification Protocols: Critical steps (such as material receipt, patient material identification, and final product labeling) should require independent double-verification by qualified personnel [68].

• Reconciliation Procedures: Comprehensive reconciliation of all materials, containers, and labels at each process step, with investigation of any discrepancies [68].

• Sample Management: Clear procedures for identification and traceability of testing samples, particularly when multiple patient samples are processed simultaneously [68].

• Change Control: Strict control of system changes through formal change control procedures, with appropriate testing and validation before implementation [68].

Diagram 2: Chain of Identity Verification Process

Essential Research Reagents and Solutions

Table 2: Essential Reagents and Materials for ATMP Sterility and Identity Research

Category	Specific Materials/Reagents	Function in Sterility/CoI Research	Key Considerations
Rapid Microbiological Methods	Nucleic acid amplification-based systems, flow cytometry-based assays	Rapid detection of microbial contamination; alternative to traditional sterility testing	Validation against compendial methods; regulatory acceptance [67] [39]
Single-Use Systems	Pre-sterilized closed system kits, integrated sensors	Reduce contamination risk during processing; maintain closed processing environment	Extractables/leachables profile; compatibility with cellular products [39] [66]
Environmental Monitoring Materials	Settle plates, contact plates, air samplers, particulate counters	Monitor controlled environments during process simulation studies	Growth promotion testing; appropriate culture media selection [39]
Unique Identifiers	2D barcodes, RFID tags, cryogenic labels	Maintain chain of identity throughout manufacturing process	Durability through processing conditions (cryogenic storage, vapor phase LN2) [68]
Cell Processing Reagents	Serum-free media, antibiotics, apoptosis detection kits	Maintain cell viability while controlling microbial growth	Impact on product quality and potency; regulatory concerns about antibiotic use [4]
Validation Materials	Biological indicators, endotoxin standards, media fill materials	Process validation and sterilization verification	Spore concentration and resistance; media fill intervention scenarios [39]

Integration for Regulatory Compliance

Documentation and Verification Strategies

Successful regulatory compliance for ATMP manufacturing licenses requires seamless integration of sterility assurance and chain of identity systems. National competent authorities expect comprehensive documentation demonstrating control throughout the product lifecycle [67] [39]. Key integration elements include:

• Pharmaceutical Quality System: Implementation of a robust PQS that encompasses both sterility and traceability requirements, with clear policies for data integrity and deviation management [39] [68].

• Validation Master Plan: A comprehensive plan covering facility, equipment, process, and computer system validation, demonstrating a holistic approach to quality assurance [68].

• Supplier Qualification: Rigorous qualification of critical suppliers, particularly those providing human-derived starting materials, single-use systems, and computerized systems for identity management [65] [68].

• Change Management: Formal change control procedures that assess potential impacts on both product sterility and traceability before implementation [68].

Preparation for Regulatory Assessments

Manufacturers should prepare for regulatory assessments by compiling evidence of effective integration:

• Contamination Control Strategy Document: A comprehensive document describing all elements of the CCS and their implementation [39].

• Data Integrity Assessment: Formal assessment of computerized systems against ALCOA+ principles, particularly for identity management systems [68].

• Process Simulation Protocols and Reports: Complete documentation of media fills and other process simulation studies, including worst-case scenarios [39].

• Traceability Studies: Evidence of effective identity preservation through mock recalls or tracking exercises [68].

The regulatory landscape for ATMPs continues to evolve, with increased emphasis on risk-based approaches, technological innovation, and harmonized standards across regions [69]. Manufacturers should engage early with national competent authorities through scientific advice procedures to ensure their approaches to maintaining sterility and chain of identity align with current expectations, ultimately facilitating successful manufacturing license approvals and bringing these innovative therapies to patients in need.

Validating Process Consistency with Limited Batch Sizes

For developers of Advanced Therapy Medicinal Products (ATMPs), demonstrating process consistency presents unique challenges due to inherent limitations in batch sizes. These complex biological products, which include gene therapies, somatic-cell therapies, and tissue-engineered medicines, are often manufactured in limited quantities because of their biological nature and the complexities of their production processes [4]. Within the European regulatory framework, manufacturers must hold a manufacturing authorization from the national competent authority of the Member State where activities are carried out, and compliance with EU Good Manufacturing Practice (GMP) is mandatory [21]. The fundamental standard for process validation is clearly defined by the European Medicines Agency (EMA) as "the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes" [70]. For ATMPs specifically, the European Commission has published detailed GMP guidelines that adapt general requirements to the specific characteristics of these products, acknowledging their novel and complex manufacturing scenarios [41] [21]. This guidance provides a regulatory foundation for implementing a risk-based approach to validation that can accommodate the practical constraints of ATMP manufacturing while ensuring product quality, safety, and efficacy.

Regulatory Framework and Batch Size Requirements

Distinction Between Validation and Stability Testing Batches

A critical regulatory distinction exists between batch size requirements for process validation versus stability testing. For stability testing of new drug substances and products, the globally accepted standard per ICH Q1A(R2) requires batches "manufactured to a minimum of pilot scale" [70]. Both the FDA and EMA confirm that stability testing batches can be at "pilot scale or a small scale batch," with industry best practices suggesting 10–15% of commercial batch volume may be acceptable [70]. In contrast, process validation for commercial marketing authorization must use commercial-scale batches in both the US and EU, regardless of the product type [70]. This requirement exists because process validation must demonstrate that the commercial manufacturing process, including all unit operations, can consistently deliver quality products. Operations at commercial scale may introduce factors not present in smaller batches, such as extended processing times requiring shift changes, equipment scaling effects, or the use of multiple material lots [70].

Lifecycle Approach to Validation

The regulatory landscape for process validation is evolving toward a lifecycle approach that extends beyond the traditional "three-batch model." Survey data from the pharmaceutical industry indicates that 86.5% of professionals agree that modifying current validation requirements toward a more scientific approach and process understanding is necessary [71]. This enhanced approach incorporates continuous process verification using statistical process control (SPC), pharmaceutical quality system monitoring, and ongoing data collection throughout the product lifecycle [71]. For ATMP manufacturers, this shift provides opportunities to demonstrate process consistency through means beyond traditional batch consistency studies, which is particularly valuable when limited by batch size constraints.

Table: Batch Size Requirements for Different Study Types

Study Type	Minimum Batch Size	Key Regulatory Standards	ATMP Considerations
Process Validation	Commercial scale	EMA: Must demonstrate commercial process capability [70]	Small batch sizes may represent commercial scale for autologous products
Stability Testing	Pilot scale (10-15% of commercial)	ICH Q1A(R2) [70]	Multiple pack sizes may be derived from one process batch
Process Verification	Not applicable (continuous monitoring)	FDA Process Validation Guidance [71]	Statistical monitoring crucial for limited batch scenarios

Methodological Approaches for Robustness Testing

Defining Robustness in Analytical Methods

For ATMP manufacturers, robustness testing provides a scientifically rigorous approach to demonstrate method reliability despite limitations in full-scale batch availability. The International Conference on Harmonisation (ICH) defines robustness as "a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage" [72]. It is essential to distinguish robustness from related concepts: ruggedness refers to reproducibility under a variety of normal test conditions (different laboratories, analysts, instruments), while robustness specifically examines the impact of deliberate variations in method parameters [73]. The ICH guidelines recommend that "one consequence of the evaluation of robustness should be that a series of system suitability parameters (e.g. resolution tests) is established to ensure that the validity of the analytical procedure is maintained whenever used" [72].

Experimental Design for Robustness Studies

Robustness testing follows a systematic approach that examines potential sources of variability in method responses. The process involves these critical steps, with special considerations for ATMPs:

• Factor Selection: Choose factors from the analytical procedure description (operational factors) and environmental conditions not explicitly specified (environmental factors) [72]. For cell-based ATMPs, this could include critical culture parameters such as pH, temperature, CO₂ levels, media component lots, or cell passage number [74].

• Level Definition: Define high and low values for each factor that slightly exceed expected variations during method transfer between instruments or laboratories [72]. The range should be practically relevant but sufficiently wide to detect potential effects.

• Experimental Design Selection: Utilize efficient screening designs that can evaluate multiple factors simultaneously with minimal experimental runs. Appropriate designs include full factorial, fractional factorial, and Plackett-Burman designs, selected based on the number of factors being investigated [73] [72].

Diagram Title: Robustness Testing Workflow

Advanced Experimental Designs

When evaluating multiple factors simultaneously, specialized experimental designs maximize efficiency:

• Full Factorial Designs: Examine all possible combinations of factors at two levels each (high and low). If investigating k factors, this requires 2^k runs. For example, 4 factors would require 16 experimental runs [73]. While comprehensive, this approach becomes impractical with more than five factors due to the exponential increase in required runs.

• Fractional Factorial Designs: Carefully chosen subsets of full factorial combinations that significantly reduce the number of required runs. These designs use a degree of fractionation (such as 1/2 or 1/4 of the full factorial runs) while still generating meaningful data about factor effects [73]. The trade-off is that some factor effects may be "aliased" or confounded with other factor interactions.

• Plackett-Burman Designs: Highly efficient screening designs that require multiples of four runs rather than powers of two, making them particularly economical for investigating larger numbers of factors (e.g., 7 factors in 12 runs) [73]. These designs are ideal when the primary interest is identifying the most critical factors affecting method performance rather than precisely quantifying each individual effect.

Table: Comparison of Experimental Designs for Robustness Testing

Design Type	Number of Runs	Key Advantages	Limitations	Best Application
Full Factorial	2^k (e.g., 16 runs for 4 factors)	No confounding of effects; Complete interaction data	Runs increase exponentially with factors	Small number of factors (<5); Critical methods
Fractional Factorial	2^(k-p) (e.g., 8 runs for 4 factors)	Balanced; Good efficiency; Some interaction information	Some effects aliased with interactions	Medium number of factors; Most robustness studies
Plackett-Burman	Multiples of 4 (e.g., 12 runs for 7 factors)	Highly efficient for many factors; Main effects clear	No interaction information; Effects aliased	Large number of factors; Initial screening

Practical Implementation and Case Studies

Application to ATMP Manufacturing Processes

For ATMP manufacturers, implementing robustness studies requires special consideration of product-specific characteristics. In cell therapy manufacturing, critical process parameters might include cell seeding density, differentiation agent concentrations, incubation times, and harvest criteria [74] [21]. A robustness study for a cell harvesting unit operation might examine factors such as enzymatic digestion time, temperature, agitation rate, and neutralization method. Recent advancements in chromatographic clarification technologies demonstrate how robustness principles can be applied to intensify processes and improve consistency while reducing operational complexity [75]. One study reported a 16% reduction in cost per gram through implementation of a novel single-use chromatographic clarification approach that improved product recovery, impurity clearance, and operational efficiency [75].

Establishing System Suitability Parameters

A key outcome of robustness testing should be the establishment of evidence-based system suitability parameters that ensure method validity during routine use [73] [72]. For ATMP methods, these parameters should reflect the critical quality attributes most sensitive to the identified influential factors. The ICH guidelines emphasize that system suitability testing should verify that the analytical system is functioning properly at the time of testing [72]. Limits should be established based on experimental data from robustness studies rather than arbitrary historical experience, creating a scientifically justified link between observed method performance and predefined acceptance criteria [72].

The Scientist's Toolkit: Essential Research Reagents and Materials

Table: Key Research Reagent Solutions for ATMP Process Development

Reagent/Material	Function	Application Example	Quality Considerations
Authenticated Cell Lines	Biological source material	Master cell bank establishment	Verify identity via STR profiling; Document origin and quality controls [74]
High-Flow Rate Sterile Filtration Systems	Media and buffer sterilization	Aseptic processing of culture media	Polyethersulfone (PES) membranes (0.22μm for serum media); Validate extractables [74]
Application-Tested Cell Freezing Solutions	Cryopreservation of cell stocks	Master cell bank creation	Slow cooling protocols; Vapor phase nitrogen storage to minimize contamination risk [74]
Chromatographic Clarifiers	Primary recovery and clarification	Harvest unit operation in mAb production	Anion exchange capacity; DNA and HCP reduction capability; Single-use compatibility [75]
Characterized Serum Lots	Cell culture supplement	Media formulation for cell expansion	Bulk purchase with batch testing; Documented quality control supporting cell growth [74]

Integration with Quality Risk Management

For ATMP manufacturers working with limited batch sizes, Quality Risk Management (QRM) principles provide a framework for justifying validation approaches based on robust scientific rationale [42]. The EU GMP guidelines specifically acknowledge that alternative approaches to traditional validation may be acceptable when "thoroughly justified by applying the principles of Quality Risk Management" [42]. This is particularly relevant when dealing with unique ATMP manufacturing scenarios where standard batch sizes may not be feasible. Critical considerations in such justifications include the pharmaceutical form (e.g., cell suspensions, tissue constructs), expiry date, ongoing stability study design, reference sampling plans, and the criticality of the drug product with associated shortage risks [42]. A well-documented QRM approach allows manufacturers to implement scientifically sound validation strategies that accommodate the practical constraints of ATMP production while maintaining regulatory compliance and ensuring product quality.

Diagram Title: Quality Risk Management Integration

Validating process consistency with limited batch sizes requires ATMP manufacturers to adopt sophisticated approaches that extend beyond traditional validation paradigms. By implementing rigorous robustness testing through appropriate experimental designs, establishing evidence-based system suitability parameters, and integrating these activities within a comprehensive Quality Risk Management framework, manufacturers can generate compelling scientific evidence of process consistency and product quality. This approach is particularly aligned with the evolving regulatory expectations for a lifecycle approach to validation that emphasizes continued process verification over discrete validation events. For researchers and drug development professionals working with ATMPs, these methodologies provide practical pathways to demonstrate process consistency and control, thereby supporting successful regulatory evaluations by national competent authorities while accommodating the practical manufacturing constraints inherent in these innovative therapies.

Navigating GMP Compliance for Starting Materials of Human Origin

The development and manufacture of Advanced Therapy Medicinal Products (ATMPs) represent one of the most innovative frontiers in modern medicine. These therapies, which include gene therapies, somatic cell therapies, tissue-engineered products, and combination ATMPs, offer revolutionary potential for treating previously untreatable conditions. However, their complex nature, particularly the use of human-derived starting materials, presents unique regulatory challenges. The European Medicines Agency (EMA) categorizes these products under a specialized regulatory framework with distinct Good Manufacturing Practice (GMP) requirements that recognize their specific characteristics and novel manufacturing scenarios [41].

For researchers and drug development professionals seeking manufacturing licenses from national competent authorities, navigating GMP compliance for starting materials of human origin is a critical foundational step. These materials—including human cells, tissues, and blood components—introduce inherent variability and potential risks that must be carefully controlled throughout the manufacturing process. The EU regulatory framework establishes a comprehensive system for ensuring these materials meet appropriate quality and safety standards before they can be incorporated into ATMPs destined for clinical trials or marketing authorization [76] [77].

The regulatory landscape for ATMPs is dynamic, with ongoing revisions to address emerging technologies and scientific advancements. As of 2025, the EMA has proposed revisions to Part IV of the EU GMP Guidelines specific to ATMPs, aiming to align them with updated Annex 1 (manufacture of sterile medicinal products), incorporate ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) principles, and provide clarity on new manufacturing technologies [39]. This evolving nature underscores the importance for researchers to maintain current knowledge of regulatory expectations.

Core Regulatory Requirements for Starting Materials

Legal Foundations and Key Directives

The regulatory framework for starting materials of human origin in the European Union is established through several key legal instruments that set binding requirements for their donation, procurement, and testing. These foundational documents create the legal basis upon which GMP compliance is assessed by national competent authorities during the manufacturing license evaluation process.

• Directive 2004/23/EC: This directive establishes quality and safety standards for the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells [76]. It serves as the cornerstone regulation for human-derived materials used in ATMP manufacturing.

• Directive 2002/98/EC: This directive addresses quality and safety standards for human blood and blood components, providing specific requirements for materials sourced from human blood [41].

• Regulation (EC) No 1394/2007: This central regulation governing advanced therapy medicinal products explicitly requires that ATMPs containing human tissues or cells must be manufactured in accordance with Directives 2004/23/EC and 2002/98/EC, creating the direct link between tissue/cell regulations and ATMP manufacturing requirements [76] [77].

These legal instruments establish the fundamental principle that human-derived starting materials must meet stringent quality and safety standards before they can be incorporated into ATMPs. The directives are further supported by implementing directives that provide detailed technical requirements, creating a comprehensive regulatory framework that researchers must navigate throughout the product development lifecycle [41].

Specific GMP Requirements for Human-Derived Materials

The EU's GMP guidelines specific to ATMPs adapt general pharmaceutical GMP requirements to the unique characteristics of products containing human-derived materials. These requirements span the entire lifecycle of the starting materials, from donor selection to final incorporation into the finished product.

• Donor Suitability Assessment: Comprehensive evaluation of donor health status and medical history must be conducted according to the requirements outlined in Directive 2004/23/EC. This includes screening for transmissible diseases and other relevant health factors that might affect product safety [77].

• Testing Requirements: Donated materials must undergo specific testing based on risk assessment, typically including serological and molecular biology testing for relevant infectious agents (e.g., HIV, HBV, HCV) [77]. The testing standards must align with current scientific knowledge and regulatory expectations.

• Traceability Systems: Manufacturers must implement a comprehensive system that enables bidirectional tracing of all human-derived materials from the donor through all processing steps to the final recipient, and vice versa. Traceability information must be maintained for a minimum of 30 years after product release [77].

• Supplier Qualification: Manufacturers must establish and maintain rigorous qualification procedures for suppliers of human-derived starting materials. This includes auditing, specification agreement, and ongoing monitoring to ensure consistent compliance with established quality parameters [77].

Table: Key EU Regulatory Documents for Human-Derived Starting Materials

Regulatory Document	Scope and Application	Key Requirements
Directive 2004/23/EC	Quality and safety standards for human tissues and cells	Donation, procurement, testing, processing, preservation, storage, and distribution requirements
Directive 2002/98/EC	Quality and safety standards for human blood and blood components	Specific standards for blood-derived materials used in ATMP manufacturing
EU GMP Guidelines Part IV (ATMPs)	GMP adaptation for advanced therapy medicinal products	Risk-based approach to manufacture and testing of ATMPs containing human-derived materials
Regulation (EC) No 1394/2007	Regulatory framework for advanced therapy medicinal products	Establishes requirement for ATMPs to comply with tissue and cell directives

Experimental Protocols and Methodologies

Donor Screening and Testing Methodologies

Implementing robust donor screening and testing protocols is fundamental to GMP compliance for human-derived starting materials. The following detailed methodology outlines the critical steps for establishing a comprehensive screening program that meets regulatory requirements.

• Donor Health History Assessment: Develop structured questionnaires and interview protocols to collect comprehensive donor health information, including medical history, travel history, infectious disease risk factors, and genetic predispositions. All questionnaires should be validated for completeness and clarity, with trained personnel conducting the assessments.

• Infectious Disease Testing: Implement a validated testing panel using approved diagnostic kits with appropriate sensitivity and specificity characteristics. Testing should include:

  • Serological tests for HIV-1/HIV-2, HBV (HBsAg, anti-HBc), HCV, HTLV-I/II, and Syphilis
  • Nucleic Acid Testing (NAT) for HIV, HBV, and HCV to reduce the window period risk
  • Additional tests based on donor epidemiology and cell/tissue type (e.g., CMV, EBV, West Nile Virus)

• Material Characterization: Establish quality specifications and testing methods for critical quality attributes of the starting material, including:

  • Cell viability assessment using trypan blue exclusion or flow cytometry methods
  • Cell count and concentration determinations
  • Phenotypic characterization via flow cytometry for relevant surface markers
  • Functional potency assays relevant to the intended biological activity

• Microbiological Testing: Conduct comprehensive microbiological evaluation including:

  • Sterility testing according to Ph. Eur. 2.6.1 or equivalent
  • Mycoplasma testing using both culture and nucleic acid amplification methods
  • Endotoxin testing using Limulus Amebocyte Lysate (LAL) assay

All testing methodologies must be properly validated according to ICH guidelines, with established acceptance criteria, reference standards, and documented procedures. The testing environment must comply with appropriate quality standards, and all equipment must be qualified and maintained under a formal calibration program.

Process Validation Approaches for Limited Starting Materials

The often limited availability of human-derived starting materials necessitates specialized approaches to process validation that differ from traditional pharmaceutical manufacturing. The EU ATMP GMP guidelines recognize these constraints and provide for alternative validation strategies.

• Risk-Based Validation Scope: Implement a comprehensive risk assessment to identify critical process parameters (CPPs) and critical quality attributes (CQAs) that directly impact product safety, identity, purity, and potency. Focus validation activities on these high-risk areas to maximize information gain from limited material availability.

• Concurrent Validation Strategy: When prospective validation with multiple full-scale batches is not feasible due to material limitations, implement a concurrent validation approach where validation studies are conducted during routine manufacturing. This strategy requires:

  • Enhanced monitoring and testing during initial manufacturing runs
  • Extensive data collection and statistical analysis
  • Clear predefined acceptance criteria for continued manufacturing
  • Specific provisions in the marketing authorization allowing this approach

• Use of Representative Models: When direct validation with the actual starting material is not possible, employ scientifically justified representative models including:

  • Cell lines with similar characteristics to the primary human materials
  • Surrogate materials with comparable physical and chemical properties
  • Small-scale models that accurately mimic full-scale manufacturing
  • Computational modeling approaches where validated

• Extended Process Characterization: Implement an extended process characterization program that continuously monitors process performance and product quality across multiple manufacturing runs, using statistical process control methods to demonstrate process capability and robustness over time.

Table: Testing Requirements for Human-Derived Starting Materials

Testing Category	Specific Tests and Methods	Acceptance Criteria	Regulatory Reference
Infectious Disease Markers	HIV-1/2 Ab, HBsAg, anti-HBc, HCV Ab, NAT for HIV/HBV/HCV	Non-reactive/negative according to test specifications	Directive 2004/23/EC
Microbiological Quality	Sterility testing (Ph. Eur. 2.6.1), Mycoplasma, Endotoxin	Sterile, Mycoplasma negative, Endotoxin limits based on product type	EU GMP Annex 1
Cell Quality Attributes	Viability, cell count, identity/phenotype, potency	Product-specific specifications based on manufacturing experience	ATMP GMP Guidelines
General Quality Parameters	Appearance, container integrity, temperature monitoring	No abnormalities, maintained within validated range	ATMP GMP Guidelines

Compliance Pathway and Documentation

Traceability and Documentation Systems

Establishing comprehensive traceability and documentation systems is a fundamental GMP requirement for human-derived starting materials. The EU ATMP GMP guidelines mandate a system that enables bidirectional tracing of all human cells and tissues from the donor through processing to the final recipient.

The traceability system must capture and maintain specific data elements including unique donor identification codes, procurement facility information, processing steps with dates and personnel, testing results, storage conditions, distribution records, and recipient identification. This information must be maintained for at least 30 years after product release, requiring robust data management systems and preservation strategies [77].

Documentation requirements extend beyond traceability to encompass the complete quality system. Specific documentation includes detailed specifications for all human-derived starting materials, comprehensive Standard Operating Procedures (SOPs) for all handling and processing activities, batch records documenting each manufacturing step, testing protocols and results, and deviation/exception reports. All documentation must comply with general GMP principles for data integrity, including contemporaneous recording, originality, accuracy, and completeness.

GMP Compliance Pathway for Human-Derived Starting Materials

Quality Risk Management Implementation

The EU ATMP GMP guidelines emphasize a risk-based approach that recognizes the diversity and complexity of products containing human-derived materials. Implementing a systematic quality risk management process is essential for successful regulatory compliance and manufacturing license approval.

• Risk Identification: Conduct comprehensive risk assessments to identify potential hazards associated with human-derived starting materials, including transmission of infectious diseases, introduction of contaminants, variability in material characteristics, and potential for mix-up or misidentification.

• Risk Analysis and Evaluation: Evaluate identified risks using structured tools such as Failure Mode and Effects Analysis (FMEA) or Fault Tree Analysis (FTA). Prioritize risks based on severity of impact, probability of occurrence, and detectability. Focus control strategies on high-priority risks that could impact patient safety or product quality.

• Risk Control Measures: Implement appropriate risk control measures based on the risk assessment findings. These may include donor screening protocols, testing strategies, segregation procedures, process controls, and specific facility design features. The extent of controls should be proportionate to the level of risk identified.

• Risk Communication and Review: Establish procedures for communicating risks and control measures to all relevant personnel. Implement regular risk review processes to assess new information and experience, modifying control strategies as needed to maintain an appropriate risk profile throughout the product lifecycle.

The risk management process should be thoroughly documented in a Quality Risk Management Plan that outlines the methodology, responsibilities, and review frequency. This documentation will be a key element evaluated by national competent authorities during manufacturing license assessments.

The Scientist's Toolkit: Essential Reagents and Materials

Successful GMP compliance for human-derived starting materials requires specific reagents, materials, and systems that ensure quality and traceability throughout the manufacturing process. The following table outlines key solutions essential for researchers working in this field.

Table: Essential Research Reagent Solutions for GMP Compliance

Reagent/Material Category	Specific Examples	Function and Application	Quality Standards
Donor Screening Reagents	FDA/CE-approved serological test kits, NAT reagents, blood collection tubes with anticoagulants	Detection of infectious disease markers, blood grouping, genetic screening	Approved diagnostic device standards with established sensitivity/specificity
Cell Culture Materials	GMP-grade culture media, growth factors, cytokines, serum alternatives, dissociation reagents	Maintenance, expansion, and differentiation of human-derived cells	GMP-grade with certificates of analysis, endotoxin testing, sterility assurance
Cryopreservation Solutions	Defined-formulation cryoprotectants (e.g., DMSO), controlled-rate freezing systems, cryogenic storage containers	Long-term preservation of cell viability and functionality	Validated cooling rates, container integrity testing, composition verification
Quality Control Reagents	Flow cytometry antibodies, viability stains, PCR reagents for mycoplasma, LAL reagents for endotoxin	Characterization, potency assessment, and safety testing	Analytical validation, specificity/sensitivity verification, stability demonstration
Traceability Systems	Unique identifier labels, barcode/RFID systems, temperature monitoring devices, electronic batch records	Maintenance of chain of identity and chain of custody	21 CFR Part 11 compliance (or equivalent), audit trail functionality, data integrity

Future Developments and Strategic Considerations

The regulatory landscape for ATMPs containing human-derived materials continues to evolve in response to technological advancements and accumulated scientific knowledge. Several key developments will impact future GMP compliance strategies.

The EMA has initiated a revision process for Part IV of the EU GMP Guidelines specific to ATMPs, with a concept paper published in May 2025 outlining proposed changes [39]. These revisions aim to align ATMP-specific requirements with the updated Annex 1 for sterile medicinal products, incorporate ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) principles more explicitly, and provide clarity on emerging technologies such as automated systems, closed single-use systems, and rapid microbiological methods [39].

Concurrently, broader EU GMP guidelines are being updated to address technological advancements, including proposed revisions to Chapter 4 (Documentation) and Annex 11 (Computerized Systems), and the introduction of a new Annex 22 addressing the use of artificial intelligence in pharmaceutical manufacturing [78]. These changes reflect the increasing digitalization of manufacturing processes and the need for appropriate governance frameworks.

For researchers and developers, these evolving regulations underscore the importance of building flexibility and adaptability into quality systems. Implementing robust quality risk management principles and maintaining ongoing engagement with regulatory authorities through scientific advice procedures can help anticipate and respond to regulatory changes. As the field advances, compliance strategies must balance regulatory requirements with the practical challenges of manufacturing innovative therapies that often involve limited, highly variable human-derived materials.

The field of Advanced Therapy Medicinal Products (ATMPs), which encompasses gene therapies, somatic-cell therapies, and tissue-engineered products, is undergoing a transformative shift from traditional centralized production to decentralized point-of-care (POC) manufacturing [4]. This paradigm moves production from large-scale facilities to academic medical centers, hospital pharmacies, and clinical sites, enabling the creation of personalized therapies tailored to individual patients [79] [80]. For researchers and drug development professionals navigating the requirements of national competent authorities, this evolution presents unique regulatory challenges and opportunities. POC models are particularly vital for autologous therapies and treatments with limited stability, such as Tumor Infiltrating Lymphocytes (TIL), where traditional centralized manufacturing and transportation are impractical [81]. This technical guide examines the current regulatory landscape, technological enablers, and compliance strategies for POC ATMP manufacturing within the framework of national authority oversight.

The Evolving Regulatory Landscape for POC Manufacturing

Foundational EU Regulatory Framework

The European regulatory framework for ATMPs is established under Regulation (EC) No. 1394/2007, which defines these products as gene therapies, somatic cell therapies, tissue-engineered products, and combined ATMPs [31]. All ATMPs require a centralized marketing authorization from the European Commission through the European Medicines Agency (EMA) [4] [31]. However, the manufacturing authorization is granted at the national level by the competent authority of the Member State where the production occurs [21]. This dual-layer regulatory oversight creates a complex environment for POC manufacturers who must satisfy both EU-wide and national requirements.

The regulatory framework is adapting to accommodate POC manufacturing innovations. The EMA's Quality Innovation Group (QIG) is actively developing guidance for advanced manufacturing technologies, including a forthcoming 'Questions and Answers' document on 3D printing and decentralized manufacturing scheduled for the 2025-2027 work plan [79]. Simultaneously, national regulators are implementing new frameworks, such as the UK's Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025, which establishes specific requirements for producing patient-specific medicines at or near the treatment site [79].

Good Manufacturing Practice (GMP) Considerations

Compliance with Good Manufacturing Practice (GMP) is mandatory for all ATMP manufacturing, regardless of scale or location [21]. The European Commission has published specific GMP guidelines for ATMPs in EudraLex Volume 4, Part IV, which acknowledges the unique challenges of these products and emphasizes a risk-based approach (RBA) to compliance [66] [21]. For POC manufacturing, critical considerations include:

• Scalability Challenges: Manufacturing multiple small batches within the same facility while maintaining product quality and consistency [66]
• Sterility Assurance: Implementing alternative sterility methods when sterile filtration is not possible for cell-based products [66]
• Starting Material Variability: Establishing controls for patient-derived materials with inherent biological variability [66]

Table 1: Key GMP Guidelines Relevant to ATMP Manufacturing

Guideline Document	Issuing Authority	Key Focus Areas	Relevance to POC Manufacturing
EudraLex Vol. 4, Part IV	European Commission	GMP specific to ATMPs	Primary guideline for ATMP-specific GMP requirements
PIC/S Annex 2A	PIC/S	Manufacture of ATMPs for human use	Important for manufacturers in PIC/S member countries
Annex 1 (Manufacture of Sterile Medicinal Products)	European Commission & PIC/S	Sterile manufacturing requirements	Critical for aseptic processing of non-filterable ATMPs

Regulatory Pathways and Expedited Programs

The EU offers several regulatory pathways to accelerate ATMP development and approval. The PRIME (Priority Medicines) scheme provides enhanced support for therapies addressing unmet medical needs, including early dialogue and accelerated assessment [31]. As of 2025, regulatory agencies are showing increased receptivity to local or decentralized manufacturing models, particularly for therapies that cannot be practically centralized [81] [79]. However, manufacturers must demonstrate rigorous harmonization of protocols and quality control across multiple sites in decentralized trials to ensure data interpretability and product consistency [81].

Point-of-Care Manufacturing Technologies and Methodologies

Automated Cell Therapy Production Systems

Closed-system automated instruments have become enablers of POC ATMP manufacturing by reducing cleanroom requirements and improving process consistency [81]. The CliniMACS Prodigy system (Miltenyi Biotec) represents a leading platform for automated cell therapy production, enabling POC manufacturing of complex therapies like CAR-T cells [80]. This integrated system performs cell separation, activation, transduction, expansion, and formulation within a single closed system, significantly reducing manual processing steps and contamination risks.

A recent study demonstrated the feasibility of POC CAR-T cell manufacturing using the CliniMACS Prodigy system in an academic medical center in Thailand [80]. The methodology included:

• Leukapheresis: Collection of starting material from patients or donors
• Automated Processing: Closed-system processing using the CliniMACS Prodigy with standardized protocols
• Quality Control Implementation: In-process testing and release criteria including identity, purity, sterility, safety, and potency assessments
• Process Optimization: Serum supplementation to address manufacturing challenges with specific CD4/CD8 ratios

This approach successfully manufactured nine CAR-T cell products for clinical use, demonstrating the viability of POC manufacturing in academic settings [80].

3D Printing of Medicines at Point-of-Care

Three-dimensional printing (3DP) of medicines is emerging as a disruptive technology for personalized dosage form manufacturing at the point-of-care [79]. This technology enables the production of patient-specific medications with precise dosages, tailored release profiles, and improved acceptability characteristics – particularly valuable for paediatric populations and patients with rare diseases [79].

Clinical trials have demonstrated the application of 3DP for producing chewable tablets for paediatric patients with rare metabolic disorders, enabling precise dosing and improved adherence [79]. The methodology typically involves:

• Formulation Development: Creating printable ink formulations with pharmaceutical-grade polymers and APIs
• Digital Design: Designing dosage forms with specific geometries, infill patterns, and dimensions to control drug release
• Printing Process: Using technologies like selective laser sintering or semi-solid extrusion to create dosage forms
• Quality Verification: Assessing printlet characteristics including drug content, dissolution, and physical properties

Table 2: 3D Printing Technologies for Pharmaceutical Manufacturing

Technology Type	Key Applications	Advantages	Current Status
Selective Laser Sintering (SLS)	Printlets, controlled-release systems	High resolution, no support material needed	Clinical evaluation stage
Semi-Solid Extrusion	Chewable formulations, orodispersible films	Room temperature processing, suitable for thermolabile drugs	Used in clinical practice for simpler treatments
Fused Deposition Modeling (FDM)	Extended-release systems, polypills	Wide material selection, mechanical strength	Preclinical development

Implementing Quality Control at Point-of-Care

Establishing robust quality control systems is essential for POC manufacturing and presents significant challenges in decentralized environments [81]. A comprehensive quality strategy should include:

• In-Process Testing: Monitoring critical quality attributes throughout manufacturing
• Release Criteria: Establishing product-specific specifications for identity, purity, potency, and safety
• Process Validation: Demonstrating consistent production of therapeutics meeting quality standards
• Environmental Monitoring: Maintaining appropriate cleanroom classification and aseptic processing conditions

For cell therapies, critical quality attributes typically include viability, identity, purity, sterility, and potency [80]. The POC CAR-T manufacturing program in Thailand implemented a panel of quality control tests including flow cytometry for immunophenotyping, mycoplasma testing, endotoxin testing, and sterility testing [80].

Regulatory Strategy for National Authority Approval

Navigating the Manufacturing Authorization Process

Obtaining a manufacturing authorization from the national competent authority requires demonstrating comprehensive GMP compliance and robust quality management systems [21]. The authorization process typically involves:

• Application Submission: Providing detailed information about facilities, equipment, personnel, and quality systems
• Site Inspection: Evaluation of manufacturing facilities and quality systems by national authority inspectors
• GMP Certification: Issuance of GMP certificate upon successful inspection, documented in the EudraGMDP database [21]

Manufacturers should engage early with national authorities through scientific advice procedures to align on development strategies and quality requirements [4] [31]. The EMA also provides support mechanisms such as the ATMP pilot for academia and non-profit organizations, which offers regulatory guidance and fee reductions [4].

Risk-Based Approach to GMP Compliance

A risk-based approach (RBA) is fundamental to navigating the evolving GMP expectations for ATMPs [66]. With some GMP guidelines not fully harmonized – particularly regarding facility classification and environmental monitoring – manufacturers must implement scientifically justified strategies that address the principles of quality and safety, even when specific regulations appear contradictory [66].

The RBA should systematically evaluate risks related to:

• Product Characteristics: Including starting materials, manufacturing process, and stability profile
• Process Design: Considering open versus closed processing steps and aseptic interventions
• Facility Design: Implementing appropriate cleanroom classifications and segregation strategies
• Patient Population: Accounting for disease indication and patient vulnerability

Diagram: Risk-Based Approach Framework for ATMP GMP Compliance

Addressing Multi-Site Manufacturing Challenges

Decentralized manufacturing across multiple clinical sites presents significant regulatory complexities [81]. When implementing multi-site manufacturing under a single Investigational New Drug Application (IND) or Clinical Trial Application (CTA), manufacturers must ensure:

• Protocol Harmonization: Identical manufacturing protocols across all sites
• Comparable QC Methods: Standardized or comparable quality control assays with demonstrated equivalence
• Quality System Integration: Coordinated quality management systems across manufacturing locations
• Training Standardization: Consistent personnel training and competency assessment

Successful multi-site manufacturing requires more extensive coordination than centralized production and demands careful planning of quality oversight and documentation systems [81].

The Scientist's Toolkit: Essential Research Reagents and Solutions

Table 3: Key Research Reagent Solutions for ATMP Development

Reagent/Category	Function	Application Examples	Quality Considerations
Cell Separation Reagents	Isolation of specific cell populations	CD4+/CD8+ selection for CAR-T manufacturing	GMP-grade, purity documentation
Cell Activation Reagents	T-cell activation and expansion	Anti-CD3/CD28 antibodies, cytokine cocktails	Endotoxin testing, potency assays
Gene Delivery Vectors	Introduction of genetic material	Lentiviral vectors for CAR gene delivery	Titer, identity, sterility, replication competence testing
Cell Culture Media	Support cell growth and maintenance	Serum-free media formulations	Composition consistency, growth promotion testing
Critical Materials	Excipients, scaffolds, matrices	Biodegradable matrices for tissue-engineered products	Biocompatibility, sterility, characterization

The regulatory landscape for POC ATMP manufacturing continues to evolve rapidly, with 2025 marking a significant inflection point for decentralized manufacturing frameworks [82] [79]. Key trends include increased adoption of digital quality management systems, regulatory acceptance of artificial intelligence in manufacturing, and greater emphasis on supply chain resilience [82]. For researchers and developers, successful navigation of national competent authority requirements will depend on:

• Early Engagement with regulators through scientific advice and qualification procedures
• Implementation of Risk-Based Approaches that address the unique challenges of POC manufacturing
• Investment in Robust Quality Systems capable of ensuring product consistency across multiple sites
• Adoption of Advanced Technologies that enhance manufacturing control and product characterization

As regulatory frameworks mature to accommodate these innovative manufacturing paradigms, POC production holds significant promise for improving patient access to personalized advanced therapies while maintaining the rigorous quality standards required for medicinal products. The ongoing collaboration between manufacturers, regulators, and healthcare providers will be essential to realizing this potential while ensuring patient safety and product efficacy.

Global Perspectives and Future Directions in ATMP Regulation

The development of Advanced Therapy Medicinal Products (ATMPs), which include cell and gene therapies, represents one of the most innovative yet complex frontiers in modern medicine. These groundbreaking therapies require sophisticated manufacturing processes and present unique challenges for regulatory agencies worldwide. For researchers, scientists, and drug development professionals navigating this landscape, understanding the divergent regulatory pathways across major jurisdictions is crucial for successful global development strategies.

This technical guide provides a comprehensive comparative analysis of the regulatory frameworks for ATMPs in the European Union (EU), the United States (US), and Japan. The focus is placed on the specific requirements of national competent authorities for ATMP manufacturing licenses, contextualized within the broader pharmaceutical quality system. As regulatory landscapes evolve rapidly, this analysis incorporates the most recent guidance and policy developments up to 2025, highlighting both persistent challenges and emerging harmonization trends.

Regulatory Framework and Key Definitions

Each region has established distinct regulatory frameworks and definitions for advanced therapies, which fundamentally influence how these products are classified and regulated.

In the European Union, Advanced Therapy Medicinal Products (ATMPs) are regulated under Regulation (EC) No 1394/2007 and are categorized into four main types: gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (sCTMPs), tissue-engineered products (TEPs), and combined ATMPs [83]. The European Medicines Agency (EMA) oversees these products through its Committee for Advanced Therapies (CAT), with final marketing authorization granted by the European Commission [84].

The United States Food and Drug Administration (FDA) regulates these products primarily as "cellular and gene therapy products" (CGTs) under the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act [85]. The Center for Biologics Evaluation and Research (CBER), specifically the Office of Therapeutic Products (OTP), holds primary responsibility for their evaluation and approval [85].

Japan's Pharmaceuticals and Medical Devices Agency (PMDA) operates under the Pharmaceuticals and Medical Devices (PMD) Act, which specifically includes "Regenerative Medical Products" as a distinct category covering gene therapies, cell therapies, and tissue-engineered products [86]. The PMDA conducts scientific reviews, while the Ministry of Health, Labour and Welfare (MHLW) grants final marketing authorization [86].

Marketing Authorization Pathways

Core Approval Processes

Table 1: Core Marketing Authorization Pathways

Region/Authority	Application Type	Legal Basis	Review Timeline (Standard)	Decision Authority
EU (EMA)	Marketing Authorization Application (MAA)	Regulation (EC) No 1394/2007	210 days (excluding clock stops)	European Commission
US (FDA)	Biologics License Application (BLA)	Public Health Service Act	10 months (standard)	FDA/CBER
Japan (PMDA/MHLW)	New Drug Application	PMD Act	Median 304 days (2019)	MHLW based on PMDA review

In the EU, the centralized marketing authorization procedure is mandatory for ATMPs, making the EMA the primary point of regulatory interaction [84]. Once granted by the European Commission, the authorization is valid across all EU Member States and the European Economic Area [83].

The US FDA requires a Biologics License Application (BLA) for marketing approval, which must demonstrate the product's safety, purity, and potency [85]. The standard review timeline is 10 months, though this can be shortened through various expedited pathways.

In Japan, the PMDA conducts the scientific assessment of applications, after which the MHLW grants formal marketing authorization [86]. Recent reforms have significantly reduced median review times to 304 days as of 2019, approaching parity with other regions [86].

Expedited Approval Pathways

Table 2: Expedited Development and Approval Pathways

Pathway	Region	Key Features	Target Conditions
PRIME	EU	Enhanced support & accelerated assessment (150-day review)	Unmet medical need
RMAT	US	Regenerative Medicine Advanced Therapy; rolling review & priority	Serious conditions
SAKIGAKE	Japan	Fast-track for first-in-world therapies (6-month target)	Novel, serious conditions
Conditional MA	EU	Approval based on less comprehensive data	Unmet need, orphan diseases
Accelerated Approval	US	Based on surrogate endpoints	Serious conditions
Conditional Early Approval	Japan	Provisional approval with post-market confirmation	Serious illnesses

The EU offers multiple expedited pathways, including the Priority Medicines (PRIME) scheme, which provides enhanced support and accelerated assessment (150 days instead of 210 days), and Conditional Marketing Authorization, which allows approval based on less comprehensive data for unmet medical needs [85].

The US FDA provides the Regenerative Medicine Advanced Therapy (RMAT) designation, which offers intensive guidance and rolling review, along with Accelerated Approval based on surrogate endpoints and Priority Review that shortens the standard 10-month review to 6 months [85] [87].

Japan's SAKIGAKE designation fast-tracks first-in-world therapies, targeting a 6-month review, provided the drug is novel, addresses a serious need, and is submitted first in Japan [86]. The Conditional Early Approval System, legislated in 2019, permits provisional approval for drugs treating serious illnesses when confirmatory trials are impractical [86].

Manufacturing & Quality Requirements

Good Manufacturing Practice (GMP) Requirements

The EU has established specific GMP guidelines for ATMPs that adapt standard EU GMP requirements to the particular characteristics of these products [41] [21]. The European Commission has published a set of GMP guidelines specific to ATMPs, which foster a risk-based approach to manufacture and testing [41]. In May 2025, the EMA released a concept paper proposing revisions to Part IV of the EU GMP guidelines specific to ATMPs, aiming to align with the revised Annex 1, incorporate ICH Q9 and Q10 principles, and adapt to technological advancements [39].

In the US, FDA mandates compliance with current Good Manufacturing Practice (cGMP) requirements under 21 CFR Parts 210 and 211 [88]. The agency has issued numerous product-specific guidances addressing manufacturing considerations for cellular and gene therapy products, with recent drafts focusing on potency assurance and manufacturing changes [88].

Japan's PMDA requires compliance with GMP standards under the PMD Act, with recent 2025 amendments strengthening quality and supply controls through new compliance officers and supply stability managers [86].

Key Manufacturing Challenges

Manufacturing authorization requirements present significant challenges across all regions. In the EU, any company manufacturing ATMPs must hold a manufacturing authorization issued by the national competent authority of the Member State where activities are carried out [21]. Regular and repeated on-site inspections evaluate compliance with GMP and the relevant marketing authorization [21].

A critical challenge in ATMP manufacturing involves the use of substances of human origin, which requires compliance with additional legislation concerning procurement, donation, and testing [41]. The complex and often small-batch manufacturing processes for living cells present particular difficulties in scaling up while maintaining quality and controlling costs [83].

Clinical Trial Requirements

Trial Approval Processes

Table 3: Clinical Trial Authorization Requirements

Region	Application Type	Reviewing Bodies	Timeline to Commence
EU	Clinical Trial Application (CTA)	National Competent Authorities & Ethics Committees	Varies by Member State
US	Investigational New Drug (IND)	FDA/CBER	30 days (unless placed on hold)
Japan	Clinical Trial Notification	PMDA & Certified Review Boards	Varies based on complexity

In the EU, since 2022, the Clinical Trials Information System (CTIS) allows centralized submission for trials across multiple EU states under the EU Clinical Trials Regulation (CTR, 536/2014) [85]. However, approval still involves both National Competent Authorities and Ethics Committees.

The US FDA requires an Investigational New Drug (IND) application including preclinical data, Chemistry, Manufacturing, and Controls (CMC) information, and Institutional Review Board (IRB) approval [85]. The FDA has 30 days to review before clinical trials can begin unless the study is placed on hold [85].

In Japan, clinical trials to support NDAs (called Chiken) require compliance with Japanese GCP standards [86]. The Clinical Trials Act (CTA) implemented in 2018 imposed legally mandated review processes through certified review boards, increasing administrative requirements but aiming to enhance trial quality [86].

Innovative Trial Designs for Small Populations

Recognizing that many ATMPs target rare diseases, regulatory agencies have developed flexibility regarding clinical trial designs. The US FDA has issued guidance specifically addressing "Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations" [89] [87]. This guidance recommends approaches such as single-arm trials utilizing participants as their own control, disease progress modeling, externally controlled studies, adaptive designs, Bayesian designs, and master protocol designs [87].

Similarly, the EMA acknowledges the challenges of small populations and encourages early dialogue with developers to discuss appropriate trial designs [41]. The PMDA has also moved toward greater acceptance of foreign clinical data, with a 2023 guideline generally waiving mandatory Japanese Phase I studies if foreign data show comparable safety profiles [86].

Post-Marketing Requirements

Safety Monitoring and Long-Term Follow-Up

Post-marketing surveillance presents particular challenges for ATMPs due to their potential for long-term effects. The US FDA typically requires 15+ years of long-term follow-up (LTFU) for gene therapies and may mandate Risk Evaluation and Mitigation Strategies (REMS) for high-risk products [85]. Recent FDA guidance emphasizes capturing post-approval safety and efficacy data using real-world evidence (RWE), electronic health records, registries, and decentralized data collection [87].

The EMA enforces a decentralized pharmacovigilance system with country-specific compliance requirements, mandatory Risk Management Plans (RMPs) for all ATMPs, and Periodic Safety Update Reports (PSURs) [85]. The EudraVigilance database tracks adverse events across the EU [85].

Japan's PMDA requires post-marketing surveillance and recently strengthened these requirements through 2025 amendments to the PMD Act, including enhanced safety monitoring provisions [86].

Comparative Regulatory Workflow

The following diagram illustrates the key stages in the regulatory pathway for ATMPs across the three regions, highlighting both parallel requirements and points of divergence.

Strategic Implications for Developers

Key Challenges in Global Development

Navigating divergent regulatory expectations increases complexity for ATMP developers. A recent study published in JAMA Internal Medicine found that only 20% of clinical trial data submitted to both the FDA and EMA matched, revealing major inconsistencies in regulatory expectations [85]. These discrepancies lead to approval delays, increased costs, and complex regulatory hurdles.

The FDA often exhibits flexibility by accepting real-world evidence and surrogate endpoints, particularly through accelerated pathways for rare or life-threatening conditions [85]. In contrast, the EMA typically requires more comprehensive clinical data, emphasizing larger patient populations and long-term efficacy before granting approval [85]. This contrast can result in therapies gaining market access more swiftly in the US, while facing delays or rejections in Europe due to more stringent data demands.

Japan has made significant strides in reducing its historical "drug lag" through reforms, with the median lag time decreasing from 4.3 years in 2008-11 to 1.3 years by 2016-19 [86]. However, challenges remain, particularly in neurology and psychiatry, where approvals continue to lag due to small domestic markets and development challenges [86].

The Scientist's Toolkit: Regulatory Strategy Essentials

Table 4: Essential Components for Navigating ATMP Regulatory Pathways

Toolkit Element	Function	Regional Considerations
Early Regulatory Advice	Anticipate requirements & align development plans	FDA Type B, EMA Scientific Advice, PMDA Consultation
Quality Risk Management	Implement ICH Q9 principles for manufacturing	Required in all regions; EMA explicitly incorporating into revised GMP
Expedited Pathway Strategy	Accelerate development and review	RMAT (US), PRIME (EU), SAKIGAKE (Japan)
Long-Term Follow-Up Plan	Address post-market safety requirements	15+ years for US gene therapies; risk-based in EU & Japan
Real-World Evidence Strategy	Support approvals and post-market requirements	FDA emphasizing for post-approval studies; EMA accepting with limitations

The regulatory landscapes for ATMPs in the EU, US, and Japan reflect both shared commitments to safety and efficacy and distinct approaches shaped by regional priorities, historical contexts, and healthcare systems. The EU maintains a comprehensive framework with specific ATMP classification and stringent data requirements. The US offers greater flexibility and expedited pathways, particularly for serious conditions with unmet needs. Japan has implemented significant reforms to reduce drug lag and create attractive incentives for innovative therapies.

For researchers and drug development professionals, success in this complex environment requires early and strategic engagement with regulatory agencies, careful planning for manufacturing quality systems, and adaptive clinical development strategies that accommodate regional differences. As global regulators continue to evolve their frameworks for these transformative therapies, maintaining current regulatory intelligence and proactive planning remains essential for navigating the divergent pathways to market approval across these key regions.

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, cell therapies, and tissue-engineered products, represent a revolutionary class of treatments for serious and life-threatening conditions [31]. The development of these complex biological products presents unique challenges, including manufacturing complexities, limited patient populations for clinical trials, and significant upfront investment requirements [90]. To address these challenges and accelerate patient access to promising therapies, regulatory agencies in key regions have established specialized designation programs that provide enhanced guidance and expedited assessment pathways [31] [91].

The PRIority MEdicines (PRIME) scheme from the European Medicines Agency (EMA), Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA), and Sakigake (meaning "pioneer" in Japanese) designation from Japan's Pharmaceutical and Medical Devices Agency (PMDA) represent three critical accelerated assessment pathways for innovative therapies [92] [93] [94]. These programs aim to facilitate the development and review of products that address unmet medical needs, particularly in the field of ATMPs [91] [95].

Understanding the similarities, differences, and strategic applications of these designation programs is essential for researchers, scientists, and drug development professionals working to advance ATMPs through the regulatory landscape. This whitepaper provides a comprehensive technical comparison of these three accelerated assessment pathways within the context of ATMP manufacturing and licensing considerations.

Regulatory Context and Definitions

Advanced Therapy Medicinal Products (ATMPs)

In the European Union, ATMPs are defined under Regulation (EC) No 1394/2007 as consisting of three main categories [31]:

• Gene Therapy Medicinal Products (GTMPs): Products containing active substances that contain or consist of recombinant nucleic acids for gene therapy purposes
• Somatic Cell Therapy Medicinal Products (SCTMPs): Products containing or consisting of engineered cells or tissues for treating, preventing, or diagnosing diseases
• Tissue-Engineered Products (TEPs): Products containing or consisting of engineered cells or tissues to regenerate, repair, or replace human tissue

Additionally, combined ATMPs incorporate one or more medical devices as an integral part of the product [31]. In the United States, similar products fall under the broader category of regenerative medicine therapies, defined to include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using such therapies [95].

Regulatory Framework for ATMP Assessment

The regulatory framework for ATMPs involves specialized committees in each region [31] [92]:

• EU: The Committee for Advanced Therapies (CAT) provides the primary scientific assessment of ATMP Marketing Authorization Applications
• US: The Office of Tissues and Advanced Therapies (OTAT) within FDA's Center for Biologics Evaluation and Research (CBER) reviews regenerative medicine therapies
• Japan: The Pharmaceuticals and Medical Devices Agency (PMDA) provides scientific assessment with specialized support for regenerative medicine products

Each region employs a combination of standard and accelerated procedures for market authorization. The EU offers standard marketing authorization, conditional marketing authorization, and exception under specific circumstances [92]. The US utilizes accelerated approval based on surrogate endpoints with post-marketing requirements to verify clinical benefit [95]. Japan has implemented a conditional/time-limited approval system that allows products to reach patients while additional efficacy data is collected [92].

Comprehensive Program Comparisons

Eligibility Criteria and Evidentiary Standards

Each designation program has distinct eligibility requirements and evidentiary standards that reflect regional regulatory philosophies and approaches to addressing unmet medical needs.

PRIME Scheme focuses on medicines that target an unmet medical need and demonstrate potential to address it with a major therapeutic advantage over existing treatments [91]. Eligibility requires preliminary clinical evidence showing the product's potential to benefit patients with unmet medical needs, though academic sponsors and small-to-medium enterprises (SMEs) can apply earlier based on compelling non-clinical data and initial clinical tolerability data [91]. The program specifically emphasizes medicines not yet authorized and still early in clinical development [91].

RMAT Designation requires that the product qualifies as a regenerative medicine therapy intended to treat, modify, reverse, or cure a serious condition [95]. Preliminary clinical evidence must indicate the therapy has the potential to address unmet medical needs for such condition [95]. Unlike the Breakthrough Therapy Designation, RMAT does not require demonstration of substantial improvement over existing therapies, recognizing the innovative nature of regenerative medicine approaches where direct comparisons may not be feasible [91] [95].

Sakigake Designation targets innovative medical products that are expected to be first-in-class, with Japan potentially among the first countries for product launch [92] [93]. The program requires that the product use a new active substance, mechanism of action, or modality, and that it targets a serious disease with high unmet medical need where early intervention is crucial [93]. Evidence requirements focus on demonstrating innovation and potential for significant patient benefit within the Japanese healthcare context.

Table 1: Eligibility Requirements and Evidentiary Standards

Criterion	PRIME	RMAT	Sakigake
Therapeutic Focus	Unmet medical need with major therapeutic advantage	Serious conditions; regenerative medicine therapy	Serious diseases; first-in-class innovation
Stage of Development	Early development (preliminary clinical evidence)	Preliminary clinical evidence	Clinical development stage
Evidence Requirement	Potential to address unmet medical need	Potential to address unmet medical need	Innovation & potential for significant benefit
Comparison to Existing Therapies	Major therapeutic advantage required	No requirement for substantial improvement	Focus on innovation rather than direct comparison
Regional Considerations	EU public health priorities	US patient population needs	Japanese healthcare context & early launch in Japan

Program Benefits and Regulatory Support Mechanisms

Each designation program offers a suite of benefits designed to accelerate development and review while maintaining regulatory standards for safety and efficacy.

PRIME Benefits include early and enhanced dialogue with EMA, appointment of a dedicated EMA contact point and Rapporteur from the Committee for Advanced Therapies (CAT) or Committee for Medicinal Products for Human Use (CHMP), and organizational commitment involving senior managers [31] [91]. A key feature is the "kick-off meeting" that initiates interaction between the sponsor, EU regulatory network experts, and the Agency to establish a platform for tailored development support [91]. Products with PRIME designation are eligible for accelerated assessment at the time of marketing authorization application, potentially reducing review timelines from 210 to 150 days [31] [96].

RMAT Benefits include all features of the Fast Track and Breakthrough Therapy designation programs, including intensive guidance on efficient drug development program beginning as early as Phase 1 [91] [95]. The program allows for discussion of potential surrogate or intermediate endpoints to support accelerated approval and enables a rolling review of the Biologics License Application (BLA) [95]. Sponsors receive early interactions to discuss potential pathways to accelerated approval, including study design and use of intermediate endpoints [95].

Sakigake Benefits include enhanced consultation and priority consultation services, with PMDA providing designated consultation windows and priority review that aims to reduce approval time by several months [92] [93]. The program offers a total development time of Sakigake-designated products of the shortest class, with PMDA providing a dedicated contact person for designated products [93]. Additionally, products may qualify for conditional/time-limited approval that allows marketing authorization while confirmatory data is collected [92].

Table 2: Program Benefits and Support Mechanisms

Benefit Type	PRIME	RMAT	Sakigake
Regulatory Interaction	Enhanced dialogue; kick-off meeting; dedicated contact	Early interactions; senior FDA staff involvement	Designated consultation windows; dedicated contact
Development Support	Scientific advice; protocol assistance	Intensive guidance on development plan	Strategic consultation on development
Review Acceleration	Accelerated assessment (150 days)	Rolling BLA review; priority review	Priority review; reduced approval time
Approval Flexibility	Conditional marketing authorization	Accelerated approval based on surrogate endpoints	Conditional/time-limited approval (up to 7 years)
Organizational Commitment	Rapporteur; CAT involvement; senior management	OTAT/CBER senior staff involvement	PMDA priority handling

Application Procedures and Strategic Considerations

The application processes for these designation programs involve specific procedures, timelines, and strategic considerations that sponsors should understand when planning global development.

PRIME Application requires submission of a letter of intent 2-3 months before the intended submission, followed by a formal application with comprehensive data package [31] [91]. The process emphasizes the importance of early interaction, with recommendations to apply based on preliminary clinical evidence showing the product's potential to address unmet medical needs. For ATMPs specifically, engagement with the CAT through classification procedures is recommended to confirm ATMP status early in development [31].

RMAT Designation Request is submitted as part of an Investigational New Drug (IND) application or as an amendment to an existing IND [95]. The request should include information and data demonstrating that the product meets the criteria for RMAT designation, with preliminary clinical evidence forming the basis for the unmet medical need determination [95]. The FDA aims to respond to RMAT designation requests within 60 calendar days of receipt [95].

Sakigake Application involves confirmation of innovation and medical need, with PMDA evaluating whether the product represents significant innovation and whether Japan is likely to be among the first countries for the product's launch [93]. The process includes designation consultation, confirmation of target disease and medical need, and evaluation of the development plan [92]. Strategic considerations include alignment with Japanese healthcare priorities and planning for early launch in the Japanese market.

Table 3: Application Characteristics and Performance Metrics

Characteristic	PRIME	RMAT	Sakigake
Application Timing	Early clinical development	With IND or IND amendment	During clinical development
Designation Timeline	Not specified	Within 60 days	Varies based on consultation
Designation Rate	24.2% of requests granted [96]	38.3% of requests granted [96]	Limited data available
Review Timeline Reduction	40.8% of standard time [96]	~50% reduction possible [96]	Several months reduction
Key Strategic Factors	EU public health need; major therapeutic advantage	Serious condition; regenerative medicine focus	Innovation; early launch in Japan

Quantitative Analysis and Impact Assessment

Designation Trends and Outcomes

Analysis of designation patterns reveals regional priorities and program effectiveness. During the period from PRIME's launch in April 2016 to December 2020, the FDA received 700 Breakthrough Therapy designation requests while EMA had 348 requests for PRIME [91]. Among these, 151 requests were made to both programs, with the agencies reaching concordant outcomes (both granting or both denying) in 62% of cases (93/151) [91]. This suggests similar perspectives across international regulators on product potential.

Therapeutic area analysis shows oncology products represent the largest category across all programs, comprising 34% (52/151) of common PRIME-Breakthrough requests, followed by hematology (10%, 15/151) and neurology (9%, 13/151) [91]. This distribution reflects the significant unmet needs in these therapeutic areas and the innovative approaches being developed.

Timeline Acceleration and Development Efficiency

Accelerated programs significantly reduce development and review timelines. A comparative study of ATMP approvals found that designated products reached market authorization much faster than those following standard pathways [96]. Specifically, the study observed that designations improved approval times after submission by more than twofold, with designated products requiring only 41.5% of standard approval time for Breakthrough therapies, 40.8% for PRIME, and 30.3% for Sakigake [96].

When comparing approval times for submissions after 2014 only, the difference, while still significant, was less pronounced (51.8%, 53.7%, and 50.2% of standard time for Breakthrough, PRIME, and Sakigake, respectively), indicating general improvements in regulatory efficiency across all pathways [96]. The mean approval times for accelerated ATMPs were 6.8 months (US), 10.4 months (EU), and 6.1 months (Japan), demonstrating the substantial time savings achievable through these programs [96].

Experimental Protocols and Methodologies

Regulatory Interaction Protocols

Effective navigation of accelerated assessment pathways requires strategic regulatory interactions following established protocols.

PRIME Kick-off Meeting Protocol involves a multidisciplinary meeting attended by experts from the EU regulatory network, the Agency, and sponsor representatives [91]. The protocol includes:

• Meeting Preparation: Submission of comprehensive data package including non-clinical proof of concept, preliminary clinical data (if available), and proposed development strategy
• Discussion Framework: Structured dialogue focusing on key development challenges, regulatory requirements, and opportunities for acceleration
• Outcome Documentation: Formal meeting minutes and agreed-upon development strategy, including timelines for subsequent interactions

RMAT Early Interaction Protocol provides for discussions between FDA and sponsors concerning potential surrogate or intermediate endpoints [95]. The methodology includes:

• Endpoint Proposal: Sponsor submission of rationale for proposed surrogate or intermediate endpoints with supporting data
• Agency Assessment: FDA evaluation of the suitability of proposed endpoints for accelerated approval
• Agreement Documentation: Formal agreement on endpoints and post-marketing requirements if accelerated approval is granted

Sakigake Consultation Protocol involves a structured consultation process with PMDA [92]. The methodology includes:

• Innovation Assessment: Comprehensive evaluation of the product's innovative characteristics and potential medical impact
• Development Plan Review: Detailed discussion of the clinical development strategy tailored to the Japanese population
• Conditional Approval Planning: Strategic planning for potential conditional/time-limited approval pathway

Evidence Generation Methodologies

Accelerated pathways often employ innovative approaches to evidence generation that balance speed with scientific rigor.

PRIME Evidence Generation emphasizes early clinical proof of concept while maintaining robust standards [91]. The methodology may include:

• Use of biomarker data and pharmacodynamic endpoints in early clinical trials
• Strategic application of historical controls where appropriate
• Adaptive trial designs that enable efficient evaluation of multiple endpoints
• Early consultation on manufacturing quality and consistency

RMAT Evidence Generation leverages flexibility in clinical development while maintaining standards for safety and effectiveness [95]. Approaches include:

• Use of intermediate clinical endpoints reasonably likely to predict long-term clinical benefit
• Incorporation of real-world evidence where appropriate to supplement clinical trial data
• Novel clinical trial designs that may include basket trials or platform trials
• Strategic use of post-marketing requirements to confirm clinical benefit

Sakigake Evidence Generation focuses on efficient development tailored to the Japanese population [92]. Methods may include:

• Bridging strategies that leverage foreign clinical data
• Development of Japan-specific clinical data where necessary
• Strategic use of conditional approval with post-marketing surveillance
• Real-world data collection to supplement clinical evidence

Research Reagent Solutions for ATMP Development

The development of ATMPs for accelerated assessment pathways requires specialized research reagents and materials that ensure product quality, consistency, and compliance with regulatory standards.

Table 4: Essential Research Reagents and Materials for ATMP Development

Reagent/Material	Function	Application in ATMP Development
Cell Separation Media	Isolation of specific cell populations from source material	Preparation of autologous and allogeneic cell therapy products
Cell Culture Media	Support cell growth, expansion, and maintenance	Ex vivo expansion of therapeutic cell populations
Cryopreservation Solutions	Maintain cell viability during frozen storage	Preservation of cell-based products for transportation and storage
Vector Production Systems	Generation of viral vectors for gene delivery	Manufacturing of gene therapy products and genetically modified cell therapies
Cell Characterization Antibodies	Identification and quantification of cell surface markers	Quality control and potency assessment of final product
Cytokine and Growth Factor Cocktails	Direct cell differentiation and expansion	Generation of specific cell phenotypes for therapeutic application
Endotoxin Testing Kits	Detection of bacterial endotoxins	Safety testing of final product and raw materials
Mycoplasma Detection Assays	Screening for mycoplasma contamination	Safety testing throughout manufacturing process
Sterility Testing Media	Detection of microbial contamination	Final product release testing
Process-Related Impurity Assays	Detection of residuals from manufacturing process	Safety assessment and product characterization

The PRIME, RMAT, and Sakigake designation programs represent significant regulatory innovations designed to accelerate the development and approval of promising ATMPs addressing unmet medical needs. While each program reflects regional regulatory frameworks and priorities, they share common objectives of facilitating patient access to innovative therapies through enhanced regulatory guidance, accelerated assessment, and flexible approval pathways.

Understanding the similarities, differences, and strategic applications of these programs is essential for effective global development of ATMPs. Each program offers distinct advantages: PRIME provides comprehensive early development support through the CAT, RMAT offers regenerative medicine-specific flexibility in evidence requirements, and Sakigake enables conditional approval with post-marketing confirmation.

The increasing convergence in regulatory thinking is evidenced by the high rate of concordant decisions between agencies and the shared focus on addressing serious unmet medical needs. For sponsors pursuing global development, strategic engagement with these accelerated assessment pathways can significantly reduce time to market while maintaining appropriate standards for safety and efficacy.

As the ATMP field continues to evolve, these designation programs will play an increasingly important role in balancing the need for rigorous evaluation with the imperative to deliver innovative treatments to patients in a timely manner. Future developments will likely include greater international harmonization, increased use of real-world evidence, and more flexible approval pathways that maintain safety standards while accelerating access to beneficial therapies.

The Hospital Exemption (HE) clause represents a significant regulatory provision within the European Union's framework for Advanced Therapy Medicinal Products (ATMPs). Established under Regulation (EC) No 1394/2007, this pathway allows designated hospitals in EU member states to prepare, manufacture, and use non-routinely produced ATMPs without obtaining a centralized marketing authorization [97]. This exemption serves critical public health needs by addressing unmet medical demands for patients with rare conditions or those lacking satisfactory treatment alternatives, while simultaneously fostering academic innovation in cellular and genetic therapies that may not attract commercial investment due to limited market potential [97] [98].

The legal foundation for HE provisions primarily stems from two key legislative instruments: Article 3(7) of Directive 2001/83/EC and Article 28(2) of the ATMP Regulation [97]. These provisions establish that HE-approved ATMPs must be: (1) manufactured under specific quality standards; (2) used exclusively within a member state's designated hospital under the direct responsibility of a physician; and (3) prescribed for an individual patient following a personalized medical approach [97]. Importantly, HE-approved products cannot be manufactured in large quantities for broad distribution and are explicitly prohibited from cross-border trade between member states [97].

Despite these overarching EU-level frameworks, implementation varies substantially across member states, creating a complex regulatory landscape for researchers, manufacturers, and healthcare providers engaged in ATMP development and administration. This whitepaper examines these national variations within the broader context of research on national competent authorities for ATMP manufacturing licenses, providing technical guidance for professionals navigating this evolving field.

Core Requirements and Implementation Variations

Defining "Non-Routine" Conditions Across Member States

A fundamental requirement for HE eligibility is that ATMPs must be manufactured and used under "non-routine" conditions [97]. This concept prevents the exemption from being used as a backdoor route to market for products that should undergo the centralized authorization procedure. However, operationalizing this concept has proven challenging, with significant disparities in how member states interpret and apply this criterion.

Table: Comparative Definitions of "Non-Routine" Conditions in Select EU Member States

Member State	Definition of "Non-Routine"	Key Criteria	Quantitative Thresholds
Germany [97]	Small-scale production and limited usage	Production scale and usage frequency	No specific numerical threshold; assessed case-by-case based on risk-benefit analysis
United Kingdom [97]	Limited production scale and frequency	Manufacturing volume and regularity	No explicit formula; production scale and frequency considered as indicators
Netherlands [97]	Small-scale production of specific ATMP types	Autologous vs. allogeneic products; production scale	No specific numbers; autologous products and small-scale preparations considered "non-routine"
Other EU States [97]	Mostly undefined	Varies by national authority	Typically undefined

As illustrated in the table, only Germany, the United Kingdom, and the Netherlands have established formal definitions for "non-routine" conditions, while most other member states lack clear guidance [97]. This regulatory ambiguity creates significant challenges for multi-center research collaborations and consistent application of the HE pathway across the EU.

Manufacturing Quality Standards and Requirements

The ATMP Regulation mandates that HE-approved products must adhere to equivalent quality standards as centrally authorized ATMPs [97]. The European Medicines Agency (EMA) has published specific Good Manufacturing Practice (GMP) guidelines for ATMPs in 2017, but national implementations vary considerably in how these standards are applied to hospital-based manufacturing.

Table: Manufacturing Quality Standards for HE-ATMPs Across Select EU Member States

Member State	Manufacturing Site Requirements	GMP Application	Batch Release Specifications
Germany [97]	Hospital or external manufacturer with license	Follows EU ATMP GMP	Quality Responsible Person required
Netherlands [97]	Hospital or external manufacturer with license	Follows EU ATMP GMP	Qualified Person (QP) mandatory for verification and release
United Kingdom [97]	Hospital or external manufacturer with license	Follows EU ATMP GMP	Quality Control personnel may substitute for QP
France [97]	Strict separation; only licensed manufacturers (not hospitals)	Follows EU ATMP GMP	Standard pharmaceutical release requirements
Italy [97]	Information not specified in search results	Follows EU ATMP GMP	Information not specified in search results
Spain [97]	Hospital or external manufacturer with license	Follows EU ATMP GMP	Information not specified in search results
Sweden [97]	Hospital or external manufacturer with license	Follows EU ATMP GMP	Information not specified in search results

A critical divergence emerges in manufacturing site authorization, with most countries permitting hospital-based production under a manufacturing license, while France maintains strict separation between manufacturing and clinical use sites [97]. Similarly, batch release mechanisms differ, with some countries requiring a formal Qualified Person (QP) and others allowing alternative quality control personnel to perform release functions [97].

Pharmacovigilance and Safety Monitoring Requirements

Despite EU-level guidance mandating equivalent pharmacovigilance standards for HE-ATMPs and authorized products, member states have established disparate safety monitoring frameworks [97]. These differences impact reporting obligations, risk management planning, and long-term safety follow-up requirements.

Table: Pharmacovigilance Requirements for HE-ATMPs in Select EU Member States

Member State	Adverse Event Reporting	Additional Safety Measures	Reporting Personnel
Germany [97]	Annual safety reporting	Required pharmacovigilance system and risk management plan	License holder
United Kingdom [97]	Serious adverse reactions	Recording of all adverse reactions	Clinician/Practitioner
Spain [97]	Standard pharmacovigilance protocols	Designated pharmacovigilance contact person	Authorized medical institution
Netherlands, Sweden, Italy [97]	All adverse events	Regular safety updates and risk management evaluation	Dedicated reporting personnel

The Netherlands, Sweden, and Italy maintain the strictest reporting standards, requiring dedicated personnel to report all adverse events and conduct ongoing risk-benefit evaluations [97]. Meanwhile, the UK focuses reporting requirements specifically on serious adverse reactions, placing responsibility on treating clinicians [97]. Germany occupies a middle position with requirements for comprehensive quality management systems and periodic safety reporting [97].

Methodological Framework for HE Implementation Research

Research Protocol for Analyzing National HE Provisions

Studying the implementation variations of Hospital Exemption provisions requires a systematic methodological approach that enables comparative analysis across regulatory jurisdictions. The following research protocol outlines key procedures for investigating how national competent authorities interpret and apply HE requirements for ATMP manufacturing licenses:

Data Collection Methodology:

• Legislative Document Analysis: Identify and review primary legal texts including national laws, implementing regulations, and official guidance documents from each member state's competent authority [97].
• Structured Stakeholder Interviews: Conduct semi-structured interviews with regulatory affairs professionals, hospital-based manufacturers, and national authority representatives to elucidate practical implementation approaches.
• Comparative Legal Research: Apply principles of comparative law to identify patterns of convergence and divergence in how member states transposed EU-level HE requirements into national frameworks.
• Case Study Development: Document specific HE authorization cases to understand how abstract legal concepts (e.g., "non-routine") are operationalized in practice.

Analysis Framework:

• Thematic Analysis: Identify recurring themes and concepts across national implementations using coding techniques for qualitative data.
• Gap Analysis: Compare national provisions against EU-level requirements to identify implementation gaps or exceeding of requirements.
• Regulatory Coherence Assessment: Evaluate internal consistency within national frameworks and alignment with broader pharmaceutical legislation principles.

Research Methodology Workflow for Analyzing HE Implementation Variations

Experimental Protocols for HE Implementation Studies

Protocol 1: Comparative Analysis of National Legislative Frameworks

• Objective: Systematically identify and compare HE provisions across EU member states to map variations in implementation approaches.
• Data Sources: Primary legislation, regulatory guidelines, competent authority websites, and peer-reviewed literature [97] [98].
• Extraction Method: Develop standardized data extraction template capturing key parameters including definitions of "non-routine," manufacturing requirements, pharmacovigilance obligations, and authorization procedures.
• Analysis Method: Apply comparative law methodology to identify patterns, categorizing approaches based on regulatory flexibility, requirements stringency, and implementation consistency.

Protocol 2: Stakeholder Perspective Analysis

• Objective: Understand practical challenges and facilitators in HE implementation from diverse stakeholder viewpoints.
• Participant Recruitment: Purposeful sampling of regulatory affairs professionals, hospital manufacturers, clinicians, and patient representatives across multiple member states.
• Data Collection: Semi-structured interviews using interview guide developed from preliminary legislative analysis.
• Analysis Approach: Thematic analysis using both deductive (based on regulatory framework) and inductive (emerging from data) coding approaches.

Essential Research Tools for HE Implementation Analysis

Table: Research Reagent Solutions for HE Regulatory Analysis

Research Tool Category	Specific Examples	Function in HE Research	Application Notes
Primary Legal Sources	EU Directives 2001/83/EC, Regulation (EC) 1394/2007 [97]	Establish foundational legal framework	Provide baseline requirements against which national implementations can be compared
National Implementation Measures	German AMG, French Public Health Code, UK MHR 2012 [97]	Illustrate national transposition approaches	Critical for identifying variations in how EU framework is adapted nationally
Regulatory Guidance Documents	EMA GMP Guidelines for ATMPs (2017) [97]	Define quality standards	Provide technical specifications for manufacturing requirements across jurisdictions
Competent Authority Resources	National regulatory agency websites, authorization databases [97]	Source of implementation details	Often contain specific procedural requirements and application forms
Comparative Analysis Frameworks	Regulatory implementation assessment tools	Enable systematic cross-jurisdictional comparison	Facilitate identification of patterns and outliers in implementation approaches

Implications for ATMP Manufacturing License Research

The variations in HE implementation across EU member states have significant implications for research on national competent authorities and ATMP manufacturing licenses. These differences create a complex regulatory ecosystem that influences everything from research and development strategies to clinical application pathways and market authorization transitions.

The regulatory fragmentation observed in HE implementations presents challenges for multi-center trials and collaborative research initiatives [97]. Researchers developing ATMPs that might utilize the HE pathway must navigate divergent national requirements, increasing administrative burdens and potentially limiting patient access to innovative therapies. This variability particularly affects academic researchers and smaller biotechnology companies with limited regulatory affairs capacity.

Furthermore, the relationship between HE authorizations and full market authorization represents a critical consideration for drug development professionals. While the HE pathway provides valuable opportunities for clinical data generation in specialized patient populations, the transition from hospital-based exemption to centralized marketing authorization requires careful strategic planning [97]. The limited precedents for such transitions add uncertainty to long-term development planning for ATMP sponsors.

Regulatory Relationships and Research Implications of HE Implementation Variations

The implementation of Hospital Exemption provisions across EU member states demonstrates significant regulatory diversity despite common foundational principles established at the EU level [97]. These variations manifest most prominently in definitions of "non-routine" conditions, manufacturing quality standards, and pharmacovigilance requirements, creating a complex landscape for researchers and product developers [97].

For professionals engaged in ATMP research and development, understanding these national variations is essential for strategic planning and regulatory compliance. The comparative analysis presented in this whitepaper provides a framework for assessing specific national requirements and developing implementation strategies that accommodate jurisdictional differences while maintaining product quality and patient safety.

Future evolution of HE implementations will likely be influenced by ongoing efforts to harmonize regulatory approaches across the EU while preserving appropriate flexibility to address specific national healthcare system needs and patient access considerations. Researchers and regulatory professionals should monitor these developments closely as they navigate the dynamic landscape of advanced therapy medicinal product development and authorization.

International Regulatory Convergence and Harmonization Efforts

International regulatory convergence and harmonization represent a critical paradigm shift in the global pharmaceutical landscape, particularly for Advanced Therapy Medicinal Products (ATMPs). This process involves the alignment of technical requirements for pharmaceutical development and marketing across international jurisdictions [99]. For researchers, scientists, and drug development professionals working with ATMPs, understanding these harmonization efforts is essential for navigating the complex regulatory pathways associated with manufacturing licenses across different competent authorities.

The globalization of pharmaceutical manufacturing and distribution has made regulatory harmonization not just beneficial but necessary. Divergent regulatory requirements create significant barriers to efficient product development, leading to approval delays, increased costs, and ultimately impeded patient access to innovative therapies [100]. Regulatory harmonization addresses these challenges by promoting common standards, reducing redundant testing, and fostering collaboration among international regulatory bodies.

For ATMP manufacturers seeking approvals across multiple regions, understanding the current state of regulatory convergence is particularly crucial. These complex biological products present unique challenges that require specialized regulatory approaches, and the evolving harmonization landscape directly impacts manufacturing license requirements, quality control systems, and market authorization pathways [38].

Key International Harmonization Initiatives

Major International Organizations and Their Roles

Table 1: Key International Regulatory Harmonization Organizations

Organization	Acronym	Primary Focus	Key Activities	Relevance to ATMPs
International Council for Harmonisation	ICH	Pharmaceutical technical requirements	Develops safety, efficacy, quality, and multidisciplinary guidelines	Harmonized requirements for product development and registration [99]
International Medical Device Regulators Forum	IMDRF	Medical device regulations	Standardized submission formats, post-market surveillance, emerging technologies	Regulation of combination ATMPs and medical devices [100]
International Pharmaceutical Regulators Programme	IPRP	Pharmaceutical regulatory convergence	Information exchange, regulatory best practices, harmonization projects	Multilateral forum addressing global regulatory challenges [99]
Pharmaceutical Inspection Co-operation Scheme	PIC/S	Good Manufacturing Practice (GMP)	Harmonizes inspection procedures, develops common GMP standards	GMP compliance for manufacturing facilities [99]
International Coalition of Medicines Regulatory Authorities	ICMRA	Strategic regulatory coordination	Executive-level forum addressing emerging challenges, crisis management	High-level coordination for complex products like ATMPs [99]

Recent Developments in Harmonization (2024-2025)

The regulatory harmonization landscape continues to evolve rapidly, with several significant developments in 2024-2025:

ICH Initiatives: In January 2025, ICH adopted the E6(R3) guideline on Good Clinical Practice (GCP), modernizing the clinical trial framework to incorporate technological advancements and emphasize risk-based approaches [100]. The upcoming ICH General Assembly in May 2025 in Madrid is expected to address ongoing Good Manufacturing Practice (GMP) harmonization efforts [100].

IMDRF Advances: The March 2025 IMDRF Management Committee Meeting in Tokyo focused on enhancing regulatory efficiency and convergence, with particular attention to standardized submission formats and post-approval change management [100]. IMDRF released two pivotal guidance documents in early 2025: "Good Machine Learning Practice for Medical Device Development: Guiding Principles" and "Characterization Considerations for Medical Device Software and Software-Specific Risk" [100].

WHO Activities: The World Health Organization continues to support global regulatory convergence through collaborative networks, harmonized technical requirements, and frameworks for joint evaluations of application dossiers and manufacturing site inspections [100].

Regional Regulatory Frameworks for ATMPs

Comparative Analysis of Regulatory Systems

Table 2: Regional Regulatory Systems for Advanced Therapies

Region	Legal Framework	Key Personnel	Manufacturing License Requirements	Product Specifics for ATMPs
European Union	Directive 2001/83/EC, ATMP Regulation	Qualified Person (QP)	GMP compliance verified through mandatory inspections	Specific GMP guidelines for ATMPs [38] [101]
United States	PHS Act Section 351, 21 CFR Parts 210 & 211	Quality Unit	Phase-appropriate GMP with pre-license inspection	Graduated GMP approach for biological products [38] [101]
Japan	Pharmaceuticals and Medical Devices Act (PMD Act)	Marketing Director, Quality Assurance Manager, Safety Management Manager ("San-yaku")	GQP, GVP, and GCTP requirements	Separate Manufacturing Manager for cell-based products [101]
Taiwan	Regenerative Medicinal Products Act	Responsible Person (with pharmacist license)	GMP implementation with resident monitor	Manufacturing and quality system supervision [101]
China	Drug Administration Law, Marketing Authorization Holder system	Quality Authorized Person	Quality management system with full-time quality personnel	Product release responsibility [102]

Regional Harmonization Efforts

African Medicines Regulatory Harmonization (AMRH): A landmark achievement was realized in early 2025 with full regional regulatory harmonization in Africa. The North Africa Medicines Regulatory Harmonization (NA-MRH) Initiative now focuses on critical regulatory functions including marketing authorization, GMP, quality management systems, pharmacovigilance, and information management systems [100].

United Kingdom's Post-Brexit Alignment: The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has been actively working to align with international standards to remain competitive globally, including increasing harmonization with ICH guidelines and providing clarity for companies navigating both UK and global markets [100].

Asia-Pacific Economic Cooperation (APEC): FDA participates in the Regulatory Harmonization Steering Committee (RHSC) under APEC's Life Sciences Innovation Forum (LSIF), which focuses on developing tools and delivering training on drug regulatory best practices and internationally harmonized guidelines [99].

Technical Requirements for ATMP Manufacturing Licenses

Chemistry, Manufacturing, and Controls (CMC) Requirements

The CMC requirements for ATMPs represent a critical aspect of manufacturing license applications across international jurisdictions. The European Medicines Agency's guideline on clinical-stage ATMPs, which came into effect in July 2025, provides a comprehensive multidisciplinary reference document that consolidates information from over 40 separate guidelines and reflection papers [38].

The organizational framework for CMC information in regulatory submissions generally follows the Common Technical Document (CTD) format, with Module 3 containing the quality data. However, terminology differences persist between regions - the EMA refers to CTD sections 3.2.S and 3.2.P as "Active substance" and "Investigational medicinal product," while the same sections are referred to as "Drug substance" and "Drug product" in other jurisdictions [38].

Quality Management Systems

Quality management systems for ATMP manufacturing must address several critical areas:

Allogeneic Donor Eligibility Determination: Significant differences exist between regulatory approaches to allogeneic donor screening. The EU provides limited general guidance through the ATMP guideline, reminding manufacturers that testing must comply with relevant EU and member state-specific legal requirements [38]. In contrast, the FDA is more prescriptive, specifying relevant communicable disease agents, testing methodologies, laboratory qualifications, and restrictions on pooling human cells or tissues from multiple donors [38].

GMP Compliance Expectations: The EU mandates GMP compliance through mandatory self-inspections with documented evidence of effective quality systems [38]. The U.S. employs a graduated, phase-appropriate approach to GMP compliance, relying on attestation in early development stages with verification through pre-license inspections at the time of biologics license application review [38].

Diagram 1: ATMP Quality Management System Framework

Product Characterization and Testing

ATMP manufacturers must conduct comprehensive product characterization and testing throughout development and production:

Potency Assays: Developers must establish relevant and validated potency assays that measure the biological activity of ATMPs. These assays should reflect the product's mechanism of action and provide meaningful data on product potency.

Identity and Purity Tests: Identity tests must be specific for the ATMP and distinguish it from other products. Purity tests should address process-related and product-related impurities, with established acceptance criteria.

Safety Testing: Safety testing includes sterility, mycoplasma, endotoxin, and adventitious agent testing. The testing strategy should be appropriate for the stage of development and the specific characteristics of the ATMP.

Experimental Protocols for Regulatory Alignment

Methodology for Comparative Regulatory Analysis

Researchers and manufacturers can employ systematic approaches to analyze regulatory requirements across jurisdictions:

Step 1: Regulatory Mapping Identify all applicable regulations, guidelines, and standards for the ATMP across target markets. This includes classification requirements, approval pathways, and specific technical requirements.

Step 2: Gap Analysis Compare technical requirements between regions to identify significant differences in CMC, non-clinical, and clinical expectations. Prioritize gaps based on potential impact on development timelines and costs.

Step 3: Convergence Assessment Evaluate areas where regulatory convergence has been achieved and where significant divergence remains. Focus on recent harmonization initiatives that may affect requirements.

Step 4: Strategy Development Create a comprehensive regulatory strategy that addresses requirements across multiple jurisdictions while identifying opportunities to leverage harmonized standards.

Protocol for Manufacturing License Applications

A standardized approach to manufacturing license applications can facilitate regulatory review across multiple jurisdictions:

Documentation Preparation: Prepare quality documents according to CTD format, ensuring comprehensive coverage of manufacturing process, quality controls, and validation data. Include region-specific requirements as necessary.

Quality System Implementation: Establish a robust quality system that meets the requirements of all target markets. Implement comprehensive documentation practices, change control procedures, and deviation management systems.

Pre-Submission Engagement: Utilize regulatory mechanisms for early feedback, such as FDA's pre-submission program and EMA's scientific advice procedures. Engage with regulators to discuss development plans and address potential issues.

Submission and Lifecycle Management: Submit applications according to regional requirements while maintaining consistency in scientific content. Implement effective post-approval change management systems to manage variations across jurisdictions.

The Scientist's Toolkit: Regulatory Research Essentials

Key Research Reagent Solutions for ATMP Development

Table 3: Essential Research Materials for ATMP Regulatory Compliance

Reagent/Material	Function in ATMP Development	Regulatory Considerations	Quality Standards
Reference Standards	Qualification of analytical methods, product comparability	Well-characterized with established traceability	Highest available quality (USP, EP, BP) with certificate of analysis
Cell Lines	Manufacturing of cell-based therapies, product characterization	Comprehensive characterization, genetic stability, microbial contamination	Master Cell Bank and Working Cell Bank systems with thorough characterization
Critical Raw Materials	Component of manufacturing process, formulation excipient	Vendor qualification, quality testing, change control	Animal-origin free, recombinant where possible, GMP-grade
Analytical Reagents	Product testing, quality control, release testing	Qualified for intended use, stability data	Appropriate grade with documented quality attributes
Culture Media/Supplements	Cell expansion, product manufacturing	Composition consistency, qualification testing	Defined formulations with minimal lot-to-lot variability

Regulatory Documentation Requirements

The regulatory documentation for ATMP manufacturing licenses requires several essential components:

Quality Overall Summary: A comprehensive summary of the quality aspects of the application, providing a detailed overview of the manufacturing process, product characterization, and control strategies.

Manufacturing Process Description: A detailed description of the manufacturing process, including all steps from raw materials to final product, with in-process controls and process validation data.

Control of Materials: Comprehensive information on the quality and controls for all materials used in manufacturing, including raw materials, reagents, components, and starting materials.

Product Characterization Data: Thorough characterization of the ATMP, including physicochemical properties, biological activity, purity, impurities, and contaminants.

Stability Data: Data demonstrating the stability of the ATMP under recommended storage conditions, supporting the proposed shelf life and storage conditions.

Implementation Challenges and Future Directions

Current Challenges in Regulatory Convergence

Despite significant progress in regulatory harmonization, several challenges remain for ATMP manufacturers:

Persisting Divergence in Technical Requirements: While substantial convergence has occurred in many areas, significant differences remain in specific technical requirements, such as donor eligibility determination, GMP implementation approaches, and expectations for comparability and potency testing [38].

Regional Legal Frameworks: Differences in legal frameworks and regulatory philosophies create inherent challenges for complete harmonization. Regional requirements based on legal mandates may continue to create divergence despite technical alignment.

Emerging Technologies: Rapidly evolving technologies such as gene editing, machine learning-enabled devices, and novel cellular therapies present new challenges for regulatory alignment as authorities develop appropriate frameworks.

Future Directions in Harmonization

The future of regulatory harmonization for ATMPs is likely to focus on several key areas:

Enhanced International Collaboration: Regulatory authorities are increasingly participating in international collaborative initiatives to address the global nature of pharmaceutical development and manufacturing. Forums such as ICMRA provide opportunities for high-level coordination on emerging issues [99].

Adaptive Regulatory Frameworks: Regulatory systems are evolving toward more adaptive approaches that can accommodate rapid technological advances while maintaining appropriate oversight and protecting patient safety.

Reliance and Recognition Mechanisms: There is growing interest in developing more efficient regulatory approaches through mutual recognition and reliance mechanisms, where regulators leverage work conducted by trusted counterparts.

Digital Transformation: Regulatory authorities are increasingly adopting digital tools and platforms to streamline processes, enhance collaboration, and improve regulatory efficiency. This includes standardized electronic submissions, data standards, and digital collaboration platforms.

Diagram 2: International Regulatory Convergence Framework

International regulatory convergence and harmonization efforts for ATMP manufacturing licenses represent an ongoing and dynamic process. While significant progress has been achieved through organizations such as ICH, IMDRF, and various regional initiatives, divergence persists in specific technical requirements and implementation approaches.

For researchers, scientists, and drug development professionals, understanding this complex landscape is essential for developing effective global regulatory strategies. By leveraging harmonized guidelines while addressing region-specific requirements, manufacturers can optimize their development approaches and facilitate efficient access to innovative ATMPs for patients worldwide.

The continued evolution of regulatory harmonization initiatives will likely focus on enhancing collaboration, developing adaptive frameworks for emerging technologies, and implementing more efficient regulatory processes. Engagement with these initiatives by all stakeholders, including regulators, industry, and academic researchers, will be critical to advancing these goals and ensuring that regulatory systems keep pace with scientific innovation while maintaining their fundamental focus on product quality, safety, and efficacy.

The field of Advanced Therapy Medicinal Products (ATMPs) is undergoing a transformative shift from traditional centralized production toward decentralized manufacturing models. This evolution is driven by the need to improve patient access to personalized therapies, particularly for autologous products with limited shelf lives, and to address critical manufacturing capacity constraints [103]. Decentralized Manufacturing (DM) is an overarching term for innovative approaches where products are manufactured across multiple locations under a centralized regulatory and quality oversight system, fundamentally changing how these therapies are produced and regulated [104].

This shift represents a significant advancement in regulatory science, requiring novel frameworks that maintain the stringent quality, safety, and efficacy standards of traditional manufacturing while enabling production closer to patients. The development of these frameworks marks a critical area of focus for National Competent Authorities (NCAs) worldwide, who must balance innovation with patient protection [105] [104]. This technical guide examines the current landscape, regulatory frameworks, implementation strategies, and future directions for decentralized manufacturing of ATMPs, providing researchers and drug development professionals with comprehensive insights into this evolving paradigm.

Current Landscape and Driving Forces

The Capacity Challenge in ATMP Manufacturing

The transition toward decentralized manufacturing is largely driven by serious capacity constraints in traditional centralized manufacturing models. Current cell and gene therapy manufacturing is experiencing a severe "capacity crunch," with estimates indicating a shortage of approximately 500% at commercial levels [103]. Although approximately 90% of developers prefer using Contract Manufacturing Organizations (CMOs), current CMO capacity remains insufficient to meet demand, with lead times for new projects often exceeding 18 months [103].

Centralized manufacturing presents particular challenges for autologous therapies, where patient-specific starting materials must be transported to manufacturing facilities and the final product shipped back to the treatment center. This process involves complex logistics, is time-consuming, and may delay the application of cell therapies to patients in need [103]. The intrinsic variability of patient-specific starting materials and the resulting therapeutic products further complicate standardized manufacturing approaches [103].

Defining the Decentralized Manufacturing Framework

Decentralized manufacturing encompasses several related concepts and terminologies, which are summarized in the table below.

Table 1: Terminology in Decentralized Manufacturing

Term	Definition	Key Characteristics
Decentralized Manufacturing [104]	Overarching term for manufacturing across multiple sites under central management	"Scale-out" rather than "scale-up" approach
Point of Care (POC) [105]	Manufacturing at or near where the product is administered	For products that "can only be manufactured" near the patient due to short shelf-life
Modular Manufacturing (MM) [105]	Decentralized, relocatable manufacturing that could be done in a factory but is deployed for specific reasons	Necessitated by "reasons relating to deployment"
Control Site [103]	Central site responsible for regulatory compliance and oversight of decentralized sites	Holds manufacturing authorization and maintains master files

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has been at the forefront of establishing a comprehensive regulatory framework for DM, which came into force in July 2025 [104]. This framework introduces two new license types: "manufacturer's license (modular manufacturing)" and "manufacturer's license (Point of Care)" [103].

Regulatory Frameworks and Implementation

Evolving Regulatory Landscape

Regulatory agencies worldwide are developing frameworks to accommodate decentralized manufacturing while maintaining rigorous quality standards. The MHRA's 2025 framework represents the first comprehensive regulatory approach specifically designed for these innovative manufacturing models [104]. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) are also actively developing approaches, with the FDA's Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative exploring distributed manufacturing platforms that can be deployed to multiple locations [103].

The MHRA's framework is built on three fundamental pillars of readiness:

• Regulatory Readiness: Development of new regulations and guidance documents by regulatory agencies [104]
• Institutional Readiness: Preparation of healthcare providers and related organizations to implement DM [104]
• Technical Readiness: Development of suitable manufacturing and testing procedures by innovators for deployment in novel locations [104]

The Designation Process and Regulatory Pathways

A critical component of the MHRA's DM framework is the designation step, where sponsors must petition for evaluation of their product's suitability for DM [105]. This process requires justification anchored in clinical benefit, which may include improved clinical outcomes, equity of access, and timeliness of treatment, particularly for conditions with narrow clinical windows of eligibility [104]. Convenience and cost reduction alone are not considered sufficient justifications [105].

The designation process can yield two possible outcomes:

• Point of Care (POC) Designation: For products with short shelf lives that "can only be manufactured" at or near the patient [105]
• Modular Manufacturing (MM) Designation: For products requiring decentralized, relocatable manufacture due to deployment reasons [105]

The MHRA has published seven specific guidances to support implementation of DM, covering designation, marketing authorization applications, clinical trial authorization, pharmacovigilance, good manufacturing practices, labeling, and comprehensive regulations [105].

Table 2: MHRA's Guidance Framework for Decentralized Manufacturing

Guidance Area	Key Focus Areas	Application Timeline
Designation Step [105]	Evaluation of product suitability for POC or MM	Preliminary decision: 30 days; Full approval: 60 days
Marketing Authorization [105]	Emphasis on process validation and comparability	Requires prior designation
Clinical Trial Authorization [105]	Control site designation, blinding procedures, real-time release testing	Reference to DM designation required
Good Manufacturing Practices [105]	Quality Management System, oversight of remote sites, DMMF	Regular inspections of control site
Pharmacovigilance [105]	Enhanced product traceability, risk management plans	Product registry maintenance
Labelling [105]	Standard requirements with limited exceptions for immediate use	POC products for immediate administration
Comprehensive Regulations [105]	Detailed legislation for commercial and investigational products	47-page guidance covering all aspects

Quality Management and Regulatory Oversight

Implementing a robust Quality Management System (QMS) is fundamental to successful decentralized manufacturing. The proposed model features a Control Site that serves as the regulatory nexus, maintaining responsibility for oversight of all decentralized manufacturing sites [103]. This Control Site must hold an appropriate manufacturing license and is responsible for maintaining Decentralised Manufacturing Master Files (DMMF) that provide detailed instructions for manufacturing at decentralized sites [104] [103].

The QMS must ensure comparability across all manufacturing sites, demonstrating that the same quality product is manufactured regardless of location [103]. This is particularly challenging given the biological variability inherent in ATMPs, especially autologous products. Strategies to ensure comparability include:

• Implementation of automated, closed-system technologies to minimize process variability [103]
• Standardized training programs across all manufacturing sites [103]
• Robust process validation and real-time release testing [105]
• Comprehensive quality agreements between the Control Site and decentralized locations [104]

Diagram: Regulatory Oversight Model for Decentralized Manufacturing

Implementation Strategies and Technical Considerations

Manufacturing Platform Technologies

Successful implementation of decentralized manufacturing requires technological solutions that minimize variability while maintaining product quality. Closed-system automated manufacturing platforms are particularly valuable as they reduce infrastructure requirements at treatment facilities and minimize operator-dependent variability [103]. These systems can be deployed as prefabricated units allowing quick expansion, creating standardized GMP manufacturing platforms across multiple locations [103].

The concept of "GMP-in-a-box" describes integrated systems that enable manufacturing in lower-grade cleanrooms, making DM feasible in diverse healthcare settings [103]. These systems typically incorporate:

• Automated, closed-system processing units
• Integrated environmental monitoring
• Real-time quality control testing capabilities
• Digital connectivity for data transfer to the Control Site

The Scientist's Toolkit: Essential Technologies for DM

Table 3: Key Research Reagent Solutions and Technologies for Decentralized Manufacturing

Technology Category	Specific Solutions	Function in DM Implementation
Automated Manufacturing Platforms [103]	Closed-system bioreactors, automated cell processing systems	Reduces operator-dependent variability, enables deployment in diverse settings
Real-Time Release Testing [105]	Rapid sterility testing, potency assays, molecular characterization	Enables product release without extended stability, critical for POC products
Digital Infrastructure [28]	Data management systems, blockchain for chain of identity	Ensures data integrity and product traceability across multiple sites
Cold Chain Technologies [28]	Temperature monitoring devices, specialized shipping containers	Maintains product quality during transport between sites
Quality Control Assays [28]	Mycoplasma testing, endotoxin detection, viability assays	Ensures product safety and quality compliance at multiple locations

Process Validation and Comparability Protocols

Demonstrating comparability between manufacturing sites is a fundamental regulatory requirement for DM [103]. A risk-based approach to comparability assessment should be implemented, focusing on Critical Quality Attributes (CQAs) most susceptible to process variations [28]. The FDA recommends a tiered approach for reporting changes between sites, while the EMA emphasizes the need for extended analytical characterization [28].

The validation strategy for DM should include:

• Process Performance Qualification at multiple manufacturing sites
• Extended characterization of products from different sites
• Staged implementation with rigorous monitoring during initial deployment
• Continuous verification through statistical process control

Manufacturing processes must be designed to accommodate the inherent variability of biological starting materials while ensuring consistent output quality. This is particularly challenging for autologous therapies, where each batch originates from a different donor [103].

Emerging Trends and Development Areas

The field of decentralized manufacturing for ATMPs continues to evolve rapidly, with several key areas of development emerging. Artificial intelligence (AI) technologies are being explored to address monitoring concerns, automation, and data management in distributed manufacturing networks [28]. Organoid technology provides more accurate disease models for product testing and validation across multiple sites [28].

International harmonization of DM frameworks remains limited, with regional differences in stability testing requirements and reporting standards [28]. The MHRA has acknowledged the importance of international engagement to support interoperability of DM frameworks across different territories [104]. As more regions develop their approaches, alignment between regulatory systems will be essential for global implementation of DM.

Regulatory Science Implications

Decentralized manufacturing represents a significant advancement in regulatory science, requiring new approaches to oversight and compliance. The control site model, with centralized regulatory responsibility for distributed manufacturing operations, offers a promising framework for maintaining quality standards while enabling scale-out manufacturing [103].

National Competent Authorities face the challenge of developing inspection approaches that effectively evaluate control systems across multiple sites without requiring individual inspection of every location [104]. The MHRA has indicated that during inspections, authorities may examine a selection of remote sites rather than all locations, placing greater emphasis on the control site's oversight systems [105].

Post-authorization monitoring of ATMPs manufactured through decentralized approaches will require enhanced pharmacovigilance systems capable of detecting potential site-specific variations in safety or efficacy [105]. Real-world data (RWD) collection will play an increasingly important role in understanding the long-term performance of these therapies, with regulators increasingly imposing RWD-based post-authorization measures to address benefit-risk uncertainties [106].

Decentralized manufacturing represents a paradigm shift in ATMP production, offering solutions to critical capacity constraints and logistical challenges. The development of comprehensive regulatory frameworks, particularly the MHRA's 2025 regulations, provides a foundation for implementing these innovative approaches while maintaining rigorous quality standards.

Successful implementation requires robust quality management systems, appropriate technological platforms, and careful attention to comparability across manufacturing sites. As the field evolves, ongoing collaboration between industry, regulators, and healthcare providers will be essential to refine these approaches and ensure that patients benefit from timely access to these transformative therapies.

The transition to decentralized manufacturing models marks an important evolution in regulatory science, demonstrating how adaptive frameworks can support innovation while protecting public health. For researchers and drug development professionals, understanding these trends is essential for navigating the future landscape of ATMP development and commercialization.

Conclusion

Securing an ATMP manufacturing license from National Competent Authorities requires navigating a complex, evolving regulatory landscape that balances innovation with patient safety. Success hinges on understanding the foundational EU regulatory framework, meticulously preparing the methodological application with robust CMC documentation, proactively addressing unique ATMP manufacturing challenges through advanced quality control systems, and leveraging international regulatory insights. As ATMP technologies advance, regulatory science continues to evolve with emerging trends including point-of-care manufacturing frameworks, increased international harmonization, and adaptive pathways for highly individualized therapies. Researchers and developers who engage early and consistently with NCAs throughout the development process will be best positioned to accelerate the delivery of these transformative therapies to patients while maintaining the highest standards of quality and safety.

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