ATMP Manufacturing Authorization in the EU: A Complete Guide to GMP Compliance and Regulatory Strategy

Abstract

This guide provides researchers, scientists, and drug development professionals with a comprehensive overview of the European Union's regulatory landscape for Advanced Therapy Medicinal Product (ATMP) manufacturing. It covers the foundational legal requirements, detailed Good Manufacturing Practice (GMP) methodologies, strategies to overcome common production challenges, and pathways for regulatory validation. The content synthesizes current EU regulations, including the latest 2025 proposed GMP revisions, and practical insights to navigate the centralized authorization process, optimize manufacturing operations, and ensure compliance from clinical trials to market approval.

What is an ATMP? Understanding the EU Regulatory Foundation and Legal Framework

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of biologically derived therapies that differ fundamentally from conventional pharmaceuticals. These innovative medicines are based on genes, cells, or tissues and offer new therapeutic avenues for diseases with limited treatment options, including genetic disorders, cancer, and chronic degenerative conditions [1]. The European Medicines Agency (EMA) categorizes ATMPs into three primary types, plus a combination category: gene therapy medicines, somatic-cell therapy medicines, tissue-engineered medicines, and combined ATMPs [2]. From a regulatory perspective, ATMPs are considered full-fledged medicinal products but are governed by specific regulations that address their distinctive characteristics alongside general pharmaceutical rules [1]. The foundational regulation for these products is Regulation (EC) 1394/2007, which established specific requirements for their authorization, supervision, and pharmacovigilance [1].

Core Categories of ATMPs

Gene Therapy Medicinal Products (GTMPs)

Gene Therapy Medicinal Products contain genes that lead to a therapeutic, prophylactic or diagnostic effect. These products work by inserting 'recombinant' genes into the body, typically created in the laboratory by bringing together DNA from different sources [2]. GTMPs are primarily developed to treat a variety of diseases, including genetic disorders, cancer or long-term diseases by addressing the underlying genetic cause [2]. The fundamental mechanism involves delivering genetic material into a patient's cells to compensate for abnormal genes or to make a beneficial protein, offering potential one-time treatments for previously incurable conditions.

Somatic-Cell Therapy Medicinal Products

Somatic-cell therapy medicines contain cells or tissues that have been manipulated to change their biological characteristics. These products may also consist of cells or tissues not intended to be used for the same essential functions in the body [2]. These therapeutic cellular preparations are used to cure, diagnose or prevent diseases through mechanisms that may include immune modulation, tissue repair, or direct replacement of damaged cells [2]. The "somatic" designation indicates that these therapies use non-reproductive cells, excluding germline modifications that would be heritable. These products often involve extensive manipulation of cells outside the body before administration to patients.

Tissue-Engineered Medicinal Products

Tissue-engineered medicines contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue [2]. These products typically combine cells with scaffolds or matrices to create functional tissues that can restore damaged anatomical structures. Unlike somatic-cell therapies that may act through secretory or immunomodulatory mechanisms, tissue-engineered products are specifically designed to reconstruct or replace histological organization, making them particularly valuable for wound healing, orthopedic applications, and organ repair.

Combined Advanced Therapy Medicinal Products

Some ATMPs may contain one or more medical devices as an integral part of the medicine, referred to as combined ATMPs [2]. A representative example is cells embedded in a biodegradable matrix or scaffold [2]. In these combination products, the medical device component typically provides structural support, delivery mechanism, or a specific microenvironment that enables the biological component to function effectively. The regulatory assessment of these products requires evaluation of both the biological active substance and the medical device components, including their interactions.

Table 1: Core Categories of Advanced Therapy Medicinal Products (ATMPs)

ATMP Category	Key Components	Primary Mechanism of Action	Therapeutic Applications
Gene Therapy Medicinal Products (GTMPs)	Recombinant genes created by bringing together DNA from different sources [2]	Insertion of genes leading to therapeutic, prophylactic or diagnostic effect [2]	Genetic disorders, cancer, long-term diseases [2]
Somatic-Cell Therapy Medicinal Products	Cells or tissues that have been manipulated to change their biological characteristics [2]	Cure, diagnose or prevent diseases through cellular actions [2]	Cancer immunotherapy, regenerative medicine
Tissue-Engineered Medicinal Products	Cells or tissues modified to repair, regenerate or replace human tissue [2]	Repair, regeneration or replacement of human tissue [2]	Wound healing, orthopedic repairs, organ replacement
Combined ATMPs	Cells or tissues combined with one or more medical devices as an integral part [2]	Structural support and biological function working together [2]	Complex tissue reconstruction requiring scaffold support

Regulatory Framework for ATMPs

The Centralized Authorization Procedure

All advanced therapy medicines in the European Union are authorized centrally via the European Medicines Agency (EMA), benefiting from a single evaluation and authorisation procedure that provides marketing authorization valid across all EU Member States [2] [1]. This centralized approach recognizes that these innovative technologies require harmonized oversight at the European level rather than fragmented national assessments. The authorization process involves a comprehensive evaluation of the product's quality, safety, and efficacy data, with particular attention to the specialized nature of these therapies.

The Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs within this framework [2]. This specialized committee provides the specific expertise needed to evaluate the complex characteristics of advanced therapies. During the assessment procedure, the CAT prepares a draft opinion on the quality, safety and efficacy of the advanced therapy medicine, which it sends to the Committee for Medicinal Products for Human Use (CHMP) [2]. The CHMP then adopts an opinion recommending or not recommending authorization by the European Commission, which makes the final decision [2].

Manufacturing Authorization and GMP Requirements

The manufacture of ATMPs in the European Union is subject to manufacturing authorisation, which any legal entity wishing to manufacture these products must obtain from the national competent authority of the Member State where they conduct manufacturing activities [3]. This authorization requires compliance with EU quality standards, specifically Good Manufacturing Practice (GMP) principles and guidelines, and the European Pharmacopeia [3]. To address the particular complexity of ATMPs, the European Commission has published detailed GMP guidelines specific to these products [3] [1].

The manufacturing process for ATMPs presents unique challenges, including the use of substances of human origin such as blood, tissues and cells, and difficulties with reproducibility when using live biological samples [3]. Additional complexities include maintaining sterility throughout manufacturing, managing extreme logistical complexity for autologous products, demonstrating comparability between production batches, and validating process consistency with limited batch sizes [3]. The regulatory framework acknowledges these challenges while maintaining rigorous quality standards.

ATMP Authorization Pathway: This diagram illustrates the interconnected regulatory pathway for Advanced Therapy Medicinal Products in the European Union, showing both manufacturing authorization (handled by national competent authorities) and marketing authorization (centrally managed by EMA/CAT).

Recent Regulatory Developments

The regulatory landscape for ATMPs continues to evolve with several significant developments. The EMA's Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials came into effect in July 2025 [4]. This comprehensive multidisciplinary reference document provides guidance on the structural organization and content expectations for clinical trial applications involving investigational ATMPs [4].

Additionally, May 2025 saw the EMA release a concept paper proposing revisions to Part IV of the EU Guidelines on Good Manufacturing Practice specific to ATMPs [5]. These proposed revisions focus on alignment with the revised Annex 1 on sterile medicinal products, integration of ICH concepts (Q9 for Quality Risk Management and Q10 for Pharmaceutical Quality System), and adaptation to technological advancements in ATMP manufacturing [5].

Another significant development is the adoption of Regulation (EU) 2024/1938 on quality and safety standards for substances of human origin (SoHO) intended for human application, published in July 2024 and applicable from 2027 [1]. This regulation replaces previous directives concerning blood, cells, and tissues and expands the regulatory scope to all human-origin substances (except solid organs for transplantation), addressing analogous safety and quality concerns [1].

Table 2: Key Regulatory Bodies and Their Roles in ATMP Oversight

Regulatory Body	Key Responsibilities	Significance for ATMP Development
Committee for Advanced Therapies (CAT)	Scientific assessment of ATMP quality, safety, efficacy; ATMP classification; certification for SMEs [2]	Provides specialized expertise for evaluating complex ATMP characteristics
National Competent Authorities	Issue manufacturing authorizations; conduct GMP inspections; supervise manufacturing sites [3]	Ensure compliance with quality standards at the member state level
European Medicines Agency (EMA)	Coordinate centralized authorization procedure; provide scientific support; publish guidelines [2] [3]	Harmonizes regulatory approach across EU member states
GMP/GDP Inspectors Working Group	Harmonize interpretation of GMP requirements; develop inspection procedures [3]	Ensures consistent application of manufacturing standards
European Commission	Grant marketing authorization based on scientific assessment; establish legal framework [2] [1]	Provides legally binding authorization for ATMPs in the EU market

ATMP Manufacturing Authorization: Key Considerations

Manufacturing Challenges and Complexities

ATMP manufacturing presents distinctive challenges that differentiate it from conventional pharmaceutical production. The use of substances of human origin composed of live cells with a short shelf life creates complex manufacturing and logistical challenges from the procurement of cellular starting material through to the final product's administration [3]. This biological variability introduces a degree of heterogeneity in the finished product that must be carefully controlled and characterized.

Additional challenges include high production and development costs due to the need for specialized premises, equipment, skilled personnel, and rigorous monitoring systems [3]. For autologous cell therapies, the manufacturing model requires scale-out rather than scale-up, with potential need for manufacturing at point-of-care [3]. Academic institutions and smaller companies often face particular challenges due to lack of qualified personnel, infrastructure, and capital for moving to late-phase studies [3].

The demonstration of comparability between production processes and batches presents another significant hurdle, particularly given the autologous nature of many products and small sample sizes that limit the number of analytical tests that can be performed [3]. These challenges necessitate sophisticated quality control strategies and potentially novel analytical approaches to ensure consistent product quality.

Quality Control and Analytical Methods

Ensuring the quality of ATMPs requires comprehensive analytical strategies addressing multiple product attributes. The following research reagent solutions represent essential materials and methods employed in ATMP development and quality control:

Table 3: Essential Research Reagent Solutions for ATMP Development and Quality Control

Research Reagent/Method	Function in ATMP Development	Application in Quality Control
Flow Cytometry Reagents	Characterization of cell surface and intracellular markers	Identity testing, purity assessment, impurity detection
PCR/qPCR Reagents	Detection and quantification of genetic elements	Vector copy number analysis, mycoplasma testing, viral clearance validation
Cell-based Potency Assays	Measurement of biological activity	Potency determination, lot release testing
Sterility Testing Media	Detection of microbial contaminants	Sterility testing for bacterial and fungal contamination
Endotoxin Testing Reagents	Detection of bacterial endotoxins	Pyrogenicity testing, safety assessment
Cytokine Detection Assays	Quantification of secretory factors	Functional assessment, safety profiling
Viability Staining Reagents	Determination of cell viability	Process optimization, product characterization

Decentralized Manufacturing and Point-of-Care Production

A significant development in ATMP manufacturing is the emergence of decentralized production models, particularly relevant for scaling-out production of autologous ATMPs [3]. Decentralized sites can be portable units allowing rapid adaptation on demand, or point-of-care manufacturing facilities such as hospitals, manufacturing nodes, or even patients' bedside [3]. The advantage of these approaches for ATMPs with limited shelf-life or limited options for storage and shipping is proximity to the patient [3].

The regulatory framework is adapting to accommodate these novel manufacturing approaches. The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions on decentralized production sites potentially near to the patient [3]. Specifically, Article 142 states that by derogation "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" [3]. This represents a significant evolution in regulatory thinking that acknowledges the practical realities of advanced therapy manufacturing while maintaining oversight through the qualified person system.

Advanced Therapy Medicinal Products represent a paradigm shift in therapeutic approaches, offering innovative treatment strategies for diseases with significant unmet medical needs. The precise classification of these products into gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs provides a framework for their regulatory oversight. The European Union has established a comprehensive regulatory pathway with specific requirements for ATMP manufacturing authorization that acknowledges both the transformative potential and unique challenges of these products. As the field continues to evolve, ongoing regulatory refinements—such as the new clinical trial requirements effective July 2025, proposed GMP revisions, and the upcoming SoHO Regulation—will continue to shape the development and manufacturing landscape for these groundbreaking therapies.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of medicines for human use that encompass gene therapy medicines, somatic cell therapy medicines, tissue-engineered medicines, and combined ATMPs [2]. These therapies offer revolutionary potential for treating various diseases and conditions through sophisticated mechanisms that involve genetic modification, cell manipulation, and tissue engineering. The European Union has established a comprehensive regulatory framework specifically designed to address the unique challenges posed by these innovative treatments while ensuring patient safety and product efficacy.

The core legal framework governing ATMPs consists primarily of Regulation (EC) No 1394/2007 and Directive 2001/83/EC, which together establish the requirements for ATMP classification, manufacturing authorization, and marketing authorization within the EU [6]. This framework recognizes that ATMPs are biologically complex products often based on live cells or tissues with limited shelf lives, requiring specialized manufacturing approaches and regulatory oversight [3]. The legislation aims to foster innovation while maintaining rigorous standards for quality, safety, and efficacy through a risk-based approach that acknowledges the distinctive characteristics of these products compared to conventional pharmaceuticals [7].

Regulation (EC) No 1394/2007: The ATMP Cornerstone

Scope and Definitions

Regulation (EC) No 1394/2007 provides the overarching regulatory framework specifically dedicated to Advanced Therapy Medicinal Products in the European Union [6]. This regulation created a tailored pathway for these complex therapies, recognizing that they did not fit perfectly within existing frameworks for conventional pharmaceuticals. The Regulation is directly applicable in all EU Member States, ensuring consistent implementation across the Union without requiring national transposition [8].

The Regulation establishes precise definitions for the different categories of ATMPs. It specifically defines 'tissue-engineered product' and 'combined ATMP', while referencing Directive 2001/83/EC for definitions of 'gene-therapy medicinal product' and 'somatic cell-therapy medicinal product' [6]. This comprehensive categorization system enables proper classification of diverse advanced therapies based on their biological composition and intended mechanism of action.

Key Provisions and Institutional Framework

Regulation (EC) No 1394/2007 introduced several critical innovations to the European regulatory landscape for medicines. Foremost among these was the establishment of the Committee for Advanced Therapies (CAT) at the European Medicines Agency [6]. The CAT serves as a multidisciplinary committee with primary responsibility for assessing the quality, safety, and efficacy of ATMPs [2]. Its composition ensures that applications for marketing authorization benefit from specialized expertise in the complex scientific and technical aspects of advanced therapies.

The Regulation also amended existing legislation, including Directive 2001/83/EC and Regulation (EC) No 726/2004, to incorporate ATMP-specific requirements [6]. Furthermore, it established procedures for certification of quality and non-clinical data specifically for micro-, small- and medium-sized enterprises (SMEs), recognizing the significant role these entities play in ATMP innovation [6]. This provision, outlined in Article 18 of the Regulation and detailed in Commission Regulation (EC) No 668/2009, offers SMEs a pathway to obtain regulatory feedback on their data without submitting a full marketing authorization application.

Table 1: Key Provisions of Regulation (EC) No 1394/2007

Provision	Scope	Legal Basis
ATMP Definitions	Est precise criteria for tissue-engineered products & combined ATMPs	Article 2
Committee for Advanced Therapies (CAT)	Creates specialized committee for ATMP assessment	Article 4-15
Centralized Authorization	Mandates centralized procedure for all ATMPs	Amends Regulation (EC) No 726/2004
SME Certification	Provides for certification of quality & non-clinical data for SMEs	Article 18
Classification Procedure	Establishes process for ATMP classification	Article 17

Directive 2001/83/EC: The Community Code Framework

Role in Regulating Medicinal Products

Directive 2001/83/EC establishes the Community code relating to medicinal products for human use in the European Union and serves as a foundational legal instrument for all medicinal products, including ATMPs [7]. While Regulation (EC) No 1394/2007 provides the specific framework for advanced therapies, Directive 2001/83/EC contains the core requirements and definitions that apply to all medicinal products, with Part IV containing specific provisions for ATMPs [7].

The Directive provides essential definitions for gene therapy medicinal products and somatic cell therapy medicinal products in Part IV of Annex I [6]. These definitions establish the legal criteria that determine whether a product falls within these categories and is therefore subject to the specific regulatory requirements for ATMPs. The definitions have been further refined through Commission Directive 2009/120/EC, which updated the scientific and technical requirements for gene therapy and somatic cell therapy medicinal products [6].

Manufacturing Authorization Requirements

Directive 2001/83/EC establishes the fundamental requirement that any legal entity manufacturing medicinal products in the EU must hold a manufacturing authorization issued by the national competent authority of the Member State where the manufacturing activities occur [3]. This requirement, articulated in Article 40 of the Directive, forms the legal basis for GMP compliance and regulatory oversight of manufacturing facilities.

The Directive mandates that all medicinal products for human use intended for the EU market must be manufactured in accordance with Good Manufacturing Practice (GMP) principles and guidelines, as well as the standards of the European Pharmacopeia [3]. Furthermore, it requires manufacturers to designate a Qualified Person responsible for ensuring that all applicable legislative requirements are met before products are released for distribution or use [3]. These foundational requirements apply equally to ATMPs, though with specific adaptations to address their unique characteristics.

Interplay Between the Framework Legislation

The relationship between Regulation (EC) No 1394/2007 and Directive 2001/83/EC is complementary and integrated. The Regulation specifically amended the Directive to incorporate provisions specific to ATMPs, creating a cohesive regulatory framework that addresses both general requirements for all medicinal products and specific provisions for advanced therapies [6]. This interplay ensures that ATMPs benefit from the established regulatory infrastructure for medicines while accounting for their distinctive scientific and technical characteristics.

The legal framework follows a layered approach, with Directive 2001/83/EC providing the general requirements for medicinal products, and Regulation (EC) No 1394/2007 adding ATMP-specific provisions that account for their unique complexity and characteristics [9]. This structure is particularly evident in the marketing authorization process, where ATMPs must meet all standard requirements for medicinal products while also complying with additional standards specific to their technological category.

Table 2: Complementary Roles of Core ATMP Legislation

Regulatory Aspect	Directive 2001/83/EC Role	Regulation (EC) No 1394/2007 Role
Legal Nature	Minimum harmonization directive requiring national implementation	Directly applicable regulation
Scope	All medicinal products for human use	Specifically Advanced Therapy Medicinal Products
Definitions	Provides definitions for gene therapy & somatic cell therapy products	Defines tissue-engineered products & combined ATMPs
Authorization Route	Various routes (national, decentralized, centralized)	Mandatory centralized procedure
Committee Oversight	Committee for Medicinal Products for Human Use (CHMP)	Committee for Advanced Therapies (CAT)
Manufacturing Requirements	General GMP requirements for all medicines	Specific GMP guidelines for ATMPs

ATMP Classification and Definitions

Product Categories

The EU regulatory framework establishes four distinct categories of Advanced Therapy Medicinal Products, each with precise legal definitions that determine the applicable regulatory pathway [2] [9]. Understanding these classifications is essential for developers and researchers to ensure appropriate regulatory strategy and compliance.

• Gene Therapy Medicinal Products (GTMPs): These products contain genes that lead to a therapeutic, prophylactic, or diagnostic effect, working by inserting 'recombinant' genes into the body [2]. According to Part IV of Directive 2001/83/EC, a gene therapy medicinal product is a biological medicinal product with specific characteristics: it contains an active substance consisting of recombinant nucleic acid used in humans to regulate, repair, replace, add, or delete a genetic sequence; and its therapeutic effect relates directly to the recombinant nucleic acid sequence or its expression product [7]. Vaccines against infectious diseases are explicitly excluded from this category.

• Somatic Cell Therapy Medicinal Products (SCTMPs): These products contain cells or tissues that have been manipulated to change their biological characteristics, or cells or tissues not intended for the same essential functions in the recipient and donor [2]. The legal definition in Directive 2001/83/EC specifies that these products must contain or consist of cells or tissues that have been subject to "substantial manipulation" or are not intended for the same essential function, and are presented as having properties for treating, preventing, or diagnosing disease through pharmacological, immunological, or metabolic action [7].

• Tissue-Engineered Products (TEPs): These contain cells or tissues that have been modified so they can be used to repair, regenerate, or replace human tissue [2]. Regulation (EC) No 1394/2007 provides the definition for these products, which typically involve substantial manipulation of cells or tissues to create functional tissue constructs for therapeutic applications.

• Combined Advanced Therapy Medicinal Products (cATMPs): These products incorporate one or more medical devices as an integral part of the medicine, such as cells embedded in a biodegradable matrix or scaffold [2]. These combination products are subject to regulatory requirements for both medicinal products and medical devices, requiring coordinated assessment by different regulatory bodies.

Substantial Manipulation Criterion

A central concept in ATMP classification is the determination of whether cells or tissues have undergone "substantial manipulation" that alters their biological characteristics, physiological functions, or structural properties relevant for the intended clinical use [7]. The framework provides guidance on manipulations that are not considered substantial, such as cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation, and vitrification [7].

The classification procedure involves submitting a request to the Committee for Advanced Therapies (CAT), which issues scientific recommendations on ATMP classification based on the legal definitions [6]. This process provides developers with regulatory certainty early in development, enabling appropriate planning for manufacturing, non-clinical studies, and clinical trials.

Manufacturing Authorization Requirements

Legal Basis and GMP Compliance

The manufacturing of ATMPs in the European Union is subject to strict regulatory requirements centered on the manufacturing authorization and Good Manufacturing Practice (GMP) compliance [3]. Article 40 of Directive 2001/83/EC establishes that any legal entity manufacturing medicinal products must hold a manufacturing authorization issued by the national competent authority of the Member State where the manufacturing activities occur [3].

GMP is defined in EU law 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" (Article 2(3) of Commission Directive (EU) 2017/1572) [3]. For ATMPs, the European Commission has published detailed guidelines on GMP specific to these products in accordance with Article 5 of Regulation (EC) No 1394/2007 [3]. These guidelines address the unique challenges presented by ATMPs, such as the use of substances of human origin with short shelf lives and the complex manufacturing processes involved.

Ongoing Regulatory Oversight

GMP compliance is not a one-time achievement but an ongoing process that continues throughout the product lifecycle [3]. Once manufacturing authorization is granted, the national competent authority conducts regular inspections of manufacturing sites to verify continued compliance with GMP requirements [3]. These inspections include assessments of premises, equipment, personnel, documentation, production processes, quality control, and the traceability system.

The European Medicines Agency plays a coordinating role in GMP activities across the EU, maintaining a compilation of GMP inspection-related procedures and forms agreed by all Member States [3]. The Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG), chaired by the EMA, works to harmonize the interpretation and implementation of GMP requirements across Member States [3].

Recent Developments and Future Directions

The regulatory framework for ATMPs continues to evolve in response to technological advancements and accumulated experience with these innovative therapies. In May 2025, the EMA released a concept paper proposing revisions to Part IV of the EU Guidelines on GMP specific to ATMPs [10]. These proposed revisions focus on several key areas:

• Alignment with Revised Annex 1: The updated Annex 1, effective since August 2023, introduced modifications in the manufacture of sterile medicinal products that need to be harmonized with ATMP-specific GMP requirements [10].

• Integration of ICH Concepts: The revision plans to incorporate principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System), promoting a systematic approach to quality management [10].

• Adaptation to Technological Advancements: The guidelines will provide clarifications on qualifying, controlling, and managing new technologies such as automated systems, closed single-use systems, and rapid microbiological testing methods [10].

• Updates on Cleanroom and Barrier Systems: The revised guidelines will offer further clarifications on expectations for cleanroom classifications and the use of barrier systems while maintaining provisions for biosafety cabinets needed for individualized ATMP batches [10].

Additionally, the 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions on decentralised production sites that could potentially facilitate manufacturing near the patient [3]. This is particularly relevant for ATMPs with limited shelf-life or autologous products, though it remains to be seen whether these proposed amendments will be adopted.

Table 3: Key Regulatory Resources for ATMP Developers

Resource	Function	Access Point
CAT Classification Procedure	Determines whether a product meets ATMP criteria	EMA Website
EudraGMDP Database	Contains manufacturing authorisations & GMP certificates	EMA Website
ATMP-specific GMP Guidelines	Provides manufacturing quality standards for ATMPs	European Commission Website
SME Certification Procedure	Offers regulatory feedback on quality & non-clinical data for SMEs	EMA Innovation Task Force
Scientific Advice Procedure	Provides regulatory guidance on development strategy	EMA or National Competent Authorities
Clinical Trials Information System	Portal for clinical trial applications in EU	EMA Website

The core legal framework consisting of Regulation (EC) No 1394/2007 and Directive 2001/83/EC establishes a comprehensive regulatory system for Advanced Therapy Medicinal Products in the European Union. This framework balances the need for rigorous oversight with flexibility to accommodate the unique characteristics of these innovative therapies. By providing precise definitions, specialized assessment procedures, and tailored requirements for manufacturing and quality control, the legislation creates a pathway for advancing these promising treatments from research to clinical application while ensuring patient safety and product quality.

The continuing evolution of this framework, including the proposed revisions to ATMP-specific GMP guidelines, demonstrates the regulatory system's capacity to adapt to scientific progress while maintaining high standards. For researchers, scientists, and drug development professionals working in this field, understanding this core legal framework is essential for successful navigation of the regulatory pathway from concept to marketed product.

When is Manufacturing Authorization Required? The Legal Obligation for ATMP Production in the EU

In the European Union, Advanced Therapy Medicinal Products represent a category of innovative medicines for human use that are based on genes, cells, or tissues. The EU regulatory framework establishes a comprehensive system to ensure that these complex biological products meet consistent standards of quality, safety, and efficacy before reaching patients. The legal foundation for ATMPs is built upon Regulation (EC) No 1394/2007, which amended the overarching medicinal products legislation (Directive 2001/83/EC and Regulation (EC) No 726/2004) to address the specific characteristics of these therapies [11]. This specialized framework categorizes ATMPs into three main types: gene therapy medicines (containing recombinant genes for therapeutic effects), somatic-cell therapy medicines (containing manipulated cells or tissues), and tissue-engineered medicines (containing cells or tissues modified to repair, regenerate, or replace human tissue) [2]. A fourth category, combined ATMPs, includes these biological components integrated with a medical device as an integral part of the product [2].

Central to this regulatory system is the requirement for manufacturing authorization, a mandatory legal obligation for any entity producing ATMPs within the EU territory. This authorization ensures that manufacturing processes consistently produce ATMPs that meet predefined quality specifications under controlled conditions. The European Medicines Agency emphasizes that all ATMPs must be authorized centrally via the EMA, benefiting from a single evaluation and authorization procedure across member states [2]. This centralized oversight is complemented by national competent authorities who implement and enforce manufacturing standards within their jurisdictions, creating a cohesive regulatory network that spans the entire ATMP lifecycle from development through post-authorization monitoring.

The Legal Basis for Manufacturing Authorization

Foundational Legislation

The legal obligation for ATMP manufacturing authorization in the EU derives from Article 40 of Directive 2001/83/EC, which establishes that "the manufacture of medicinal products... shall be subject to authorization" [3]. This foundational requirement applies universally to all medicinal products for human use, with ATMPs being subject to these general rules alongside product-specific provisions outlined in Regulation (EC) No 1394/2007 [11]. The manufacturing authorization system operates under the principle that no legal entity may manufacture ATMPs within the EU without first obtaining this authorization from the national competent authority of the member state where the manufacturing activities occur [3]. This geographical linkage ensures that each manufacturing facility falls under the direct supervision of the authority where it is physically located, while still adhering to harmonized EU standards.

The legal framework distinguishes between two interconnected but distinct authorizations: the manufacturing authorization (covering production activities) and the marketing authorization (allowing placement on the market). A manufacturing authorization is required regardless of whether the ATMP is intended for commercial distribution or for use in clinical trials, though specific exemptions may apply for hospital-based preparations under certain conditions. The legislation mandates that manufacturing authorization holders must employ a Qualified Person who bears ultimate responsibility for ensuring that each production batch has been manufactured and tested in compliance with EU laws and marketing authorization requirements before release [3]. This dual system of facility authorization and batch release creates multiple checkpoints to protect patient safety throughout the manufacturing process.

Definition of Manufacturing Activities

The legal framework broadly defines "manufacturing" to encompass "any total or partial manufacture" of a medicinal product, along with various associated activities [3]. For ATMPs, this comprehensive definition typically includes:

• All manufacturing steps from the initial processing of raw materials (including cells and tissues of human origin) through to the finished product
• Quality control testing throughout the production process
• Packaging of the final ATMP product
• Labeling activities in accordance with approved specifications
• Importation of ATMPs from third countries into the EU territory
• Storage and distribution activities under specified conditions

The legal obligation extends beyond complete manufacturing processes to include partial manufacturing, meaning that even facilities performing only certain steps in the production chain (such as cell processing or final formulation) require appropriate authorization for those specific activities. This comprehensive scope ensures regulatory oversight across what are often distributed manufacturing networks for ATMPs, particularly for autologous products where starting materials move between collection sites, processing facilities, and treatment centers.

When Manufacturing Authorization is Required

General Rule and Scope

The fundamental rule under EU law is straightforward: any legal entity engaged in manufacturing ATMPs must hold a manufacturing authorization issued by the national competent authority of the member state where the manufacturing activities are performed [3]. This requirement applies regardless of the organization's nature—including commercial companies, academic institutions, and non-profit organizations—and covers ATMPs intended both for clinical trials and for commercial distribution following marketing authorization. The comprehensive scope of this obligation ensures consistent quality standards across the diverse ecosystem of ATMP developers in Europe.

The requirement extends to all categories of ATMPs, recognizing their shared characteristics as biological entities with complex manufacturing processes. Gene therapy medicinal products involving viral vectors or plasmid DNA, somatic cell therapies utilizing manipulated immune cells or stem cells, and tissue-engineered products combining cells with scaffold materials all fall within this regulatory perimeter. The integral role of starting materials of human origin (such as blood, tissues, and cells) in ATMP manufacturing introduces additional regulatory considerations, as these materials must be sourced in accordance with EU standards for quality and safety alongside the manufacturing authorization requirements for the finished product [3].

Specific Applications and Contexts

Table 1: Manufacturing Authorization Requirements Across Different Contexts

Context of Manufacturing	Manufacturing Authorization Required?	Governing Framework	Key Considerations
Commercial production (post-Marketing Authorisation)	Yes	Directive 2001/83/EC, Regulation (EC) No 1394/2007	Full GMP compliance required; ongoing inspections
Clinical trial supply	Yes (with limited exceptions)	Clinical Trials Regulation, GMP guidelines	Phase-appropriate GMP; IMPD requirements
Hospital exemption	Case-by-case determination	National implementation of Directive 2001/83/EC	Non-routine preparation; specific medical prescription
Academic/non-profit research	Yes	Same as commercial entities	EMA pilot programs offer support; fee reductions possible
Multi-site manufacturing	Yes for each site	GMP guidelines for ATMPs	Coordinated quality systems; qualified person responsibility

Manufacturing authorization is required across multiple contexts, though specific applications present unique considerations:

• Clinical Trial Manufacturing: ATMPs intended for use in clinical trials must be manufactured under appropriate authorization, with Good Manufacturing Practice requirements applied in a manner proportionate to the product's development stage [3] [4]. The manufacturing standards should ensure patient safety while recognizing that process characterization may be less complete during early development phases.

• Multi-site Operations: For ATMPs involving manufacturing steps at multiple locations (a common scenario with collection, processing, and administration at different sites), each production site must hold its own manufacturing authorization specific to the activities performed there [3]. This distributed model presents significant logistical challenges but is essential for maintaining quality control across geographically separated operations.

• Academic and Non-profit Development: Recognizing the important role of academic institutions in ATMP innovation, the EMA has established a pilot program offering increased regulatory support, including guidance on meeting manufacturing authorization requirements [2]. While the legal obligations remain the same, this initiative provides tailored assistance to help non-commercial developers navigate the regulatory process.

• Combined ATMPs: For products combining viable cells or tissues with medical devices, manufacturing authorization encompasses both the biological and device components, requiring expertise in both regulatory domains [2]. The integrated nature of these products necessitates coordinated quality systems that address the distinct requirements of each element.

Exemptions and Special Cases

Hospital Exemption and Non-Routine Preparation

The EU regulatory framework provides a limited exemption from the centralized marketing authorization requirement for ATMPs prepared on a non-routine basis according to specific quality standards and used in a hospital setting under the direct professional responsibility of a medical practitioner [11]. This "hospital exemption" allows for the custom preparation of ATMPs for individual patients in accordance with a medical prescription, recognizing the practical realities of personalized medicine approaches. However, it is crucial to note that this exemption applies specifically to marketing authorization, not manufacturing authorization. The precise regulatory status of hospital-exempt ATMP manufacturing varies across member states, with national competent authorities interpreting and implementing the requirements differently.

Even under the hospital exemption, manufacturing activities must generally comply with quality standards equivalent to GMP, though the application may be adapted to the specific context of hospital preparation. National authorities typically exercise oversight over these activities, requiring some form of authorization or registration specific to the hospital setting. The exemption is intended for non-routine production, meaning that large-scale or industrialized manufacturing of ATMPs within hospital facilities would not qualify and would require full manufacturing authorization regardless of the setting.

Decentralized Manufacturing and Point-of-Care Production

The emerging paradigm of decentralized manufacturing for ATMPs, particularly those with limited shelf lives or requiring customization near the patient, presents regulatory challenges to the traditional site-based authorization model. Current EU law requires each production site to hold a manufacturing authorization, which creates practical difficulties for point-of-care manufacturing at hospital bedsides or in mobile units [3]. However, proposed reforms to the pharmaceutical legislation may introduce greater flexibility for these distributed manufacturing models.

The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions that would allow derogation from the manufacturing authorization requirement for decentralized sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central authorized site [3]. This proposed change would facilitate more adaptable manufacturing networks for ATMPs while maintaining oversight through the qualified person system. Until such reforms are adopted, however, the traditional site-specific authorization requirement remains in force for all manufacturing locations, regardless of their scale or relationship to a central facility.

Good Manufacturing Practice Requirements for ATMPs

Core GMP Principles

The manufacturing authorization for ATMPs is contingent upon strict adherence to Good Manufacturing Practice standards, which represent the minimum requirements that manufacturers must meet in their production processes [3]. EU law defines GMP as "the part of quality assurance which ensures that medicinal products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use" [3]. For ATMPs, these principles take on particular significance due to the complex, often patient-specific nature of the products and the use of biological starting materials with inherent variability.

The GMP framework for ATMPs encompasses several core principles:

• Quality Risk Management: A systematic approach to identifying, evaluating, and controlling risks to product quality throughout the manufacturing process, incorporating principles from ICH Q9 [10]
• Pharmaceutical Quality System: A comprehensive system requiring documented procedures, change control, and deviation management to ensure product consistency, aligned with ICH Q10 concepts [10]
• Facility and Equipment Controls: Specialized requirements for cleanroom classifications, environmental monitoring, and the qualification of equipment used in ATMP manufacturing [10]
• Process Validation: Demonstration that manufacturing processes can consistently produce ATMPs meeting predetermined quality attributes

ATMP-Specific GMP Considerations

Table 2: Key GMP Challenges Specific to ATMP Manufacturing

GMP Area	Specific ATMP Challenges	Regulatory Expectations
Quality Control	Limited sample sizes (especially autologous); complex analytical methods	Risk-based testing strategies; process controls over batch testing
Facility Design	Simultaneous production of multiple patient-specific batches	Effective segregation; containment strategies; cleaning validation
Supply Chain Controls	Complex logistics for cell collection and product delivery	Temperature monitoring; chain of identity verification; transport validation
Personnel Training	Highly specialized technical procedures	Demonstrated aseptic competency; process-specific training programs
Documentation Systems	Tracking individual patient batches	Robust record-keeping; electronic systems for traceability
Sterility Assurance	Limited terminal sterilization options; manual processing steps	Environmental monitoring; aseptic process validation; media fills

The biological nature of ATMPs introduces several manufacturing challenges that shape the application of GMP principles:

• Starting Materials of Human Origin: ATMPs often begin with human cells or tissues that present unique challenges regarding variability, contamination risks, and limited availability [3]. GMP requirements address donor screening, testing for infectious diseases, and traceability systems to follow these materials from donor to patient.

• Limited Shelf Life and Logistics: Many ATMPs have short stability periods, creating extreme logistical complexity from cell collection through final product administration [3]. GMP controls must ensure maintenance of appropriate storage conditions throughout this chain and establish validated expiration dates based on stability studies.

• Process Consistency and Validation: Demonstrating manufacturing consistency is particularly challenging for ATMPs due to the inherent variability of biological systems and, for autologous products, the absence of traditional batch concepts [3]. Manufacturers must implement extensive process controls and monitoring to compensate for these challenges.

• Automated and Closed Systems: Recent technological advances in automated processing and closed single-use systems offer potential solutions to some ATMP manufacturing challenges [10]. The GMP framework is evolving to address the qualification, control, and management of these emerging technologies.

The European Commission has published detailed GMP guidelines specific to ATMPs, with a current revision proposed in May 2025 to better align with updated sterile product requirements (Annex 1) and incorporate modern quality management concepts [10]. These ATMP-specific guidelines provide tailored interpretation of how general GMP principles should be applied to the unique manufacturing scenarios presented by advanced therapies.

The Manufacturing Authorization Process

Application and Assessment

The process for obtaining manufacturing authorization involves a detailed application to the national competent authority of the member state where the manufacturing activities will take place. The application must comprehensively demonstrate how the facility, equipment, personnel, and processes will comply with EU GMP standards [3]. Key components of the application typically include:

• Detailed information about the manufacturing facilities, equipment, and critical systems
• Documentation of quality management systems, including organizational structure and responsibilities
• Qualifications and CVs of key personnel, particularly the Qualified Person who will bear regulatory responsibility for batch certification
• Standard operating procedures governing manufacturing, quality control, and facility operations
• Validation plans for critical processes, cleaning procedures, and analytical methods
• Detailed descriptions of the ATMPs to be manufactured and their manufacturing processes

The national competent authority carefully assesses the application against established requirements, which may include on-site inspections of the manufacturing facility to verify the accuracy of the application and evaluate GMP compliance firsthand [3]. These pre-authorization inspections pay particular attention to facility design, environmental controls, personnel training, and quality system implementation. The assessment timeframe varies by member state but typically spans several months from application submission to authorization decision.

Ongoing Compliance and Inspections

Manufacturing authorization represents an ongoing commitment to GMP compliance rather than a one-time achievement. Authorization holders are subject to regular repeated inspections by national competent authorities to verify continued adherence to GMP requirements [3]. The frequency and depth of these routine inspections are typically risk-based, considering factors such as the complexity of the manufacturing processes, the history of compliance, and the therapeutic criticality of the products manufactured.

In addition to routine surveillance, significant changes to manufacturing processes, facilities, or equipment require regulatory review and approval through variation procedures [12]. The EU variations framework categorizes changes based on their potential impact on product quality, safety, or efficacy, with corresponding regulatory pathways:

• Type IA variations (minor, low-risk changes) are notified to authorities without prior approval
• Type IB variations (minor, notification-required) follow a streamlined review process
• Type II variations (major changes) require comprehensive assessment and approval before implementation

A revised variations framework effective January 2025 introduces additional flexibility, including annual bundling options for Type IA variations and a new Type 0 category for immediate safety-related changes [12] [13]. This evolving regulatory landscape underscores the dynamic nature of manufacturing authorization maintenance throughout the ATMP lifecycle.

Guidance and Support Mechanisms

Recognizing the complexities of ATMP manufacturing authorization, EU regulators have established multiple support mechanisms for developers:

• Scientific Advice and Protocol Assistance: The EMA and national competent authorities offer opportunities for manufacturers to seek formal scientific advice on meeting regulatory requirements, including GMP considerations [3] [11]. This proactive engagement helps developers design appropriate manufacturing strategies and quality systems before submitting authorization applications.

• EMA Pilot for Academia and Non-profits: A dedicated pilot program provides enhanced regulatory support to academic and non-profit organizations developing promising ATMPs [2]. This initiative includes guidance throughout the regulatory process and potential fee reductions to facilitate access to the authorization system for non-commercial developers.

• Training Materials and Resources: The EMA, in collaboration with organizations like EATRIS, has developed online training modules to help ATMP developers navigate the regulatory environment [2]. These resources cover topics including ATMP classification, environmental risk assessment, and quality considerations in clinical development.

Key Regulatory Actors

Table 3: Key Regulatory Bodies in ATMP Manufacturing Authorization

Regulatory Body	Role in Manufacturing Authorization	Key Responsibilities
National Competent Authorities	Primary authorization and oversight	Issue manufacturing authorizations; conduct GMP inspections; batch release
European Medicines Agency	Coordination and harmonization	Scientific assessment of marketing applications; GMP guideline development
Committee for Advanced Therapies	Scientific expertise	ATMP classification; scientific advice; contributes to guideline development
GMP/GDP Inspectors Working Group	GMP interpretation and harmonization	Develops common GMP standards; coordinates inspection activities
European Directorate for Quality of Medicines	Quality standards	Sets pharmacopoeial standards; quality control guidance

The manufacturing authorization ecosystem involves multiple regulatory bodies with distinct roles:

• National Competent Authorities: These member state agencies serve as the primary point of contact for manufacturing authorization applications and maintain direct oversight of authorized manufacturers through regular inspections [3]. They are responsible for assessing applications, issuing authorizations, and monitoring ongoing compliance.

• European Medicines Agency: While the EMA does not directly issue manufacturing authorizations, it plays a crucial role in coordinating and harmonizing GMP activities across the EU [3]. The agency maintains a compilation of agreed inspection procedures and forms, chairs the GMP/GDP Inspectors Working Group, and provides scientific advice to manufacturers.

• Committee for Advanced Therapies: As the EMA's expert committee on ATMPs, the CAT provides specialized scientific input on ATMP classification and development [2]. While focused primarily on marketing authorization assessment, the CAT's scientific opinions influence manufacturing expectations for specific product categories.

The EudraGMDP database serves as a central repository for information related to manufacturing authorizations and GMP compliance across the EU [3]. This publicly accessible database contains manufacturing authorizations, GMP certificates, and non-compliance statements, providing transparency regarding the regulatory status of ATMP manufacturers.

The manufacturing authorization requirement for ATMPs in the EU represents a fundamental legal obligation rooted in the overarching framework for medicinal products, with additional specificity for the unique characteristics of advanced therapies. This authorization system ensures that ATMP manufacturing occurs under controlled conditions that consistently yield products of appropriate quality, minimizing risks to patient safety while supporting the development of these innovative therapies. The requirement applies broadly across different manufacturing scenarios, with limited exceptions primarily related to non-routine hospital preparation.

The EU regulatory landscape for ATMP manufacturing continues to evolve, with proposed revisions to GMP guidelines in 2025 aiming to better align ATMP-specific requirements with general GMP principles and emerging manufacturing technologies [10] [14]. Simultaneously, reforms to the variations framework seek to streamline post-authorization change management, reflecting the dynamic nature of ATMP process development [12] [13]. These ongoing refinements demonstrate the regulatory system's adaptation to the specific challenges of ATMP manufacturing while maintaining the core objective of protecting public health through rigorous quality standards.

For researchers, scientists, and drug development professionals working with ATMPs, understanding the scope and requirements of manufacturing authorization is essential for successful product development. Early engagement with regulatory authorities through scientific advice procedures and utilization of available support mechanisms can facilitate navigation of this complex regulatory pathway, ultimately contributing to the advancement of these promising therapies for patients in need.

Diagrams

Diagram 1: ATMP Manufacturing Authorization Decision Pathway

Diagram 2: ATMP Manufacturing Authorization Ecosystem

Table 4: Key Regulatory Resources for ATMP Manufacturing Authorization

Resource	Purpose/Function	Source/Availability
EudraGMDP Database	Public database of manufacturing authorizations and GMP compliance status	EMA website [3]
GMP Guidelines Part IV	ATMP-specific Good Manufacturing Practice requirements	European Commission publications [10]
CAT Classification Procedures	Determination of whether a product qualifies as an ATMP	EMA Committee for Advanced Therapies [2]
Scientific Advice Procedure	Pre-submission regulatory guidance on development strategy	EMA and National Competent Authorities [11]
Variation Classification Tool	Determination of appropriate category for manufacturing changes	CMDh and EMA websites [12] [13]
ATMP Training Modules	Educational resources on regulatory requirements	EMA TransMed Academy [2]
Environmental Risk Assessment	Guidance for ATMPs containing genetically modified organisms	EMA regulatory resources [2]

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of medicines in the European Union, encompassing gene therapies, somatic-cell therapies, and tissue-engineered products [2]. These therapies, which include treatments based on genes, cells, or tissues, embody the shift toward personalized medicine and potential one-time curative treatments for a range of diseases [15]. The regulatory framework governing these products is equally specialized, built upon a two-tiered structure consisting of the European Medicines Agency (EMA) and the National Competent Authorities (NCAs) of EU Member States. For researchers, scientists, and drug development professionals, understanding the distinct yet interconnected roles of these bodies is fundamental to navigating the complex journey of ATMP development, manufacturing authorization, and market access [3]. This framework is designed to ensure that these innovative therapies meet stringent standards of quality, safety, and efficacy while fostering an environment that encourages their development [2].

The European Medicines Agency (EMA): Centralized Role for ATMPs

The EMA serves as the central pillar for the scientific evaluation and supervision of medicines across the European Economic Area (EEA). For ATMPs, its role is particularly critical.

Mandatory Centralized Authorization

Unlike conventional medicines, all ATMPs must be authorized via the EMA's centralized procedure [16]. This ensures a single evaluation and authorization process valid across all EU member states, providing a streamlined pathway for these complex products [2].

The Committee for Advanced Therapies (CAT)

A cornerstone of the EMA's structure for ATMPs is the Committee for Advanced Therapies (CAT). This committee provides the specialized expertise required to evaluate ATMPs. Its key functions include [2]:

• Conducting the initial scientific assessment of ATMP marketing authorization applications, preparing draft opinions on quality, safety, and efficacy for the Committee for Medicinal Products for Human Use (CHMP).
• Classifying medicines to determine whether they qualify as ATMPs.
• Contributing to scientific advice for developers of advanced therapies.
• Developing scientific guidelines and following emerging scientific developments in the field.

Support and Guidance for Developers

The EMA offers extensive support to ATMP developers. This includes [2]:

• Scientific Advice and Protocol Assistance: Providing guidance on development strategies to meet regulatory requirements.
• ATMP Classification: Offering a procedure for developers to confirm whether their product is classified as an ATMP early in development.
• Pilot for Academia and Non-Profits: Dedicating support for non-commercial developers targeting unmet medical needs, including fee reductions and regulatory guidance [2].

National Competent Authorities (NCAs): National Implementation and Oversight

While the EMA handles centralized authorization, NCAs are the national bodies responsible for implementing EU directives and regulations within their respective member states. Their roles are diverse and essential for the operational aspects of ATMP development and manufacturing.

Key Responsibilities of NCAs

• Manufacturing Authorization: Any legal entity manufacturing ATMPs within the EU must hold a manufacturing authorization issued by the NCA of the member state where the activities occur [3]. This involves assessing applications and conducting regular Good Manufacturing Practice (GMP) inspections to ensure ongoing compliance [3].
• Clinical Trial Authorization: NCAs are responsible for authorizing clinical trials within their territories [17].
• Pharmacovigilance: Monitoring the safety of medicines once they are on the market.
• Expert Contribution: Supplying scientific experts to serve on EMA committees, including the CAT [17].

List of National Competent Authorities

The table below provides the contact information for the NCAs in EU/EEA member states responsible for human medicines.

Table 1: National Competent Authorities for Human Medicines in the EU/EEA

Country	Authority Name	Contact Details
Austria	Austrian Agency for Health and Food Safety	Tel: +43 5 0555-0 · www.ages.at [17]
Belgium	Federal Agency for Medicines and Health Products (FAMHP)	Tel: +32 2 528 40 00 · www.famhp.be [17]
Bulgaria	Bulgarian Drug Agency	Tel: +359 2 890 35 55 · www.bda.bg [17]
Croatia	Agency for Medicinal Products and Medical Devices	Tel: +385 1 4884 100 · www.halmed.hr [17]
Cyprus	Ministry of Health - Pharmaceutical Services	Tel: +357 22608620 · www.moh.gov.cy/phs [17]
Czechia	State Institute for Drug Control	Tel: +420 272 185 333 · www.sukl.cz [17]
Denmark	Danish Medicines Agency	Tel: +45 7222 7400 · www.laegemiddelstyrelsen.dk [17]
Estonia	State Agency of Medicines	Tel: +372 737 41 40 · www.ravimiamet.ee [17]
Finland	Finnish Medicines Agency	Tel: +358 29 522 3341 · www.fimea.fi [17]
France	National Agency for the Safety of Medicine and Health Products	Tel: +33 1 55 87 30 00 · www.ansm.sante.fr [17]
Germany	Federal Institute for Drugs and Medical Devices	Tel: +49 (0)228-207-30 · www.bfarm.de [17]
Germany	Paul Ehrlich Institute	Tel: +49 6103 77 0 · www.pei.de [17]
Greece	National Organization for Medicines	Tel: +30 213 2040 200 · www.eof.gr [17]
Hungary	National Centre for Public Health and Pharmacy	Tel: +36 1 476 1100 · www.nnk.gov.hu [17]
Ireland	Health Products Regulatory Authority (HPRA)	Tel: +353 1 676 4971 · www.hpra.ie [17]
Italy	Italian Medicines Agency	Tel: +39 06 5978401 · www.aifa.gov.it [17]
Latvia	State Agency of Medicines	Tel: +371 7078424 · www.zva.gov.lv [17]
Lithuania	State Medicines Control Agency	Tel: +370 5 263 9264 · www.vvkt.lt [17]
Malta	Malta Medicines Authority	Tel: +356 23439000 · www.medicinesauthority.gov.mt [17]
Netherlands	Medicines Evaluation Board	Tel: +31 (0) 88 224 8000 · www.cbg-meb.nl [17]
Norway	Norwegian Medical Products Agency	Tel: +47 22 89 77 00 · www.dmp.no [17]
Poland	Office for Registration of Medicinal Products, Medical Devices and Biocidal Products	Tel: +48 (22) 492 11 00 · www.urpl.gov.pl [17]
Portugal	National Authority of Medicines and Health Products	Tel: +351 217987100 · www.infarmed.pt [17]
Romania	National Authority of Medicines and Medical Devices	Tel: +4021 317 11 00 · www.anm.ro [17]
Slovakia	State Institute for Drug Control	Tel: +421 2 5070 1111 · www.sukl.sk [17]
Slovenia	Agency for Medicinal Products and Medical Devices	Tel: + 38 6 8 2000 500 · www.jazmp.si [17]
Spain	Spanish Agency Of Medicines And Medical Devices	www.aemps.gob.es [17]
Sweden	Swedish Medical Products Agency	Tel: +46 18 17 46 00 · www.lakemedelsverket.se [17]

The ATMP Manufacturing Authorization Process

The manufacturing of ATMPs in the EU is subject to a rigorous authorization process that directly involves NCAs and is underpinned by EMA-level guidelines and coordination.

The Legal Foundation

A Manufacturing Authorization is a legal requirement for any entity producing medicinal products in the EU, issued by the NCA of the member state where the manufacturing activities take place [3]. This authorization demands full compliance with Good Manufacturing Practice (GMP) principles and guidelines, which are the cornerstone of quality assurance for medicines [3].

Interaction Between Regulators and Applicants

The process involves multiple interactions between the manufacturer and the regulators:

• Application and Assessment: The manufacturer submits an application for a manufacturing authorization to the relevant NCA, which reviews and assesses it based on EU standards [3].
• Ongoing Supervision: After authorization is granted, the NCA conducts regular and repeated GMP inspections of the manufacturing site to ensure continued compliance [3].
• EMA's Coordinating Role: The EMA, through the GMP/GDP Inspectors Working Group, works to harmonize the interpretation and application of GMP rules across the EEA. It also provides scientific advice and maintains the EudraGMDP database, which contains records of manufacturing authorizations and GMP certificates [3].

Specifics for ATMPs: Challenges and Guidelines

ATMP manufacturing presents unique challenges, including the use of substances of human origin with short shelf-lives, complex logistics, and the need to maintain sterility throughout a often highly manipulated process [3]. To address this, the European Commission has published detailed GMP guidelines specific to ATMPs [3]. Furthermore, a new EMA guideline on clinical-stage ATMPs came into effect in July 2025, consolidating over 40 previous documents to provide a multidisciplinary reference for quality, non-clinical, and clinical requirements in clinical trials [4].

Regulatory Pathways and Interactions

Navigating the regulatory pathway for an ATMP requires understanding how the EMA and NCAs interact throughout a product's lifecycle.

Diagram 1: ATMP Regulatory Pathway in the EU. This diagram illustrates the logical relationships and interactions between a product developer, the National Competent Authority (NCA), the European Medicines Agency (EMA) with its Committee for Advanced Therapies (CAT), and the European Commission (EC) throughout the regulatory process for an Advanced Therapy Medicinal Product.

From Manufacturing to Marketing Authorization

As shown in Diagram 1, the journey involves clear steps and interactions:

• A developer interacts with the NCA to obtain a manufacturing authorization and is subject to its GMP inspections [3].
• Concurrently, the developer can seek scientific advice and ATMP classification from the EMA [2].
• The marketing authorization application is submitted solely to the EMA via the centralized procedure [16].
• The EMA's CAT assesses the application and provides a draft opinion to the CHMP [2].
• Following a positive CHMP opinion, the European Commission grants a marketing authorization valid across the EU [2].

International Considerations: Mutual Recognition Agreements (MRAs)

The EU has MRAs with several countries to facilitate trade and regulatory cooperation. These agreements allow for the mutual recognition of GMP inspections and waive batch testing upon import. However, it is crucial for developers to note that ATMPs are explicitly excluded from the scope of most MRAs, including those with Australia, Canada, Japan, and New Zealand [18]. A notable exception is the MRA with Switzerland, which does include ATMPs [18]. This underscores the highly specialized and carefully regulated nature of these products on a global scale.

For researchers and developers, engaging with regulators and utilizing available resources is critical for successful ATMP development.

Table 2: Essential Regulatory Resources and Reagents for ATMP Development

Resource/Reagent	Function & Purpose	Regulatory Body
EudraGMDP Database	Public database for verifying manufacturing authorizations and GMP compliance of sites.	EMA [3]
ATMP Classification Procedure	Formal procedure to confirm a product's status as an ATMP early in development.	EMA/CAT [2]
Scientific Advice & Protocol Assistance	Guidance on regulatory strategy, study design, and data needed to support an application.	EMA & NCAs [2] [3]
Guideline on Clinical-Stage ATMPs	Primary multidisciplinary reference for quality, non-clinical, and clinical data in Clinical Trial Applications (effective July 2025).	EMA [4]
GMP/GDP Inspectors Working Group Q&A	Provides additional interpretation of EU GMP guidelines on specific technical topics.	EMA [19]
ATMP Pilot for Academia/Non-Profits	Enhanced regulatory support, including fee reductions, for non-commercial developers.	EMA [2]

The successful development and authorization of an ATMP in the European Union hinges on a clear understanding of the well-defined, collaborative roles of the EMA and National Competent Authorities. The EMA provides centralized scientific assessment, overarching guidance, and coordination, while the NCAs are indispensable for granting and supervising national manufacturing authorizations and ensuring day-to-day GMP compliance. For researchers and drug development professionals, proactively engaging with both bodies through scientific advice, utilizing available resources, and adhering to the specific guidelines for these complex products is not just beneficial—it is essential for navigating the regulatory landscape efficiently and bringing transformative advanced therapies to patients.

The Role of the Committee for Advanced Therapies (CAT) in Classification and Scientific Assessment

The Committee for Advanced Therapies (CAT) is a pivotal scientific committee within the European Medicines Agency (EMA), established by Regulation (EC) No 1394/2007 on advanced therapy medicinal products (ATMPs) [20] [1]. In the context of ATMP manufacturing authorization, the CAT's scientific assessments form the foundational step that determines the applicable regulatory pathway. For developers of products based on genes, cells, or tissues, understanding the CAT's role is crucial for navigating the complex EU regulatory landscape [21]. The committee comprises some of Europe's foremost experts in advanced therapies, providing the specialized scientific expertise required to evaluate these innovative, often highly complex medicinal products [20]. Their work ensures that ATMPs meet rigorous standards of quality, safety, and efficacy before they can be authorized for the EU market, thereby protecting public health while facilitating patient access to groundbreaking treatments.

The CAT's Dual Role in Classification and Scientific Assessment

The CAT fulfills two distinct but interconnected functions within the ATMP regulatory framework: providing scientific recommendations on ATMP classification and conducting the detailed scientific assessment of marketing authorization applications.

Scientific Recommendation on ATMP Classification

The scientific recommendation on ATMP classification is a specific procedure established by EU regulation for ATMP developers [21]. Available to any applicant developing a product based on genes, cells, or tissues, this voluntary procedure helps determine whether a product meets the scientific and legal definition of an ATMP and, if so, which specific category it belongs to [21] [1]. According to Article 17 of the ATMP Regulation, the EMA delivers a recommendation within 60 days of receiving a valid request, following consultation with the European Commission [21]. This classification procedure is particularly valuable given the technical complexities and borderline cases that often arise when categorizing innovative biological medicines.

Table 1: Types of Advanced Therapy Medicinal Products (ATMPs)

ATMP Category	Definition	Key Characteristics
Gene Therapy Medicinal Product (GTMP)	Contains genes that lead to therapeutic, prophylactic or diagnostic effect [2].	Works by inserting 'recombinant' genes into the body; used for genetic disorders, cancer, or long-term diseases [2].
Somatic-Cell Therapy Medicinal Product (sCTMP)	Contains cells or tissues that have been manipulated to change their biological characteristics [2].	Cells/tissues not intended for the same essential functions in the body; used to cure, diagnose, or prevent diseases [2].
Tissue-Engineered Medicines	Contains cells or tissues that have been modified to repair, regenerate, or replace human tissue [2].	Based on cells or tissues developed in laboratories for tissue regeneration, repair, or replacement [1].
Combined ATMP	Contains one or more medical devices as an integral part of the medicine [2].	Example: cells embedded in a biodegradable matrix or scaffold [2].

Scientific Assessment of Marketing Authorization Applications

For ATMPs undergoing the centralized marketing authorization procedure, the CAT conducts a comprehensive scientific assessment of the quality, safety, and efficacy data [20] [1]. The committee prepares a draft opinion on each ATMP application, which it submits to the Committee for Medicinal Products for Human Use (CHMP) [20] [1]. The CHMP then issues a final opinion recommending or not recommending authorization, which forms the basis for the European Commission's final decision [1]. This assessment process is particularly rigorous for ATMPs due to their complex biological nature, potential long-term risks, and innovative mechanisms of action.

Detailed Procedure for ATMP Classification

Application Process and Timelines

The classification procedure begins when a developer submits a request using specific EMA forms, accompanied by detailed scientific and regulatory information about the product [21]. The process follows a structured timeline with specific submission dates aligned with the CAT's monthly meetings in Amsterdam [21]. The procedure is free of charge, making it accessible to developers of all sizes, including academia and small and medium-sized enterprises (SMEs) [21].

Table 2: CAT Classification Procedure Overview

Aspect	Description
Legal Basis	Article 17 of Regulation (EC) N° 1394/2007 [21]
Type of Procedure	Voluntary but strongly advised in case of classification doubt [21]
Cost	Free of charge [21]
Timetable	60-day evaluation period from receipt of valid request [21]
Decision Maker	CAT, after consultation with the European Commission [21]
Binding Nature	Not legally binding, but generally followed by National Medicines Agencies [21]

Key Considerations in Classification Decisions

The CAT evaluates several scientific and regulatory factors when classifying potential ATMPs. A central consideration is whether cells or tissues have undergone substantial manipulation or are intended for use for different essential functions [2]. For example, stem cells are categorized as ATMPs when they undergo substantial manipulation or are used for a different essential function [2]. The CAT also considers the product's mechanism of action, biological characteristics, and whether it incorporates medical devices (in the case of combined ATMPs) [21] [2]. The committee's assessment is based on the legal definitions provided in the ATMP Regulation and related directives, applied to the specific characteristics of the product in question [21].

CAT's Role in the ATMP Marketing Authorization Pathway

The relationship between ATMP classification and the subsequent marketing authorization process is sequential and interdependent, as visualized below.

Methodological Framework for ATMP Classification and Assessment

The CAT employs a rigorous methodological approach when evaluating ATMPs, drawing upon established regulatory and scientific principles.

Experimental and Documentation Protocols

ATMP developers must provide comprehensive documentation to support both classification requests and marketing authorization applications. For classification, this includes detailed information about the product's manufacturing process, characterization, and mechanism of action [21]. For marketing authorization, the evidence requirements are substantially more comprehensive, encompassing:

• Quality Data: Detailed information on manufacturing processes, quality control, and product characterization, following Good Manufacturing Practice (GMP) guidelines for ATMPs [1].
• Non-Clinical Data: Results from in vitro and in vivo studies demonstrating proof of concept, safety, and dose-finding [2].
• Clinical Data: Evidence from clinical trials demonstrating safety and efficacy in the target patient population, often requiring long-term follow-up to monitor delayed adverse events [2].

The CAT places particular emphasis on the risk-based approach, requiring robust risk management systems and pharmacovigilance plans tailored to address the specific safety concerns of ATMPs, including potential tumorigenicity, unintended biodistribution, and long-term biological effects [2].

Analytical Framework for ATMP Classification

The methodological approach to ATMP classification involves a systematic assessment against established legal criteria:

Regulatory Tools and Support Mechanisms for ATMP Developers

The CAT provides several additional regulatory tools and support mechanisms to facilitate ATMP development.

Table 3: CAT Regulatory Tools and Support Mechanisms

Tool/Mechanism	Purpose	Target Audience
ATMP Certification	Certification of quality and non-clinical data for SMEs [20].	Small and medium-sized enterprises (SMEs) [20].
Scientific Advice	Advice on ATMP development plans, in cooperation with the Scientific Advice Working Party (SAWP) [20].	All ATMP developers [20].
Pilot for Academia	Increased regulatory support for academic and non-profit developers [2].	Academia and non-profit organizations [2].
Training Materials	Online training modules to help navigate the ATMP regulatory environment [2].	ATMP developers, available via TransMed Academy [2].

Current Developments and Future Perspectives in ATMP Regulation

The regulatory landscape for ATMPs is evolving rapidly. The European Commission has proposed a full reform of EU pharmaceutical legislation that would transform the CAT from a permanent scientific committee to a working party [21]. The CAT scientific recommendation on ATMP classification would be replaced by a general procedure of EMA's scientific recommendation on regulatory status, covering medicines at large, including ATMPs [21]. However, this remains a proposal subject to change during the legislative process.

Simultaneously, new regulations are being implemented that affect ATMP development. The Substances of Human Origin (SoHO) Regulation (EU) 2024/1938, applicable from 2027, will replace existing directives on blood, cells, and tissues, expanding regulation to all human-origin substances (except solid organs) and establishing SoHO national authorities with authorization, oversight, and control functions [1]. This regulation aims to scale up the availability of such substances, promote cross-border circulation, and enhance cooperation among public health authorities across EU Member States [1].

Furthermore, ongoing initiatives like the EU-US-Multiregional Joint Task Force aim to develop common principles and standards for ATMP development, facilitating global alignment and potentially streamlining international regulatory requirements [22]. These developments highlight the dynamic nature of ATMP regulation and the continuing central role of scientific assessment in ensuring both patient safety and access to innovative therapies.

Table 4: Key Regulatory Resources for ATMP Development

Resource	Function	Application in ATMP Development
Reflection Paper on ATMP Classification (EMA/CAT/600280/2010) [21]	Provides guidance on interpreting ATMP legal definitions and classification criteria.	Essential preparatory reading before submitting classification request.
Procedural Advice on ATMP Classification (EMA/CAT/99623/2009) [21]	Details procedural requirements for submission and evaluation of classification requests.	Guides the formal application process and documentation requirements.
Good Manufacturing Practice (GMP) Guidelines for ATMPs [1]	Sets standards for manufacturing quality and consistency.	Critical for establishing compliant manufacturing processes.
CAT Quarterly Highlights and Approved ATMPs [23]	Provides updates on CAT activities and recently approved ATMPs.	Offers insights into current regulatory thinking and precedents.
SoHO Regulation ((EU) 2024/1938) [1]	Regulates quality and safety standards for substances of human origin.	Governs the use of human tissues and cells as starting materials for ATMPs.

The Committee for Advanced Therapies plays an indispensable role in the European regulatory framework for advanced therapies, serving as the scientific arbiter for both ATMP classification and marketing authorization assessment. Its multidisciplinary expertise ensures that innovative biological medicines are evaluated against the highest scientific standards, balancing the imperative of patient safety with the need to facilitate access to groundbreaking treatments. For researchers, scientists, and drug development professionals working in the ATMP field, understanding the CAT's functions, procedures, and methodological approaches is fundamental to successfully navigating the EU regulatory system from product conception through to marketing authorization and beyond. As the ATMP field continues to evolve, the CAT's role in providing scientific clarity and regulatory oversight will remain crucial to the responsible advancement of these transformative therapies.

The Road to Compliance: A Step-by-Step Guide to GMP and Manufacturing Authorization

The European Union's regulatory framework for Advanced Therapy Medicinal Products (ATMPs) establishes a comprehensive system to ensure these innovative therapies meet stringent quality, safety, and efficacy standards. ATMPs—encompassing gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs—represent the cutting edge of medicinal innovation, often offering potential one-time curative treatments for previously untreatable conditions [2]. Under EU law, any legal entity manufacturing medicinal products must obtain a manufacturing authorisation from the national competent authority of the Member State where the activities occur [3]. This authorisation necessitates strict adherence to Good Manufacturing Practice (GMP) principles, defined as "the part of quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use" [3] [24].

Recognizing the unique challenges posed by ATMPs—including the use of substances of human origin, complex manufacturing processes, and often limited shelf-life—the European Commission established dedicated GMP guidelines. These are found in EudraLex Volume 4, Part IV: Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products [25] [26]. Published in 2017, Part IV provides a standalone GMP framework tailored to ATMPs, acknowledging their distinct nature from conventional biologics and other medicinal products. This specific guidance was developed in accordance with Article 5 of Regulation (EC) No 1394/2007 on ATMPs and operates alongside the centralised marketing authorisation procedure mandatory for all ATMPs in the EU [3] [2] [24].

Core GMP Guidelines for ATMPs: Part IV and Governing Directives

The Legal Basis of Part IV GMP

Part IV of EudraLex Volume 4 serves as the primary GMP guidance for ATMP manufacturers, created to address the specific characteristics and challenges of these products. Its legal foundation is established through several key directives and regulations [25]:

• Commission Directive (EU) 2017/1572: Supplements Directive 2001/83/EC regarding GMP principles for medicinal products for human use.
• Commission Delegated Regulation (EU) 2017/1569: Specifies GMP principles and guidelines for investigational medicinal products for human use, supplementing Regulation (EU) 536/2014 on clinical trials.
• Regulation (EC) No 1394/2007: The overarching regulation on advanced therapy medicinal products that mandated the creation of specific GMP guidelines for ATMPs.

A significant feature of Part IV is its standalone nature. When it was adopted, the European Commission simultaneously updated Annex 2 of EudraLex Volume 4 to remove all references to ATMPs, directing manufacturers to rely exclusively on Part IV for ATMP-specific GMP guidance [26]. This deliberate separation created a dedicated regulatory pathway for ATMPs but also means that general updates to other parts of the GMP guidelines—such as the recent revision of Annex 1—are not automatically reflected in the ATMP-specific rules [27].

Key Principles and Scope of Part IV

Part IV builds upon established GMP principles while incorporating necessary flexibility for ATMP complexities. It emphasizes a risk-based approach (RBA), granting manufacturers ownership over implementing appropriate control measures for their unique manufacturing processes [26]. The guidelines cover the entire manufacturing spectrum for ATMPs, from managing starting materials of human origin to final product release.

Notably, Section 1.15 of Part IV explicitly states that "These Guidelines do not intend to place any restrain on the development of new concepts of new technologies. While this document describes the standard expectations, alternative approaches may be implemented by manufacturers if it is demonstrated that the alternative approach is capable of meeting the same objective" [26]. This provision creates a balance between ensuring product quality, safety, and efficacy while encouraging continued innovation in ATMP development and manufacturing.

Critical Annexes and Related GMP Documents

The Role of Annexes in ATMP GMP

While Part IV operates as the primary ATMP GMP document, several annexes from EudraLex Volume 4 provide critical supplementary guidance for specific scenarios. The applicability of these annexes to ATMPs requires careful assessment, particularly given the standalone nature of Part IV. The following table summarizes the key GMP documents and their relevance to ATMP manufacturing:

Table 1: Key EU GMP Documents Relevant to ATMP Manufacturing

Document	Title/Subject	Relevance to ATMPs	Key Considerations
EudraLex Vol. 4, Part IV	GMP specific to ATMPs	Primary, standalone guideline	Tailored to ATMP complexities; mandatory for authorized ATMPs and investigational ATMPs in clinical trials [26] [24]
Annex 1	Manufacture of Sterile Medicinal Products	Context-dependent	Not automatically applicable per Part IV; however, many ATMP processes requiring aseptic handling may align with its principles, especially when sterile filtration isn't possible [26]
Annex 13	Good Manufacturing Practice for Investigational Medicinal Products	Applicable	Provides GMP requirements for ATMPs used in clinical trials [25]
Annex 2	Manufacture of Biological Active Substances and Medicinal Products for Human Use	Not applicable	Specifically excluded for ATMPs; Part IV is the controlling guidance [25] [26]
PIC/S Annex 2A	Manufacture of Advanced Therapy Medicinal Products for Human Use	Alternative reference	PIC/S approach differs from EU, keeping ATMPs within annexes and frequently referencing Annex 1 [26]

Proposed Revisions to Part IV

On 8 May 2025, the European Medicines Agency (EMA) issued a Concept Paper proposing a significant revision of Part IV [27] [10]. The proposed updates aim to address several critical areas:

• Alignment with Revised Annex 1: Harmonizing ATMP-specific GMP requirements with the modified provisions for manufacturing sterile medicinal products, particularly emphasizing the development and implementation of a Contamination Control Strategy (CCS) [10].
• Integration of ICH Concepts: Incorporating principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) to promote systematic quality risk management and robust pharmaceutical quality systems [27] [10].
• Adaptation to Technological Advancements: Providing clarifications on qualifying, controlling, and managing new technologies such as automated systems, closed single-use systems, and rapid microbiological testing methods [10].
• Updates on Cleanroom and Barrier Systems: Offering further clarifications on expectations for cleanroom classifications and the use of barrier systems while maintaining provisions for biosafety cabinets essential for manual manipulations in individualized ATMP batches [10].
• Legal References and Definitions: Updating references and definitions related to starting materials of human origin following new regulations on quality and safety standards for these substances [10].

The public consultation period for this revision concluded on 8 July 2025 [10] [28]. The proposed changes signify a potential evolution in the regulatory landscape for ATMPs, aiming to enhance clarity, incorporate modern quality management principles, and reflect technological progress in the field.

The Manufacturing Authorisation Process for ATMPs

Pathway to Authorization

Obtaining a manufacturing authorisation for ATMPs involves a structured process with multiple regulatory actors. The pathway from application to authorized manufacturing involves several key stages and entities, as illustrated in the following workflow:

Diagram 1: ATMP Manufacturing Authorisation Process

Key Actors and Their Roles

The manufacturing authorisation ecosystem for ATMPs involves multiple specialized entities with distinct responsibilities:

• Manufacturing Authorisation Applicant/Holder: The legal entity (company or institution) manufacturing ATMPs that must comply with EU quality standards to obtain and maintain the authorisation. They must establish and maintain a Pharmaceutical Quality System and employ a Qualified Person (QP) responsible for ensuring compliance with authorisation requirements and applicable legislation [3] [24].

• National Competent Authorities (NCAs): Regulatory bodies in each Member State responsible for assessing manufacturing authorisation applications, conducting regular on-site GMP inspections, controlling laboratory samples, and taking regulatory action in cases of non-compliance. For ATMPs, NCAs are also responsible for the official batch release of these biological medicinal products [3] [24].

• European Medicines Agency (EMA): Coordinates and harmonizes GMP activities across the EU to ensure common interpretation. It chairs the Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG), maintains the compilation of GMP inspection-related procedures, and operates the EudraGMDP database containing manufacturing authorisations, GMP certificates, and non-compliance statements [3] [24].

• Committee for Advanced Therapies (CAT): EMA's expert committee responsible for the scientific assessment of ATMPs during the marketing authorisation procedure. The CAT prepares draft opinions on ATMP quality, safety, and efficacy, provides recommendations on ATMP classification, and advises on pharmacovigilance and risk management systems [2].

Practical Implementation and Compliance Strategies

Implementing a Risk-Based Approach

Given the unique challenges and regulatory complexities of ATMP manufacturing, a robust risk-based approach (RBA) is fundamental to successful GMP compliance. The RBA involves scientifically identifying risks inherent to the specific ATMP manufacturing process based on a holistic understanding of the product, materials, equipment, process closure, and other critical elements [26]. This approach is particularly vital when guidance documents do not directly address specific manufacturing scenarios, allowing manufacturers to demonstrate that their operations meet the quality, efficacy, and reliability principles underpinning the regulations.

Practical implementation of RBA for ATMPs should focus on:

• Product-Specific Risk Assessment: Systematic evaluation of risks associated with the specific ATMP's characteristics, including source materials (autologous vs. allogeneic), manufacturing complexity, and product stability.
• Process Understanding: Deep knowledge of critical process parameters and their impact on product quality attributes, particularly for personalized ATMPs with inherent biological variability.
• Control Strategy Development: Implementing tailored control measures based on the risk assessment, focusing on the points of highest risk to product quality and patient safety.
• Continuous Improvement: Regularly reviewing and updating the risk assessment as process knowledge increases throughout the product lifecycle.

Addressing Key ATMP Manufacturing Challenges

ATMP manufacturers face several distinct challenges that require specialized strategies for GMP compliance:

Table 2: Key ATMP Manufacturing Challenges and Compliance Strategies

Challenge	GMP Impact	Potential Compliance Strategy
Use of human origin materials with short shelf-life	Complex logistics and limited time for quality control [3]	Robust supply chain management, validated transport conditions, real-time quality control methods
Inability to use sterile filtration	Entire process may need aseptic handling [26]	Strict environmental controls, closed processing systems, rigorous aseptic process validation
High variability in starting materials (especially autologous)	Batch consistency challenges [3] [26]	Process validation demonstrating control of variability, defined acceptance criteria for starting materials
Scalability limitations for personalized ATMPs	Multiple small batches manufactured concurrently [26]	Scale-out approach with standardized processes per batch, facility design supporting parallel processing
Complex and costly manufacturing processes	Significant resource investment with long return timeline [3]	Phase-appropriate GMP implementation, leveraging risk-based approaches to focus resources

The Scientist's Toolkit: Essential Elements for ATMP GMP Compliance

Successful navigation of the ATMP GMP landscape requires specific tools and approaches:

Table 3: Essential Toolkit for ATMP GMP Compliance

Tool/Element	Function/Purpose	Application in ATMP Context
Pharmaceutical Quality System	Ensures medicinal products have the quality required for their intended use [24]	Overall framework for managing quality throughout the ATMP lifecycle
Quality Risk Management (ICH Q9)	Proactive identification and control of potential quality issues [10]	Systematic approach to addressing ATMP-specific risks (variability, sterility, etc.)
Contamination Control Strategy	Comprehensive approach to prevent microbial contamination [10]	Critical for aseptic processes where terminal sterilization or sterile filtration isn't feasible
Closed Processing Systems	Physical separation of product from processing environment [26]	Enables reduced cleanroom classification while maintaining sterility assurance
EudraGMDP Database	Repository of GMP compliance information [3] [24]	Due diligence on manufacturing partners and understanding regulatory compliance status

Future Directions and Regulatory Evolution

The regulatory landscape for ATMP GMP continues to evolve rapidly. The proposed revision of Part IV signals a significant step toward modernizing the framework to better align with current technological capabilities and quality management principles [27] [10]. Additionally, ongoing developments in decentralized manufacturing models may necessitate further regulatory adaptations. The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions that could allow decentralized manufacturing sites to operate under the responsibility of a central site's Qualified Person, potentially easing the regulatory burden for point-of-care ATMP manufacturing [3].

The European Commission and EMA's joint action plan on ATMPs, along with initiatives like the ATMP pilot for academia and non-profit organizations, demonstrate a commitment to addressing the specific needs of ATMP developers while maintaining high quality standards [2]. Furthermore, the EMA's publication of the Guideline on clinical-stage ATMPs (effective July 1, 2025) provides consolidated multidisciplinary guidance for investigational ATMPs, representing another step toward regulatory clarity in this rapidly advancing field [4].

As the ATMP sector continues to mature, manufacturers must maintain awareness of evolving regulatory expectations while implementing robust, science-based quality systems that can adapt to both regulatory changes and product-specific challenges. The successful navigation of this complex landscape requires ongoing engagement with regulatory authorities, strategic application of risk-based principles, and commitment to quality throughout the product lifecycle.

The development and manufacturing of Advanced Therapy Medicinal Products (ATMPs) represent one of the most innovative yet challenging frontiers in modern medicine. ATMPs—encompassing gene therapies, somatic cell therapies, and tissue-engineered products—introduce unique complexities that demand robust, adaptable quality systems [2]. Within the European Union, ATMPs are strictly regulated under Regulation (EC) No 1394/2007, which mandates specific quality and safety standards throughout the product lifecycle [6]. Unlike conventional pharmaceuticals, ATMPs often utilize viable biological materials with inherent variability, complex manufacturing processes, and limited shelf lives, necessitating quality systems that can effectively manage these unique challenges [3].

The International Council for Harmonisation (ICH) developed the Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) guidelines to provide structured frameworks for ensuring product quality, safety, and efficacy. For ATMP manufacturers seeking authorization in the EU, integrating these principles is not merely beneficial—it is fundamental to navigating the stringent regulatory landscape and achieving compliance with Good Manufacturing Practice (GMP) requirements specific to ATMPs [3] [27]. This technical guide examines the integration of ICH Q9 and Q10 principles within the context of EU ATMP manufacturing authorization, providing researchers and drug development professionals with a comprehensive framework for building effective, compliant quality systems.

ATMP Manufacturing Authorization in the EU: The Regulatory Framework

Legal Foundations and Key Requirements

In the European Union, any legal entity intending to manufacture ATMPs must obtain a manufacturing authorization from the national competent authority of the Member State where the manufacturing activities occur [3]. This requirement is established under Article 40 of Directive 2001/83/EC for medicinal products for human use. The authorization process requires demonstration of full compliance with EU GMP standards, which for ATMPs are detailed in the dedicated GMP guidelines specific to ATMPs published by the European Commission in 2017 according to Article 5 of Regulation (EC) No 1394/2007 [3]. The regulatory framework emphasizes that quality assurance is an ongoing process that continues throughout the product lifecycle, with manufacturing sites subject to regular and repeated inspections by competent authorities to verify continued GMP compliance [3].

The European Medicines Agency (EMA) plays a coordinating role in harmonizing GMP activities across member states, while the Committee for Advanced Therapies (CAT) provides specialized scientific evaluation of ATMPs [2]. Importantly, ATMPs are authorized centrally through the EMA, ensuring a single evaluation procedure applies across the EU/EEA market [2]. Recent regulatory developments include a 2025 concept paper proposing revisions to EU GMP Part IV (specific to ATMPs) to better align with updates in other GMP annexes and incorporate modern quality concepts, including those from ICH Q9 and Q10 [27].

Unique ATMP Manufacturing Challenges

ATMP manufacturers face distinct challenges that directly impact quality system design, largely stemming from the use of substances of human origin composed of live cells with limited shelf lives [3]. The table below summarizes these key challenges and their quality system implications:

Table: Key ATMP Manufacturing Challenges and Quality System Implications

Challenge Category	Specific Challenges	Impact on Quality System Design
Process Complexity	Use of biological materials with inherent variability; complex manipulation steps; autologous vs. allogeneic processes [3]	Requires enhanced process controls; rigorous raw material qualification; extensive characterization and validation
Logistical Concerns	Limited shelf life; maintaining cold chain; collection of patient cells and transportation to manufacturing facility [3]	Necessitates robust supply chain controls; real-time monitoring; contingency planning
Production Model	Scale-out manufacturing for autologous products; potential need for decentralized manufacturing sites [3]	Demands multi-site quality management; standardized procedures across locations; centralized oversight
Technical Hurdles	Maintaining sterility throughout process; difficulty validating process consistency with small batch sizes [3]	Requires advanced aseptic processing controls; innovative process validation approaches; risk-based testing strategies

These challenges necessitate a pharmaceutical quality system that is both rigorously structured and sufficiently adaptable—precisely what the integrated ICH Q9 and Q10 framework provides.

Core Principles of ICH Q9 and ICH Q10

ICH Q9: Quality Risk Management

ICH Q9 establishes a systematic quality risk management (QRM) process that provides a proactive approach to identifying, assessing, controlling, communicating, and reviewing risks to product quality [29] [30]. The guideline is built on two fundamental principles: first, that quality risk assessment should be based on scientific knowledge and ultimately link to patient protection; and second, that the level of effort, formality, and documentation of the QRM process should be commensurate with the level of risk [29]. For ATMP manufacturers, this risk-based approach is particularly crucial given the unique risk profiles and often limited historical manufacturing data for these innovative products.

The QRM process follows a structured workflow that can be visualized as follows:

QRM Process Flow

ICH Q10: Pharmaceutical Quality System

ICH Q10 describes a comprehensive pharmaceutical quality system (PQS) model designed to complement existing GMP requirements by emphasizing product lifecycle management and continual improvement [30]. The guideline establishes three primary objectives: (1) achieving product realization by ensuring products consistently meet required quality standards; (2) establishing and maintaining a state of control through effective process performance and product quality monitoring; and (3) facilitating continual improvement of both processes and products [30].

The PQS model encompasses four key process elements along with management responsibilities that form the system foundation:

Table: Core Elements of the ICH Q10 Pharmaceutical Quality System

PQS Element	Key Components	Implementation Considerations for ATMPs
Process Performance & Product Quality Monitoring	Real-time and periodic monitoring; statistical process control; stability testing [30]	Enhanced real-time monitoring of critical process parameters; extended process and product characterization; customized stability protocols
Corrective and Preventive Action (CAPA) System	Deviation detection; root cause investigation; corrective and preventive actions [30]	Specialized investigation techniques for biological products; enhanced preventive actions based on process understanding
Change Management System	Formal evaluation and approval of changes; impact assessment; implementation planning [30]	Rigorous assessment of changes to biological processes; comparability protocols for process changes
Management Review	Periodic assessment of system performance; data-driven decision making [30]	Regular review of novel process parameters; specialized metrics for ATMP manufacturing
Management Responsibilities	Quality policy establishment; resource planning; quality culture promotion [30]	Active management commitment to addressing unique ATMP challenges; fostering science-based quality decisions

Integration Methodology: Implementing ICH Q9 and Q10 in ATMP Manufacturing

Strategic Integration Framework

Successful integration of ICH Q9 and Q10 principles within ATMP manufacturing requires a systematic approach that aligns with regulatory expectations while addressing product-specific challenges. The relationship between the PQS framework and risk management processes can be visualized as follows:

PQS and QRM Integration Framework

Implementation Roadmap and Experimental Approaches

Implementing an integrated PQS for ATMP manufacturing follows a phased approach that aligns with product development stages. The following table outlines key methodologies and their application points:

Table: Implementation Methodologies for Integrated Quality Systems

Implementation Phase	Key Methodologies	Protocol Details	ATMP-Specific Considerations
System Design	- Quality System Gap Analysis- Risk-Based Scope Definition- Process Mapping	Conduct comprehensive assessment against ICH Q10 model elements; identify existing system strengths and gaps	Focus on cell-based process peculiarities; address autologous vs. allogeneic differences; consider decentralized manufacturing models [3]
Risk Assessment	- Failure Mode Effects Analysis (FMEA)- Hazard Analysis Critical Control Points (HACCP)- Risk Ranking and Filtering	Apply structured risk assessment tools to manufacturing process; document rationale for risk decisions	Prioritize risks related to patient-specific materials; assess risks in novel purification processes; evaluate starting material variability [3]
Control Strategy	- Critical Process Parameter (CPP) Identification- Quality by Design (QbD) Principles- Process Analytical Technology (PAT)	Define proven acceptable ranges for CPPs; establish correlation between CPPs and Critical Quality Attributes (CQAs)	Account for raw material variability; implement real-time release testing where appropriate; address limited sample sizes [3]
Performance Monitoring	- Statistical Process Control (SPC)- Trend Analysis- Quality Metrics	Establish process capability indices; monitor trends in key parameters; set action limits	Develop customized control charts for biological processes; monitor donor-to-donor variability; track novel potency measures

Implementing an effective pharmaceutical quality system for ATMP manufacturing requires specific tools and approaches tailored to the unique characteristics of advanced therapies. The following table outlines essential resources and their applications:

Table: Essential Research Reagent Solutions for ATMP Quality Systems

Tool Category	Specific Applications	Function in Quality System	ATMP-Specific Considerations
Risk Assessment Tools	FMEA, HACCP, Risk Ranking and Filtering, Fault Tree Analysis	Systematic identification, analysis, and evaluation of risks to product quality and patient safety [29]	Application to novel manufacturing processes; addressing limited historical data; handling high inherent variability of biological systems
Process Characterization Assays	Cell potency assays, viability testing, genetic stability assessment, identity testing	Determination of Critical Quality Attributes (CQAs) and establishment of product specifications	Development of clinically relevant potency measures; characterization of novel cell types; addressing small sample sizes [3]
Quality Management Software	Electronic QMS, Document Management Systems, Learning Management Systems	Automation of quality processes; ensuring data integrity; facilitating management review	Adaptation to multi-site manufacturing models; handling complex batch records; managing customized manufacturing processes [30]
Data Analysis Platforms	Statistical analysis software, Process monitoring tools, Trend analysis applications	Process performance quantification; identification of improvement opportunities; supporting continual improvement	Analysis of complex biological data sets; handling limited batch numbers; managing correlated process parameters

Regulatory Considerations and Compliance Strategy

Addressing EU-Specific Requirements

For ATMP manufacturers seeking authorization in the European Union, several specific regulatory considerations must be addressed within the quality system. The EU regulatory framework for ATMPs includes stringent requirements for donor eligibility determination, traceability, and GMP compliance specific to advanced therapies [6] [3]. Recent guidance emphasizes that "immature quality development may compromise use of clinical trial data to support a marketing authorization," highlighting the importance of robust quality systems even during early development stages [4].

Manufacturers must implement comprehensive change management systems that can accommodate the rapid technological evolution characteristic of ATMP development while maintaining regulatory compliance. The EU's variations regulation (Commission Regulation (EC) No 1234/2008) establishes specific requirements for reporting changes to authorized products, which must be incorporated into the PQS [6]. Additionally, pharmacovigilance legislation (including Regulation (EU) No 1235/2010 and Directive 2010/84/EU) establishes specific requirements for safety monitoring of ATMPs that should be integrated into the quality system [6].

Preparation for Regulatory Interactions

Effective quality systems facilitate successful regulatory interactions by ensuring comprehensive documentation and data-driven decision making. Manufacturers should prepare for scientific advice procedures with regulatory authorities, particularly through the EMA's priority medicines (PRIME) scheme, which provides opportunities for enhanced regulatory guidance on quality development [11]. The integrated PQS should generate the necessary evidence to support applications for conditional marketing authorization or accelerated assessment where appropriate, leveraging the risk-based approach to justify development decisions [11].

Manufacturers should also anticipate the increasing regulatory focus on knowledge management as a key enabler of effective quality systems. Regulatory assessments now frequently evaluate how organizations capture and utilize process and product knowledge throughout the lifecycle, making this an essential component of the PQS [30]. Documenting the application of quality risk management principles to key development and manufacturing decisions provides regulators with confidence in the robustness of the quality system.

Building a pharmaceutical quality system that effectively integrates ICH Q9 and Q10 principles provides ATMP manufacturers with a robust framework for addressing the unique challenges of advanced therapies while meeting stringent EU regulatory requirements. The integrated system enables science-based, risk-informed decision making throughout the product lifecycle, from initial development through commercial manufacturing. For researchers and drug development professionals working with ATMPs, implementing this comprehensive approach to quality is not merely a regulatory obligation—it is an essential component of delivering safe, effective, and innovative therapies to patients in need. As the regulatory landscape continues to evolve, with proposed revisions to EU GMP guidelines specifically addressing ATMPs, the foundational principles established in ICH Q9 and Q10 will remain essential to successful quality management [27].

In the European Union, the manufacture of Advanced Therapy Medicinal Products (ATMPs) is strictly regulated and requires formal authorization before any manufacturing activities can commence. This requirement stems from the complex nature of ATMPs, which include gene therapies, cell-based therapies, and tissue-engineered products that often exhibit inherent variability due to their biological origins [2]. The manufacturing authorization process ensures that these innovative therapies maintain consistent quality, safety, and efficacy profiles despite their complexity.

The legal foundation for ATMP manufacturing authorization is established under Article 40 of Directive 2001/83/EC, which mandates that any legal entity manufacturing medicinal products must hold a manufacturing authorization from the National Competent Authority (NCA) of the member state where the manufacturing activities occur [3]. This framework is further specified for ATMPs through Regulation (EC) No 1394/2007 and detailed Good Manufacturing Practice (GMP) guidelines adapted specifically for ATMPs published by the European Commission in 2017 [3]. These regulations collectively create a robust system designed to address the unique challenges presented by ATMP manufacturing while ensuring patient safety and product quality.

Prerequisites for Application Submission

Before submitting a manufacturing authorization application, applicants must ensure they meet several critical prerequisites. These foundational requirements demonstrate to regulatory authorities that the organization possesses the necessary infrastructure, expertise, and systems to undertake GMP-compliant manufacturing of ATMPs.

Facility and Quality System Requirements

• GMP-Compliant Facilities: Manufacturing sites must be designed and maintained in accordance with EU GMP standards, with specific attention to the Guidelines on GMP Specific to ATMPs. This includes appropriate cleanroom classifications, environmental monitoring systems, and material flow designed to prevent cross-contamination [3].
• Quality Management System: Implementation of a comprehensive Pharmaceutical Quality System as described in ICH Q10 is mandatory. This system must cover all aspects of operations, including documentation control, deviation management, corrective and preventive actions (CAPA), change control, and internal audit programs [31].
• Qualified Personnel: Organizations must employ sufficiently qualified staff with expertise relevant to ATMP manufacturing. Most critically, they must have a designated Qualified Person (QP) who bears responsibility for certifying that each product batch has been manufactured and tested in compliance with relevant regulations [3].

Technical Documentation Preparation

• Manufacturing Process Description: Detailed documentation of the entire manufacturing process, including in-process controls and intermediate specifications, must be prepared [15] [32].
• Validation Strategies: Preliminary documentation regarding process validation, analytical method validation, and cleaning validation approaches should be established, even if full validation data will be generated post-authorization [31].
• Supplier Qualifications: Documentation demonstrating qualification of critical suppliers, particularly for starting materials of human or animal origin, must be available [3] [33].

Required Documentation for Application

The manufacturing authorization application requires comprehensive documentation demonstrating compliance with all regulatory requirements. The application dossier follows a modular structure similar to the Common Technical Document (CTD) format, with specific adaptations for ATMPs [34].

Administrative and Quality Documentation

Table 1: Core Documentation Modules for Manufacturing Authorization Application

Module	Documentation Requirements	Purpose and Significance
Administrative Information	Completed application form, Site Master File, organizational charts, personnel qualifications, manufacturing authorizations for other sites (if applicable)	Demonstrates legal compliance and organizational capability [3] [35]
Manufacturing Process Description	Detailed step-by-step manufacturing process, in-process controls, process validation data or strategy, batch records	Provides evidence of process understanding and control [15] [32]
Quality Control Documentation	Specifications for starting materials, intermediates, and final product, analytical procedures, method validation data, stability data	Demonstrates ability to verify product quality [31] [32]
Premises and Equipment Documentation	Facility layout diagrams, equipment qualification (IQ/OQ/PQ), cleaning validation, environmental monitoring data	Establishes suitable manufacturing environment [3]
Quality Assurance Systems	Quality Manual, document control procedures, deviation management, CAPA system, change control, supplier qualification	Shows robust quality system implementation [3]

The Site Master File deserves particular attention as it provides regulatory authorities with a comprehensive overview of the manufacturing site's quality management systems, facilities, equipment, and operations. This document should be carefully structured to accurately reflect the GMP status of the site and its specific suitability for ATMP manufacturing [3].

ATMP-Specific Documentation Considerations

For ATMP manufacturers, several specialized documents require particular emphasis:

• Donor Screening and Testing Protocols: Detailed procedures for donor eligibility determination, especially for allogeneic products, including testing for relevant communicable diseases and procedures for cell poolings where applicable [4].
• Traceability Systems: Comprehensive systems ensuring full traceability from donor to patient and vice versa, as required by the ATMP Regulation [3] [33].
• Environmental Risk Assessment (ERA): For ATMPs containing genetically modified organisms (GMOs), a thorough ERA must be included, addressing containment measures and potential environmental impacts [31] [33].
• Storage and Transport Protocols: Detailed procedures for cryopreservation, storage conditions, and transportation validation data, particularly critical for ATMPs with limited shelf lives [3].

Submission Pathways and Regulatory Interactions

The manufacturing authorization application follows defined pathways with opportunities for strategic regulatory interactions that can significantly enhance the likelihood of success.

Application Submission Process

The manufacturing authorization application is submitted directly to the National Competent Authority (NCA) where the manufacturing site is located [3]. The submission process typically involves:

Figure 1: Manufacturing Authorization Application Journey

Following submission, the NCA conducts a completeness check within approximately 30 days, followed by a detailed assessment period typically lasting 60-90 days. During this assessment, reviewers evaluate the submitted documentation for compliance with GMP standards and ATMP-specific requirements [3]. A critical component of the evaluation process is the on-site GMP inspection, where regulators verify that the actual facilities, equipment, operations, and quality systems align with the submitted documentation [3]. Successful completion of this process results in the granting of the manufacturing authorization.

Strategic Regulatory Interactions

Engaging with regulatory authorities throughout the development process significantly strengthens manufacturing authorization applications:

• Simultaneous National Scientific Advice (SNSA): This pilot program allows applicants to receive coordinated feedback from two NCAs simultaneously, promoting alignment on regulatory expectations and identifying potential issues early [36].
• EMA Innovation Task Force (ITF): Briefing meetings provide a platform for early dialogue on innovative manufacturing technologies or novel ATMPs, facilitating informal exchanges before formal submission [33].
• National Scientific Advice: Individual NCAs offer scientific advice procedures addressing product-specific questions related to manufacturing processes, quality controls, and validation strategies [36].

These interactions are particularly valuable for addressing ATMP-specific challenges such as decentralized manufacturing models, point-of-care production, and novel analytical methods for complex biological products [15] [3].

Compliance and Post-Authorization Responsibilities

Securing manufacturing authorization initiates an ongoing obligation to maintain compliance and fulfill post-authorization responsibilities.

Ongoing Compliance Obligations

Table 2: Post-Authorization Compliance Activities

Activity	Frequency	Key Requirements
GMP Compliance Maintenance	Continuous	Adherence to GMP guidelines, maintenance of quality systems, ongoing personnel training [3]
Regular Inspections	Typically every 2-3 years	Routine GMP inspections conducted by NCAs to verify ongoing compliance [3]
Pharmacovigilance	Continuous	System for monitoring adverse reactions, reporting of suspected adverse reactions to authorities [34]
Product Quality Review	Annually	Structured annual review of product quality records, trends, and changes [35]
Variation Management	As needed	Submission of variations for manufacturing process changes per classification guidelines [35]

Manufacturing authorization holders must maintain GMP compliance through continuous monitoring and improvement of their quality systems. This includes regular self-inspections, documentation of observations, and implementation of corrective actions [3]. The Qualified Person plays a critical role in this ongoing compliance by certifying each batch before release and ensuring that quality defects are properly investigated and reported [3].

Handling Variations and Changes

Any changes to the authorized manufacturing process must be managed through the variation regulation framework. Variations are classified based on their potential impact on product quality, safety, or efficacy:

• Type IA Variations: Minor changes requiring notification within 12 months of implementation [35].
• Type IB Variations: More significant changes requiring prior approval before implementation, typically assessed within 30 days [35].
• Type II Variations: Major changes requiring comprehensive assessment before approval, with a typical timeline of 60-90 days [35].

For ATMPs, even seemingly minor changes may have significant implications due to product complexity, necessitating careful assessment and often comparability studies to demonstrate that the change does not adversely affect product quality [31] [4].

Common Challenges and Strategic Solutions

ATMP manufacturers face several unique challenges throughout the authorization process that require strategic approaches.

Technical and Operational Challenges

• Demonstrating Process Consistency: The inherent biological variability of ATMPs makes demonstrating process consistency particularly challenging. Solution: Implement advanced process analytics, digital monitoring tools, and comprehensive characterization methods to establish robust process understanding [15].
• Decentralized Manufacturing: Point-of-care manufacturing and multi-site production present significant regulatory challenges. Solution: Develop harmonized standard operating procedures, centralized quality control, and comparable protocols across all manufacturing sites [15] [3].
• Limited Shelf Lives: Many ATMPs have very short shelf lives, complictaining quality control testing before patient administration. Solution: Implement rapid testing methods, parametric release strategies where justified, and intermediate testing points [3].

Regulatory and Strategic Challenges

• Divergent National Requirements: While EU regulations are harmonized, national interpretations and additional requirements can vary. Solution: Engage in Simultaneous National Scientific Advice and leverage the EU Innovation Network to promote alignment [36].
• Complex Supply Chains: ATMPs often involve complex supply chains with multiple facilities handling starting materials and intermediates. Solution: Establish comprehensive quality agreements with all partners and implement robust track-and-trace systems [3] [33].
• Technology Evolution: The ATMP field evolves rapidly, with new manufacturing technologies emerging frequently. Solution: Engage regulators early through ITF briefings and protocol assistance when implementing novel technologies [33].

The manufacturing authorization landscape for ATMPs continues to evolve, with ongoing initiatives to optimize manufacturing processes, promote standardization, and enhance quality controls while maintaining the flexibility needed for these innovative therapies [15]. By understanding the documentation requirements, submission pathways, and compliance obligations outlined in this guide, manufacturers can navigate this complex regulatory environment more effectively, ultimately accelerating patient access to these transformative therapies.

Within the European Union's regulatory framework for Advanced Therapy Medicinal Products (ATMPs), the control of starting materials represents a critical juncture where quality assurance and regulatory compliance intersect. ATMPs, which encompass gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered products, are characterized by their complex biological starting materials—human tissues, cells, and blood [2]. The manufacturing authorization for ATMPs under EU law necessitates rigorous documentation and control strategies for these materials, as their variable biological nature directly impacts final product quality, safety, and efficacy. The European Medicines Agency (EMA) emphasizes that unregulated advanced therapies may put patients at significant risk, causing serious side effects without proven benefits, which often originates from inadequate control of starting materials [2].

The regulatory significance of starting material control extends throughout the ATMP lifecycle. From initial donor selection through processing and final product release, each manipulation of these biological substances must comply with evolving directives and guidelines. Recent regulatory developments, including the EMA's 2025 concept paper proposing revisions to Part IV of the EU Guidelines on Good Manufacturing Practice (GMP) specific to ATMPs, highlight the continued emphasis on this area [10]. The revisions specifically address updates to "legal references and definitions related to starting materials of human origin," reflecting the dynamic nature of the regulatory landscape [10]. This whitepaper provides a comprehensive technical guide to navigating these requirements, offering researchers, scientists, and drug development professionals detailed methodologies and frameworks for ensuring compliance while maintaining scientific rigor.

Regulatory Framework for ATMP Starting Materials

Definition and Classification of ATMPs

The regulatory framework for ATMP starting materials begins with understanding how ATMPs are defined and classified. The EMA categorizes ATMPs into three main types: gene therapy medicines, which contain recombinant genes that lead to therapeutic, prophylactic, or diagnostic effects; somatic-cell therapy medicines, which contain cells or tissues that have been manipulated to change their biological characteristics; and tissue-engineered medicines, which contain cells or tissues modified to repair, regenerate, or replace human tissue [2]. Additionally, some ATMPs may combine these elements with medical devices, classified as "combined ATMPs" [2]. Each category presents distinct considerations for starting material control, particularly regarding the extent of manipulation and the point at which the biological material transitions from a starting material to a drug substance.

The Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs within the EU, providing the specialized expertise required to evaluate these complex products [2]. For starting materials, this evaluation includes recommendations on classification and critical assessment of the quality, safety, and efficacy implications of the biological source materials. The CAT's evaluation informs the Committee for Medicinal Products for Human Use (CHMP), which adopts an opinion recommending or against authorization by the European Commission [2]. This multi-layered assessment process underscores the regulatory importance of well-characterized and properly controlled starting materials in ATMP development and commercialization.

Key Directives and Guidelines

The control of starting materials for ATMPs operates within a complex framework of EU directives and guidelines that have evolved to address the unique challenges these products present. The foundational regulation (EC) No 1394/2007 establishes the core framework for ATMPs in the EU, but several other directives specifically impact starting material control:

• Directive 2001/83/EC establishes the community code relating to medicinal products for human use, with specific provisions for ATMPs [37].
• Directive 2009/41/EC contains provisions on the contained use of genetically modified micro-organisms, relevant for certain gene therapy ATMPs [38].
• Directive 2001/18/EC addresses the deliberate release into the environment of genetically modified organisms, impacting environmental risk assessments for ATMPs containing GMOs [38].

The regulatory framework continues to evolve, with the EMA proposing revisions in 2025 to Part IV of the EU GMP guidelines specific to ATMPs [10]. These proposed revisions aim to align ATMP-specific GMP requirements with the updated Annex 1 (sterile manufacturing), incorporate principles from ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System), and provide clarifications on expectations for cleanroom classifications and barrier systems [10]. For starting materials specifically, the revisions will update "legal references and definitions related to starting materials of human origin" following the publication of new regulations on quality and safety standards for substances of human origin intended for human application [10].

Table 1: Key EU Directives and Guidelines Relevant to ATMP Starting Materials

Directive/Guideline	Scope	Key Implications for Starting Materials
Regulation (EC) No 1394/2007	ATMP Framework Regulation	Defines ATMPs and establishes centralized authorization procedure
Directive 2001/83/EC	Community Code on Medicinal Products	Sets requirements for quality, safety, and efficacy of medicinal products including ATMPs
Directive 2002/98/EC	Standards for Blood Components	Establishes quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components
Directive 2004/23/EC	Standards for Tissues and Cells	Sets standards for the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells
EU GMP Part IV (Under Revision)	GMP for ATMPs	Provides specific Good Manufacturing Practice requirements for ATMPs, including starting material controls

Compliance Requirements for Starting Materials

Donor Eligibility and Selection Criteria

The foundation of ATMP starting material control begins with rigorous donor eligibility assessment to prevent the transmission of infectious diseases and ensure the quality of the final product. EU directives mandate comprehensive donor screening and testing protocols that must be integrated into the ATMP manufacturer's quality system. The United States FDA's approach in its Human Cells, Tissues, and Cellular and Tissue-Based Products regulations provides a reference point, though EU-specific requirements must be followed [38]. Donor eligibility determination encompasses several critical components:

• Medical History Review: Comprehensive assessment of the donor's medical history, behavioral risk factors, and potential exposure to transmissible diseases through standardized questionnaires and interviews.
• Physical Assessment: Evaluation of the donor's physical condition focused on identifying signs of potential infectious diseases that might contraindicate donation.
• Laboratory Testing: Performance of specific licensed, approved, or cleared tests for relevant communicable disease agents, including HIV, Hepatitis B, Hepatitis C, and other pathogens based on the nature of the starting material and its intended use.

The implementation of these requirements must be documented in standard operating procedures, and each donor's eligibility determination must be recorded and maintained in the product documentation. For autologous donations, where the donor is also the recipient, different considerations apply, though many quality control measures remain essential. The complexity of donor eligibility is compounded in the EU by variations in implementation across member states, creating challenges for developing standardized approaches for multi-national trials or marketing applications [38].

Quality Control and Testing Requirements

ATMP starting materials must undergo comprehensive quality control testing to establish their suitability for manufacturing. The testing regimen varies based on the material type (tissues, cells, or blood), degree of manipulation, and intended use, but generally includes the following parameters:

• Identity Testing: Confirmation of the starting material's identity through morphological assessment, cell surface marker analysis, or other specific identifiers.
• Purity and Impurity Assessment: Evaluation of microbial contamination (sterility), endotoxin levels, and presence of process-related impurities.
• Potency and Viability Assessment: Measurement of biological activity, viability, and functional characteristics predictive of the material's performance in manufacturing.
• Characterization Testing: Analysis of phenotypic and genotypic markers, differentiation potential, and other relevant biological characteristics.

These testing protocols must be validated according to regulatory standards, with established acceptance criteria based on scientific rationale and process capability. The testing frequency (e.g., per donation, per batch) should be justified based on risk assessment and previous testing history. The table below outlines core testing requirements for different starting material types:

Table 2: Quality Control Testing Requirements for ATMP Starting Materials

Test Category	Specific Assays	Tissues	Cells	Blood
Microbiological	Sterility, Mycoplasma, Adventitious Viruses	Required	Required	Required
Identity	Cell Surface Markers, Morphology, Histology	Required	Required	Required (Blood Typing)
Viability/Potency	Viability, Growth Potential, Metabolic Activity	Conditional	Required	Required
Purity	Endotoxin, Residual Reagents, Process Impurities	Required	Required	Required
Genetic Stability	Karyotyping, Genetic Fingerprinting	Conditional	Conditional	Not Typically Required

Traceability and Documentation Systems

Maintaining complete traceability of starting materials from donor to recipient and vice versa represents a fundamental requirement under EU directives for ATMPs. This system ensures that, in the event of a quality or safety issue, all affected products can be identified and appropriate actions taken. The traceability system must capture and maintain at minimum the following information:

• Donor Identification: Unique donor code, demographic information, and eligibility determination.
• Starting Material Information: Unique identifier for the starting material, collection date and location, processing history, and storage conditions.
• Recipient Information: For allogeneic products, recipient identification and administration details.
• Distribution Records: Complete chain of custody from collection through processing, storage, and distribution.

The traceability system must be designed to facilitate rapid retrieval of information in both directions—from donor to final product and from final product back to donor. This requires robust data management systems, standardized identification methods, and procedures for reconciling records at each step of the process. Documentation requirements extend to all aspects of starting material control, including donor screening and testing records, processing and preservation protocols, quality control test results, storage conditions monitoring, and distribution records. These documents must be retained for specified periods—typically a minimum of 30 years after product expiration—and be readily available for regulatory inspection [2] [10].

Technical Implementation and Experimental Protocols

Process Flow for Starting Material Control

The control of starting materials follows a detailed workflow from donor selection through to final product release. The diagram below visualizes this comprehensive process, highlighting critical decision points and quality control checkpoints:

Diagram 1: Starting Material Control Workflow

Detailed Methodologies for Key Experiments

Donor Eligibility Assessment Protocol

The donor eligibility assessment represents the first critical control point in the starting material lifecycle. The following detailed protocol ensures compliance with EU directives:

Objective: To establish standardized procedures for determining donor eligibility for tissues, cells, and blood intended for use in ATMP manufacturing.

Materials and Equipment:

• Donor medical history questionnaire (approved version)
• Physical assessment equipment (thermometer, blood pressure monitor, etc.)
• Sample collection kits for infectious disease testing
• Certified laboratory facilities for testing
• Secure document storage system

Procedure:

• Informed Consent Process: Obtain informed consent using ethics committee-approved documentation, ensuring the donor understands the nature of donation, testing to be performed, and potential outcomes.
• Medical History Interview: Conduct comprehensive medical history interview using standardized questionnaire covering:
  • Demographic information
  • Past medical history, including malignancies, infections, autoimmune disorders
  • Surgical history, including prior transplants or transfusions
  • Travel history to regions with endemic infections
  • Behavioral risk factors for communicable diseases
  • Medication history, including prior gene therapy
• Physical Assessment: Perform focused physical examination assessing for signs of infectious disease or other conditions that might affect starting material quality.
• Sample Collection: Collect blood samples using aseptic technique for required infectious disease testing.
• Laboratory Testing: Submit samples to certified laboratory for testing against required panel, typically including:
  • HIV-1 and HIV-2 (NAT and serology)
  • Hepatitis B (HBsAg, anti-HBc, HBV NAT)
  • Hepatitis C (anti-HCV, HCV NAT)
  • Syphilis (serology)
  • Additional tests based on donor history and material type
• Eligibility Determination: Review all collected information against established acceptance criteria to determine final eligibility status.

Acceptance Criteria:

• No identified risk factors for communicable diseases
• Negative results on all required infectious disease testing
• No physical findings suggestive of infection
• No history of prior gene therapy or certain high-risk exposures

Documentation: Maintain complete records of all steps in donor record, including original consent form, completed questionnaire, physical assessment findings, test results, and eligibility determination justification.

Cell Viability and Potency Assay Protocol

For cellular starting materials, viability and potency assessment provides critical quality data. This flow cytometry-based protocol offers comprehensive characterization:

Objective: To quantitatively assess viability, cell surface markers, and functional characteristics of cellular starting materials.

Principle: Multiparameter flow cytometry allows simultaneous assessment of multiple cellular characteristics, including viability, specific surface markers indicative of cell type and differentiation status, and functional markers predictive of biological activity.

Materials and Reagents:

• Flow cytometry buffer (phosphate-buffered saline with fetal bovine serum)
• Viability dye (e.g., 7-AAD or propidium iodide)
• Fluorescently-conjugated antibodies against target antigens
• Isotype control antibodies
• Cell fixation buffer (if intracellular staining required)
• Flow cytometer with appropriate laser and detector configuration

Procedure:

• Sample Preparation: Prepare single-cell suspension from starting material, determining total and viable cell count.
• Staining Panel Design: Design antibody panel based on starting material type and critical quality attributes, ensuring fluorochrome compatibility and including appropriate viability marker.
• Staining Procedure:
  • Aliquot approximately 1×10^6 cells per staining tube
  • Add viability dye and incubate 10-15 minutes
  • Add antibody cocktail and incubate 20-30 minutes protected from light
  • Wash cells twice with flow cytometry buffer
  • Resuspend in appropriate volume for acquisition
• Data Acquisition: Acquire data on flow cytometer, collecting sufficient events for statistical analysis (typically ≥10,000 viable cell events).
• Data Analysis: Analyze data using flow cytometry analysis software, including:
  • Viability percentage calculation
  • Percentage positive for each marker compared to isotype controls
  • Complex analysis of co-expression patterns if required

Acceptance Criteria: Establishment of acceptance criteria should be based on process capability and correlation with manufacturing outcomes, but typically includes:

• Viability ≥70% for most cellular starting materials
• Expression of characteristic markers within expected range
• Absence or minimal presence of undesirable markers

Validation Requirements: Assay validation should establish precision, accuracy, specificity, and robustness, with defined limits of detection and quantification for critical parameters.

The Scientist's Toolkit: Essential Research Reagent Solutions

The implementation of compliant starting material control requires specialized reagents and materials designed to meet regulatory expectations while providing robust scientific data. The following table details essential solutions for researchers developing control strategies for tissues, cells, and blood in ATMP manufacturing:

Table 3: Essential Research Reagent Solutions for Starting Material Control

Reagent/Material Category	Specific Examples	Function in Starting Material Control	Regulatory Considerations
Donor Screening Kits	FDA-approved/CE-marked infectious disease testing kits, genetic screening arrays	Standardized assessment of donor eligibility and detection of transmissible agents	Requires appropriate regulatory status (CE marking), validation for intended use, inclusion in quality system
Cell Characterization Antibodies	Flow cytometry antibodies (CD markers, lineage-specific markers), immunohistochemistry antibodies	Identification and quantification of specific cell populations, assessment of differentiation status	Validation for specific application, documentation of specificity and cross-reactivity, stability data
Cell Culture and Preservation Media	Serum-free media, cryopreservation solutions, cytokine cocktails	Maintenance of cell viability and function during processing and storage	Composition documentation, endotoxin testing, sterility assurance, absence of animal components where required
Microbiological Testing Systems	Automated blood culture systems, PCR-based mycoplasma detection, endotoxin testing kits	Detection of bacterial, fungal, and mycoplasmal contamination, endotoxin quantification	Validation for specific cell types, inclusion of appropriate controls, defined limits of detection
Process Ancillary Materials	Enzymes for cell dissociation (collagenase, trypsin), cytokines, growth factors, antibodies for selection	Facilitation of processing steps while maintaining cell quality and function	Sourcing documentation, qualification testing, demonstration of removal during processing where required
Reference Standards and Controls	Cell line controls, quantitative standards for assays, isotype controls	System suitability testing, assay qualification, quantification standards	Traceability to recognized standards, stability data, appropriate characterization

Quality Risk Management Principles

The control of starting materials must be integrated into a systematic quality risk management process as emphasized in the proposed revisions to EU GMP Part IV, which plans to incorporate principles from ICH Q9 [10]. This approach requires manufacturers to identify, assess, control, and communicate risks associated with starting materials throughout their lifecycle. Implementation involves:

• Risk Identification: Systematic assessment of potential failure modes in starting material control, including donor screening, testing, processing, and storage.
• Risk Analysis: Evaluation of the severity of potential harm and probability of occurrence for each identified risk.
• Risk Control: Implementation of measures to reduce risks to acceptable levels, including process controls, testing strategies, and acceptance criteria.
• Risk Review: Periodic reassessment of risks based on accumulated data and experience.

This risk-based approach should be documented in a comprehensive risk management file for the ATMP, with specific sections addressing starting material-related risks. The application of quality risk management principles is particularly important for justifying the extent of controls applied to different starting materials and for establishing scientifically sound specifications.

Environmental Risk Assessment Considerations

For ATMPs containing or consisting of genetically modified organisms, EU directives require specific environmental risk assessment as part of the marketing authorization application [38]. This assessment must address potential risks related to the starting materials, particularly when they contain or are derived from GMOs. Key considerations include:

• Containment Levels: Appropriate physical and biological containment measures during handling of starting materials.
• Waste Management: Procedures for decontamination and disposal of waste materials containing GMOs.
• Accident Management: Protocols for handling spills or other accidental releases of starting materials containing GMOs.
• Post-Market Monitoring: Plans for monitoring potential environmental effects after product authorization.

The environmental risk assessment must be conducted in accordance with Directive 2009/41/EC and Directive 2001/18/EC, with specific guidance available from the EMA on the data requirements and assessment methodology [38] [2]. This represents an additional layer of regulatory consideration beyond the quality-focused controls for starting materials.

The control of starting materials—tissues, cells, and blood—represents a foundational element of ATMP manufacturing authorization in the EU regulatory framework. Compliance requires meticulous attention to donor eligibility assessment, comprehensive quality control testing, complete traceability systems, and integration of quality risk management principles. The regulatory landscape continues to evolve, as evidenced by the EMA's 2025 proposed revisions to GMP guidelines for ATMPs, which will further refine expectations for starting material control [10].

For researchers, scientists, and drug development professionals, successful navigation of these requirements demands both scientific rigor and regulatory awareness. Implementation of the detailed methodologies and frameworks presented in this technical guide provides a pathway to establishing compliant control strategies for ATMP starting materials. As the field advances, with increasing globalization of ATMP development and emergence of new technologies, the harmonization of starting material controls across regions remains an important objective to facilitate efficient global development of these promising therapies [38]. Through continued attention to these critical requirements, the ATMP field can realize its potential to address unmet medical needs while ensuring patient safety and product quality.

The Role of the Qualified Person (QP) in Batch Certification and Release

Within the European Union's regulatory framework for medicinal products, the Qualified Person (QP) holds a pivotal and legally mandated role in safeguarding public health. The QP's duty to certify batches of medicinal products for release is a critical control point, ensuring that every batch placed on the market or used in clinical trials has been manufactured and checked in accordance with the law, the requirements of the Marketing Authorisation (MA) or Clinical Trial Authorisation (CTA), and Good Manufacturing Practice (GMP) [39] [40]. This function is enshrined in EU GMP Annex 16, which provides the definitive guideline on certification by a QP and batch release [41]. In the context of Advanced Therapy Medicinal Products (ATMPs)—innovative and often complex therapies based on genes, cells, or tissues—the QP's role becomes even more critical. ATMP manufacturing authorization in the EU requires that the manufacturer must have a QP responsible for ensuring that all applicable legislative and quality standards are met [3]. This guide explores the technical responsibilities, legal accountabilities, and specific challenges of the QP, with a particular focus on the ATMP development landscape.

The Legal and Regulatory Framework of the QP

The position of the QP is established in EU directives and further detailed in the EudraLex Volume 4 guidelines, specifically in Annex 16 [41] [25]. The QP is not merely a title but a personal legal responsibility. When a QP signs a batch certification, they are personally liable for the decision; a defective batch certified knowingly could lead to personal legal consequences for the QP [42]. This level of accountability is unique compared to quality roles in other regions, such as the United States.

A fundamental principle of the QP's work is their reliance on a validated and effective Pharmaceutical Quality System (PQS). The QP must have ongoing assurance that the PQS is well-founded, which requires a deep understanding of systems for handling deviations, out-of-specification (OOS) results, change control, and annual Product Quality Reviews (PQR) [39]. The QP operates with full authority, and their certification decision cannot be overruled by company management [42].

Table 1: Core EU Regulatory Documents Governing QP Activities

Document Name	Relevance to the QP	Legal Status
EudraLex Vol. 4, Annex 16: Certification by a Qualified Person and Batch Release [41]	Provides the primary guidance on the QP's duties for batch certification and release.	Legally enforceable guideline.
Directive 2001/83/EC [3]	The foundational legal act for medicinal products for human use, establishing the requirement for a QP.	EU Directive (transposed into national law).
Commission Directive (EU) 2017/1572 [25]	Supplements Directive 2001/83/EC, specifying principles of GMP for human medicinal products.	EU Directive.
EMA Q&A on Remote Certification [43] [39]	Clarifies expectations for remote batch certification by QPs, including traceability and error reduction.	Interpretive guidance (reflects current regulatory expectations).

For ATMPs, the regulatory landscape includes additional layers. All ATMPs are authorized centrally via the European Medicines Agency (EMA) [2]. The manufacturer must hold a manufacturing authorization from the national competent authority of the Member State where the production occurs, and this authorization is contingent upon having a QP [3]. The European Commission has also issued detailed GMP guidelines specific to ATMPs to address their unique complexities [3].

The Batch Certification and Release Process: A Methodological Workflow

The batch release process is a meticulous sequence of verification and decision-making, culminating in the QP's certification. The following workflow and diagram outline the core methodology.

QP Batch Release Workflow

The methodology can be broken down into the following critical steps, which the QP must systematically review before certification:

• Verification of Manufacturing and Packaging: The QP reviews the complete batch manufacturing and packaging records to ensure all steps were performed correctly and in sequence according to the approved procedures [40].
• Verification of Testing and Results: All analytical test results and Certificates of Analysis (CoA) for the finished product and its components are scrutinized to confirm the batch meets its predefined specifications [40].
• Review of Deviations and Investigations: The QP must oversee and assess all deviations from the standard process, out-of-specification (OOS) results, and any ongoing investigations (e.g., complaints) to evaluate their impact on batch quality [39].
• Confirmation of GMP Compliance: The QP must ensure that all critical manufacturing and quality control processes have been validated and that the batch was produced in a state of control and in compliance with GMP [39].
• Confirmation of MA/CTA Compliance: The QP verifies that the batch conforms to the specific details outlined in the product's Marketing Authorization or Clinical Trial Authorization [40].
• QP Certification: Only after confirming that all requirements in steps 1-5 are satisfied does the QP formally certify the batch by signing the batch certificate [40]. This certification is a prerequisite for the batch to be released to the market [40].

For imported medicinal products, importation is considered a final manufacturing step. These products must undergo rigorous quality testing within the EU and receive QP certification before being transferred to saleable stock [40].

The QP's Role in the Context of ATMP Manufacturing Authorization

The manufacturing of ATMPs presents unique challenges that directly impact the QP's responsibilities. The European regulatory framework recognizes these challenges, and the QP's role is adapted accordingly.

Table 2: ATMP Manufacturing Challenges and Implications for the QP

ATMP Challenge	Description	QP Consideration
Variable Starting Materials	Use of autologous cells or tissues with inherent biological variability [3].	The QP must ensure the quality system is robust enough to handle variability and that incoming material checks are stringent.
Complex & Short Shelf-Life	Products often have limited shelf-life, complicating logistics and testing [3].	The QP must confirm that storage, transport conditions, and release timelines are rigorously defined and adhered to.
Process Validation Difficulty	Small batch sizes (e.g., autologous) limit the ability to perform traditional process validation [3].	The QP must rely on extensive process characterization and validation of critical process parameters instead of large-scale batch data.
Decentralized Manufacturing	Potential for manufacturing at multiple sites or point-of-care to be close to the patient [3].	The QP is responsible for ensuring GMP compliance across all sites under the authorization, requiring robust oversight and quality agreements.

A critical tool for the QP in the context of ATMPs and imported active substances is the QP Declaration. This is a formal declaration required for marketing authorisations to confirm that the active substance has been manufactured in accordance with GMP [44]. For ATMPs, this provides a mechanism for the QP to gain assurance over the complex supply chains often involved in these products.

Table 3: Key Components of a QP Declaration for an Active Substance

Component	Purpose	Data Source
Identification	Clearly identify the active substance and its manufacturer.	Drug Substance Master File (DSMF), Quality Agreements.
GMP Compliance Statement	Declare that the active substance was manufactured in compliance with GMP standards.	GMP certificates from EudraGMDP database, audit reports of the manufacturing site.
Supply Chain Verification	Confirm knowledge and oversight of the entire supply chain.	Audit reports of starting material suppliers, transaction documents.
QP Signature	Personal legal attestation to the truth of the declaration.	N/A

For ATMPs classified as investigational medicinal products (IMPs), the QP's role is equally critical. Sponsors manufacturing IMPs outside the EU must submit a QP declaration to ensure equivalence to EU GMP, and each IMP batch must be QP-certified before release for use in a clinical trial [42].

The Scientist's Toolkit: Essential Documentation for QP Certification

For researchers and developers, understanding the documentation required for batch release is crucial for successful interactions with the QP and regulatory authorities. The following table acts as a "toolkit" of essential documents.

Table 4: Key Research and Regulatory Documentation for Batch Release

Document/Item	Function in Batch Release	Relevant Stage
Batch Manufacturing Record	Provides a complete, step-by-step account of the production of a specific batch, allowing the QP to verify correct procedures were followed.	GMP Manufacturing
Analytical Test Results & CoA	Certifies that the drug substance, excipients, and finished product conform to their predetermined quality specifications (identity, purity, potency, etc.).	Quality Control
Marketing Authorisation (MA)	Serves as the definitive regulatory document against which the QP verifies that the batch's composition, manufacturing, and control comply.	Regulatory Compliance
Qualified Person (QP) Declaration	Provides the QP with assurance that imported active substances were manufactured in compliance with GMP, as they cannot personally supervise overseas operations.	Supply Chain Oversight
Deviation & Investigation Reports	Informs the QP of any unplanned events during manufacturing or testing, allowing for a risk assessment of their impact on product quality.	Pharmaceutical Quality System
Stability Data	Provides evidence that the product will remain within specification throughout its proposed shelf-life under the recommended storage conditions.	Product Development & QC
Quality Agreements	Defines the responsibilities and quality metrics between the MAH and contract manufacturers, which the QP relies upon for oversight of outsourced activities.	Outsourced Activities

The role of the Qualified Person in batch certification and release is a non-negotiable element of the EU's commitment to medicinal product quality and patient safety. For developers of Advanced Therapy Medicinal Products, integrating an understanding of the QP's responsibilities and requirements early in the research and development process is paramount. The QP's personal legal accountability, combined with their reliance on a robust Pharmaceutical Quality System and comprehensive documentation, creates a powerful gatekeeping function. Navigating the specific challenges of ATMPs—from variable starting materials to complex logistics—requires a close and collaborative relationship between scientists, manufacturers, and the QP. By aligning experimental protocols and manufacturing process development with the regulatory framework outlined in this guide, researchers can streamline the path from the laboratory bench to the authorized, QP-certified batch that reaches patients.

Navigating ATMP Manufacturing Hurdles: Cost, Logistics, and Emerging Solutions

Advanced Therapy Medicinal Products (ATMPs), encompassing gene therapies, somatic-cell therapies, and tissue-engineered products, represent a paradigm shift in medicine, offering potential one-time curative treatments for a range of diseases [2]. In the European Union, the manufacturing of these innovative therapies is strictly regulated. Any company wishing to manufacture ATMPs must hold a manufacturing authorisation issued by the national competent authority of the Member State where the activities are carried out [45] [3]. This authorisation verifies that the manufacturer complies with EU quality standards, primarily Good Manufacturing Practice (GMP) principles and the relevant parts of the European Pharmacopoeia [45] [3]. The European Medicines Agency (EMA) plays a key role in coordinating and harmonizing GMP activities across the EU, ensuring a common interpretation of the rules [3]. The manufacturing process itself is a critical component of the Marketing Authorisation Application, where manufacturers must demonstrate the reproducibility of the medicine's composition, a task particularly challenging for complex, living biological products like ATMPs [45].

Analysis of Core Manufacturing Challenges

The unique biological nature of ATMPs, which often involves the use of substances of human origin and live cells, introduces a distinct set of manufacturing hurdles. These challenges directly impact the viability, affordability, and widespread availability of these transformative therapies.

High Development and Production Costs

The cost of ATMP manufacturing is significantly driven by specialized infrastructure, raw materials, and extensive quality control requirements.

• Specialized Facilities and Manual Processes: Manufacturing often requires highly specialized cleanroom facilities and equipment [15]. Many processes rely on manual handling steps within these cleanrooms, which increases personnel costs and reduces facility utilization efficiency, as suites may be dedicated to a single product [46]. Automating these processes is complex and can require substantial upfront investment [15] [46].
• Costly Raw Materials and Technologies: The production of viral vectors and plasmids used in gene therapies is a major cost driver, compounded by the use of patented or licensed technologies that require upfront or milestone payments [46]. Furthermore, the use of a large number of single-use consumables in manual processes adds to the material costs [46].
• Complex and Extensive Quality Control (QC): The QC strategy for ATMPs is typically extensive. Cell-based potency assays, in particular, are often complex, customized, and time-consuming, requiring large QC departments and potentially expensive outsourcing [46].

Table 1: Primary Drivers of High Costs in ATMP Manufacturing

Cost Driver Category	Specific Examples	Impact
Facilities & Personnel	Specialized cleanrooms; manual processing; dedicated suite occupancy [46] [3]	High capital and operational expenditure; low facility utilization efficiency
Materials & Equipment	GMP-grade plasmids/viral vectors; licensed technologies; single-use consumables [46]	High cost of goods sold (COGs); complex supply chain management
Quality Control & Analytics	Elaborated, cell-based potency assays; extensive in-process testing; stability studies [47] [46]	Large QC teams required; high costs for assay development and performance

Extreme Logistical Complexity

The "live" nature of ATMPs, especially in autologous therapies (where the product is made from a patient's own cells), creates a highly complex and rigid logistics chain.

• Chain of Identity and Product Tracking: For autologous therapies, the product is patient-specific, requiring an unwavering chain of identity from cell collection through to final product administration back to the same patient [3].
• Challenges of Starting Material Collection and Transport: The process begins with the collection of a patient's cells (apheresis), which then must be transported from the clinic to the manufacturing facility. This starting material has a short shelf life and often requires controlled temperature conditions during transit, adding to the complexity [3].
• Limited Shelf-Life and Cold Chain Logistics: The final ATMP product itself is often fragile and has a very short shelf life, sometimes measured in days [46] [3]. This necessitates a tightly controlled and reliable cold chain for distribution back to the treating hospital and patient, leaving little room for logistical delays [3].

Process and Product Variability

Achieving batch-to-batch consistency is a fundamental tenet of pharmaceutical manufacturing but is exceptionally difficult with ATMPs due to their inherent biological variability.

• Variable Biological Starting Materials: Cells derived from different patients or donors exhibit natural donor-to-donor variability in quality, potency, and growth characteristics [47]. This biological diversity makes it challenging to establish a standardized, reproducible manufacturing process [3].
• Challenges in Process Robustness and Reproducibility: For some cell therapies, process steps can have flexible durations based on individual cell growth, making cleanroom and personnel planning difficult and inefficient [46]. This lack of a fixed-timeline process challenges traditional manufacturing validation approaches [3].
• Demonstrating Comparability: Any change or improvement made to the manufacturing process requires a demonstration of product comparability to ensure that the change does not adversely impact the product's critical quality attributes, safety, or efficacy. This is a particular hurdle during scale-up [47] [3].

Figure 1: Interrelationship of Core ATMP Manufacturing Challenges

Detailed Experimental Protocols for Addressing Key Challenges

To overcome these challenges, researchers and manufacturers employ specific experimental methodologies during product and process development.

Media Fill Simulation for Aseptic Process Validation

Objective: To validate the aseptic manufacturing process by simulating the actual cell culture process using a microbial growth medium instead of patient cells. This confirms that the process can be conducted without introducing microbial contamination [47].

Methodology:

• Preparation: The culture medium (e.g., Tryptic Soy Broth) is prepared as the simulation material.
• Process Simulation: All manual handling and process steps identical to the actual ATMP manufacturing procedure are performed under normal production conditions, including the same duration, equipment, and number of operators.
• Incubation: The final simulated product is incubated under controlled conditions for at least 14 days to promote the growth of any potential contaminants.
• Analysis: The containers are inspected for turbidity, indicating microbial growth. The test is successful only if no contamination is detected, proving the aseptic capability of the process.

Tumorigenicity Testing for Cell-Based ATMPs

Objective: To assess the potential risk of tumor formation associated with the administration of the cell-based product, a critical safety concern, especially for therapies involving stem cells [47].

Methodology:

• For Pluripotent Stem Cell (PSC)-derived products: An in vivo teratoma formation assay is conducted. This involves injecting the cell product into immunocompromised mice (e.g., NOG/NSG mice). The animals are monitored for the formation of teratomas (tumors containing multiple tissue types), which validates the pluripotency of the starting materials but also detects residual undifferentiated PSCs in the final drug product [47].
• For somatic cell-based therapies: Tumorigenicity is assessed using in vivo studies in immunocompromised models. More sensitive in vitro methods, such as digital soft agar assays or detailed cell proliferation characterization tests, are now recommended over conventional soft agar assays to detect rare transformed cells in the therapeutic product [47].

Process Comparability Exercise

Objective: To demonstrate that a modified manufacturing process (e.g., during scale-up) produces a product with comparable quality, safety, and efficacy to the product from the initial process [47].

Methodology:

• Critical Quality Attributes (CQAs) Identification: Define the product's CQAs (e.g., viability, identity, purity, potency) that are most susceptible to process changes.
• Analytical Characterization: Perform an extended battery of analytical tests on multiple batches from both the old and new processes.
• Risk-Based Assessment: Compare the data using statistical methods. The focus is on CQAs with the highest risk of impact.
• Staged Testing: If analytical comparability is demonstrated, non-clinical or clinical studies may still be required in a staged approach to confirm that no adverse impact on safety or efficacy has occurred.

The Scientist's Toolkit: Key Research Reagent Solutions

Navigating ATMP development requires a suite of specialized reagents and materials to ensure product quality, safety, and efficacy.

Table 2: Essential Materials and Reagents for ATMP Research and Manufacturing

Tool/Reagent	Primary Function	Application Example in ATMPs
GMP-grade Viral Vectors	Gene delivery vehicle	Used in Gene Therapy Medicinal Products (GTMPs) to insert recombinant genes into a patient's cells [46].
Cell Culture Media & Supplements	Supports cell growth and viability	Formulated to expand somatic cells or stem cells ex vivo under defined conditions; may contain cytokines and growth factors [47].
Cryoprotective Agents (CPAs)	Protects cells during freezing	Dimethyl sulfoxide (DMSO) is commonly used to cryopreserve final ATMP products or intermediate cell stocks for storage and transport [48].
Biodegradable Matrices/Scaffolds	Provides 3D structure for tissue growth	Used as the medical device component in Combined ATMPs to support cells in tissue-engineered products [2].
Single-Use Bioreactors	Scalable cell expansion system	Closed, automated systems used for GMP-compliant scale-up of cell cultures, reducing manual handling and contamination risk [47].

The path to making ATMPs widely available is paved with significant technical and regulatory challenges centered on high costs, extreme logistical complexity, and inherent product and process variability. Addressing these issues requires a multi-faceted approach, combining robust experimental validation like media fills and comparability studies, adherence to a evolving GMP framework specific to ATMPs, and the strategic application of new technologies. The EU's regulatory environment, built around the manufacturing authorisation and supervised by national authorities and the EMA, provides a structured pathway to ensure that these breakthrough therapies meet the stringent quality and safety standards required for patient administration, thereby turning the promise of curative treatments into a tangible reality.

Implementing a Risk-Based Approach for Sterility Assurance and Contamination Control Strategies (CCS)

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic-cell therapies, and tissue-engineered products, represent a revolutionary class of medicines for treating serious diseases [2]. Their complex biological nature, often comprising living cells or viral vectors, introduces unique manufacturing challenges that fundamentally differ from traditional pharmaceuticals. Sterility assurance becomes particularly challenging as these products typically cannot undergo terminal sterilization and are frequently administered parenterally, making contamination control throughout manufacturing not just a regulatory requirement but a critical patient safety imperative [49].

The European regulatory framework for ATMPs requires centralized marketing authorization through the European Medicines Agency (EMA), with scientific assessment overseen by the Committee for Advanced Therapies (CAT) [2]. The revised EU GMP Annex 1, effective August 2023, has significantly strengthened requirements for sterile medicinal product manufacturing, emphasizing a systematic, risk-based approach to contamination control [50] [51] [52]. For ATMP developers seeking manufacturing authorization, implementing a robust, scientifically sound Contamination Control Strategy (CCS) is now a fundamental expectation that demonstrates comprehensive process understanding and control [4].

This technical guide examines the implementation of a risk-based CCS aligned with EU GMP Annex 1 requirements, providing ATMP researchers and developers with practical methodologies to support successful regulatory authorization and ensure product quality and patient safety.

Regulatory Framework for ATMPs and Sterility Assurance

EU ATMP Classification and Regulatory Oversight

ATMPs are classified into three main categories within the European regulatory framework [2]:

• Gene Therapy Medicines: Contain genes that lead to therapeutic, prophylactic, or diagnostic effects through insertion of recombinant genes into the body.
• Somatic-Cell Therapy Medicines: Contain manipulated cells or tissues that have been altered to change their biological characteristics or are used for non-homologous functions.
• Tissue-Engineered Medicines: Contain cells or tissues that have been modified to repair, regenerate, or replace human tissue.

Combined ATMPs incorporate one or more medical devices as integral components, such as cells embedded in a biodegradable matrix or scaffold [2]. The Committee for Advanced Therapies (CAT) provides specialized scientific assessment of ATMP marketing authorization applications, evaluating quality, safety, and efficacy data before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion [2].

EU GMP Annex 1 and the Contamination Control Strategy

The 2023 revision of EU GMP Annex 1 marks a paradigm shift in sterility assurance requirements, moving from isolated compliance activities toward integrated risk management systems [51]. The guideline defines the CCS as "a planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality" [50].

The regulatory framework emphasizes three critical components arranged in order of importance [51]:

• Design (process, equipment, facility, and utilities)
• Control (personnel training, gowning, cleaning, and sanitization)
• Monitoring (personnel, in-process, material, environmental, and utilities monitoring)

This hierarchical approach reinforces that organizations cannot monitor their way out of poor design, forcing manufacturers to fundamentally reconsider contamination control philosophies [51]. For ATMPs, this is particularly relevant given their complex manufacturing processes and sensitivity to environmental conditions.

Core Components of a Contamination Control Strategy

Comprehensive Risk Assessment

A robust Quality Risk Management (QRM) process, aligned with ICH Q9 principles, forms the foundation of an effective CCS [51] [53]. The CCS requires systematic risk assessment across all potential contamination sources, which can be categorized using the 5M diagram (Ishikawa) approach [50]:

• Raw Materials: Quality of biological starting materials, excipients, and components
• Machine: Equipment design, cleanliness, maintenance status, and single-use systems
• Manpower: Personnel training, aseptic technique, gowning qualification, and behavior
• Medium: Production environment including air, water, and surfaces
• Method: Operating procedures, process parameters, and cleaning validation

For ATMP manufacturing, risk assessment methodologies have evolved beyond simple matrices toward more sophisticated failure mode and effect analysis (FMEA) approaches that consider complex interactions between different contamination control elements [51]. The FMEA method, applied in upstream processing of biological systems, evaluates risks by quantifying the impact of process parameters and operating conditions on system specifications [54].

Facility and Equipment Controls

Barrier technologies have become central to modern contamination control strategies, with Annex 1 strongly recommending isolators and Restricted Access Barrier Systems (RABS) over conventional cleanroom setups [51] [52]. Successful implementation requires careful consideration of the entire production ecosystem, not just the barrier system itself [51].

Isolator technology provides the highest level of contamination control but presents implementation challenges around decontamination validation, material transfer procedures, and facility integration [51]. RABS configurations must provide equivalent protection to isolators and often require substantial modifications to existing systems to meet updated standards, particularly regarding operator interface design and background environment control [51].

Process and Environmental Monitoring

Environmental monitoring programs must demonstrate proactive contamination control rather than reactive compliance activities [51]. The revised Annex 1 requires continuous particle monitoring in ISO 5/Grade A areas, necessitating significant investment in automated monitoring systems and data management infrastructure [51].

Rapid microbiological methods offer potential for real-time contamination detection and faster deviation investigation, though implementation has been complicated by validation requirements and regulatory acceptance criteria [51]. Organizations must demonstrate these methods provide equivalent or superior performance compared to traditional microbiological methods while meeting stringent validation requirements for sterile manufacturing [51].

Personnel Training and Quality Culture

Personnel-related contamination risks represent a significant challenge in ATMP manufacturing, particularly with complex manual processes [51] [52]. Effective CCS implementation requires not just procedural changes but fundamental cultural shifts in how personnel approach contamination control activities [51].

Annex 1 mandates regular retraining of operators, aseptic technique verification before cleanroom work, and comprehensive gowning qualification programs [52]. Beyond qualification, fostering a culture of quality awareness ensures personnel understand their critical role in contamination control and feel empowered to identify and address potential risks [52] [49].

Table 1: Key Contamination Types and Control Measures in ATMP Manufacturing

Contamination Type	Sources	Risks	Control Measures
Microbial [50] [49]	Environment, raw materials, equipment, personnel	Product sterility compromise, patient infections	Environmental monitoring, aseptic processing, barrier systems
Particulate [50] [49]	Equipment wear, fibers, dust, packaging materials	Embolism, inflammation, allergic reactions	Air filtration, cleanroom controls, garment controls
Chemical [50] [49]	Residual solvents, cleaning agents, leachables	Product stability issues, adverse events	Material qualification, cleaning validation, extractables/leachables studies
Cross-Contamination [50] [49]	Shared equipment, inadequate segregation	Product mix, allergen exposure	Campaign manufacturing, dedicated equipment, cleaning verification

Implementation Methodologies for CCS

Structured Approaches to CCS Development

Several structured methodologies have emerged to support CCS development and implementation:

ECA Foundation Three-Phase Approach [50] This methodology aligns with FDA process validation stages:

• Phase 1 (CCS Development): Process understanding, mapping, and risk analysis to identify contamination sources and preventative measures
• Phase 2 (CCS Document Compilation): Integration of all documentation into a single, comprehensive CCS document
• Phase 3 (CCS Assessment): Ongoing review and maintenance to ensure continued effectiveness

PDA Three-Level Governance Model [50] This framework establishes interdependent quality system levels:

• Level 1 (Individual Elements): Fundamental controls including facility design, materials selection, and personnel training
• Level 2 (Quality Processes): Classification and validation of individual elements to demonstrate control capability
• Level 3 (Monitoring Systems): Continuous monitoring, trend analysis, and data utilization for corrective actions

West Pharmaceutical Services Evolution Model [49] This practical implementation strategy employs a phased approach:

• Step 1 (Foundation): Stabilization and standardization through behavior training and procedure harmonization
• Step 2 (Data Analytics): Digitization of processes and monitoring systems for trend analysis and predictive indicators
• Step 3 (Integration): Full integration of knowledge systems and risk management focused on continuous improvement

ATMP-Specific Implementation Considerations

Manufacturing Process Characterization ATMP developers must demonstrate comprehensive process understanding through rigorous characterization studies [4]. This includes identifying Critical Process Parameters (CPPs) that impact Critical Quality Attributes (CQAs) related to sterility and purity [53]. Process characterization provides the scientific foundation for establishing meaningful control strategies and specification limits.

Allogeneic Donor Eligibility Determination For allogeneic ATMPs, donor screening and testing present unique regulatory challenges [4]. Unlike more prescriptive FDA requirements, EU guidelines reference compliance with relevant EU and member state-specific legal requirements without detailing a unifying strategy [4]. Manufacturers must implement robust donor screening protocols that address emerging pathogen risks while meeting jurisdictional requirements [4].

Phase-Appropriate GMP Compliance The EMA's guideline on clinical-stage ATMPs emphasizes GMP compliance throughout development [4]. However, implementation should be phase-appropriate, balancing regulatory expectations with practical development considerations [4]. Early-phase trials may implement graduated controls, while pivotal trials require full GMP compliance verified through pre-license inspection [4].

Diagram 1: CCS Implementation Cycle. This workflow illustrates the continuous improvement process for contamination control strategy development and maintenance.

Essential Research Reagents and Materials for CCS Implementation

Table 2: Essential Research Reagent Solutions for ATMP Contamination Control Studies

Reagent/Material	Function in CCS Implementation	Application Examples
Rapid Microbiological Methods [51]	Real-time detection of microbial contamination	Environmental monitoring, in-process testing
Automated Particle Counters [51] [52]	Continuous monitoring of particulate levels	Grade A/B area monitoring, product quality assessment
HEPA Filter Testing Materials [52]	Verification of air filtration system integrity	Facility qualification, ongoing performance verification
Culture Media [52]	Microbial growth promotion for validation	Media fills, environmental monitoring, sterility testing
Chemical Indicators [49]	Detection of residual cleaning agents	Cleaning validation, surface monitoring
Bioburden Testing Systems [51]	Quantification of microbial load	In-process testing, raw material release

Quantitative Requirements and Performance Metrics

Established Regulatory Limits

The revised Annex 1 has introduced specific bioburden control limits to provide clear benchmarks for manufacturers [51]. A maximum limit of 10 CFU/100 ml before first filtration has been established, with flexibility for justified higher limits in specific circumstances such as fermentation processes or herbal components [51].

Environmental monitoring requirements have been strengthened, particularly for Grade A zones where continuous particle monitoring is now mandatory [51] [52]. The establishment of clear action and alert limits based on historical data trends is essential for demonstrating control state [51].

ATMP-Specific Performance Indicators

For ATMP processes, process capability indices (Cpk, Ppk) should be established for critical sterility-related parameters [53]. These quantitative measures demonstrate the ability of the manufacturing process to consistently produce sterile products within established specification limits [53].

Aseptic Process Simulation (APS) success rates must meet or exceed historical benchmarks, with zero growth failures expected for commercial manufacturing [52]. The APS should incorporate worst-case conditions and accurately represent actual production activities to provide meaningful validation of aseptic processes [52].

Table 3: Key Quantitative Metrics for CCS Effectiveness Assessment

Performance Area	Metric	Target/Benchmark
Environmental Monitoring [51] [52]	Grade A particle counts	Continuous compliance with ISO 5 limits
Microbial Control [51]	Bioburden levels	<10 CFU/100ml before filtration
Personnel Qualification [52]	Aseptic technique success	100% media fill success
Barrier System Integrity [51]	Decontamination cycle efficacy	6-log reduction of biological indicators
Quality System [51]	Deviation investigation effectiveness	>95% CAPA effectiveness

Integration with ATMP Manufacturing Authorization

CCS in the Marketing Authorization Application

For ATMP developers seeking manufacturing authorization, the CCS represents a critical component of the Marketing Authorization Application (MAA) [2] [4]. The CCS documentation should comprehensively demonstrate control across the product lifecycle, from raw material management through finished product release [50] [51].

The Chemistry, Manufacturing, and Controls (CMC) section of the MAA must clearly articulate how the CCS ensures consistent product quality and sterility [4]. This includes comprehensive process validation data, container-closure integrity studies, and demonstrated effectiveness of all control measures [4].

Regulatory Inspection Preparedness

Recent inspections since the implementation of revised Annex 1 have identified recurring compliance gaps that ATMP manufacturers should proactively address [51]:

• Design gaps in barrier technology integration
• Inadequate operator training in proper aseptic techniques
• Insufficient environmental monitoring programs
• Poor documentation of risk assessment and decision-making processes

Preparation for regulatory inspections should include comprehensive gap assessments against Annex 1 requirements, with particular attention to the integration of quality risk management principles throughout the contamination control lifecycle [51]. Manufacturers should be prepared to demonstrate not just procedural compliance but genuine understanding of contamination risks and effectiveness of control strategies [51].

Implementing a robust, risk-based Contamination Control Strategy is fundamental to successful ATMP manufacturing authorization in the EU. The revised EU GMP Annex 1 requirements demand a holistic, scientifically sound approach that prioritizes design-based solutions over detection-based controls. By adopting structured implementation methodologies, leveraging appropriate technologies, and fostering a culture of quality excellence, ATMP developers can navigate the complex regulatory landscape while ensuring product quality and patient safety.

The integration of continuous improvement principles ensures the CCS remains effective throughout the product lifecycle, adapting to process changes and incorporating emerging technologies and regulatory expectations. For ATMP researchers and developers, mastering these contamination control strategies represents not just a regulatory requirement but a critical competency that enables the successful translation of innovative therapies from research to clinical practice.

In the European Union, an Advanced Therapy Medicinal Product (ATMP) manufacturing authorization is a mandatory requirement for any legal entity wishing to industrially produce these innovative therapies [3]. Issued by national competent authorities, this authorization confirms that the manufacturer complies with EU quality standards, primarily Good Manufacturing Practice (GMP) principles and guidelines, and the European Pharmacopeia [3]. The manufacturing process itself is a critical determinant of the final product's critical quality attributes (CQAs), which directly correlate with patient safety and therapeutic efficacy [55]. The European Medicines Agency (EMA) plays a central role in the scientific assessment and regulatory harmonization for ATMPs, with its Committee for Advanced Therapies (CAT) providing specialized expertise [2].

The current regulatory landscape is dynamic, with the EMA having released a concept paper in May 2025 proposing revisions to Part IV of the EU GMP guidelines specific to ATMPs [10]. These revisions aim to align ATMP manufacturing standards with the updated Annex 1 on sterile medicinal products, integrate modern quality risk management principles from ICH Q9 and Q10, and provide clarifications for emerging technologies like automated systems and closed single-use systems [10]. Furthermore, the Horizon Europe funding program highlights the EU's strategic focus on overcoming ATMP manufacturing challenges, specifically calling for proposals that integrate computational modelling, automation, robotics, or digital/AI solutions to refine and optimize production processes [15] [56]. This guide explores how these technologies can be leveraged to meet stringent regulatory requirements while advancing the production of transformative therapies.

Core Manufacturing Technologies and Their Regulatory Alignment

Automation and Robotics

Automation is pivotal in enhancing the reproducibility and scalability of ATMP processes, particularly for complex, labor-intensive manual tasks.

• Application in Scale-Out and Scale-Up: Automated, closed-system bioreactors are being deployed for the clinical-grade expansion of human mesenchymal stromal cells (MSCs) [57]. These systems enable 3D culture using microcarriers, yielding cell products that are comparable to those from traditional planar systems while supporting scalable production for allogeneic therapies [57].
• Regulatory and Quality Considerations: The qualification and control of automated systems are a focal point of the proposed 2025 revisions to GMP guidelines [10]. Manufacturers must validate that automation does not detrimentally impact product quality and instead enhances batch-to-batch consistency—a key challenge in ATMP manufacturing [3] [15].

Closed and Single-Use Systems

These technologies are instrumental in mitigating contamination risks and improving manufacturing flexibility.

• Contamination Control: Closed systems, including single-use bioreactors and tubing sets, reduce the need for extensive human intervention and lower the risk of microbial contamination during production [57]. The proposed GMP revisions offer further clarification on the use of such barrier systems, including isolators and Restricted Access Barrier Systems (RABS), acknowledging their value in maintaining aseptic conditions [10].
• Logistical Simplification: For autologous therapies, which involve a patient-specific product journey from cell collection to final product administration, closed single-use systems provide a self-contained environment that simplifies logistics and enhances process integrity [3].

Digital, AI, and Modeling Solutions

Digital tools and artificial intelligence represent a frontier for optimizing ATMP manufacturing intelligence and control.

• Process Analytical Technology (PAT) and Advanced Modeling: The integration of PAT, advanced modeling, and AI is being pursued to boost overall process efficiency. These tools enable real-time monitoring and predictive control of critical process parameters [57].
• Platform Technologies and AI-Assisted Tools: The exploration of platform technologies in manufacturing and quality control is a key objective of recent EU funding calls [15] [56]. The integration of AI-assisted tools in bioprocessing was a prominent topic at the Bioprocessing Summit Europe 2025, indicating its growing adoption in the field [57].
• Quality Risk Management: The planned incorporation of ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) into the ATMP-specific GMP guidelines will provide a systematic framework for using digital tools to manage product quality throughout the lifecycle [10].

Table 1: Summary of Core Technologies and Their Primary Benefits

Technology Category	Key Applications	Primary Regulatory & Quality Benefits
Automation & Robotics	Scalable bioreactor expansion, cell sorting, fill-finish operations	Enhanced batch-to-batch reproducibility, reduced human error, streamlined scale-up [15] [57]
Closed & Single-Use Systems	Cell culture, media transfer, final product formulation	Simplified contamination control, reduced cleaning validation, flexibility for decentralized manufacturing [10] [57]
Digital, AI & Modeling	Real-time process monitoring, predictive control, data analysis	Proactive quality risk management, optimized process parameters, data-driven decision-making [15] [10] [57]

Experimental Protocols for Technology Implementation

Robust experimental design is essential for validating that new technologies maintain or improve product quality. The following protocols provide a framework for generating the evidence required for regulatory submissions.

Protocol: Qualifying an Automated, Closed-Seed Train Bioreactor

Objective: To validate that an automated, single-use bioreactor system produces mesenchymal stromal cells (MSCs) that are equivalent to those from a validated planar culture system [57].

Methodology:

• Cell Culture: Inoculate human Wharton's jelly-derived MSCs into both the test system (automated stirred-tank bioreactor with microcarriers) and the control system (traditional planar culture flasks) [57].
• Process Monitoring: Monitor and record Critical Process Parameters (CPPs)
  • In-process controls: pH, dissolved oxygen (DO), temperature, and agitation speed [57].
  • Cell culture metrics: Glucose consumption, lactate production, and cell growth kinetics [57].
• Analytical Testing: Upon harvest, perform a comprehensive analysis of Critical Quality Attributes (CQAs) on cells from both systems:
  • Identity: Flow cytometry for standard MSC surface markers (e.g., CD73+, CD90+, CD105+, CD14-, CD19-, CD34-, CD45-, HLA-DR-) [57].
  • Viability: Trypan blue exclusion assay [57].
  • Potency: Trilineage differentiation potential (osteogenic, adipogenic, chondrogenic) and immunosuppressive function in a co-culture assay [57].
  • Purity: Testing for endotoxin and mycoplasma [57].

Data Analysis: Use statistical comparability testing (e.g., t-tests, equivalence margins) to demonstrate that the CQAs of the bioreactor-expanded cells are not inferior to those from the planar system. The output should confirm the automated process maintains the defined cell specification [57] [55].

Protocol: Validating an AI-Based In-Process Potency Predictor

Objective: To develop and validate a machine learning model that uses in-process metabolite data to predict final product potency, enabling real-time release testing (RTRT) strategies.

Methodology:

• Data Collection: From historical manufacturing batches (minimum of 30-50 batches recommended for model training), collect data on:
  • Input Features: In-process metabolite levels (e.g., glucose, lactate, glutamate) and process parameters (e.g., DO, pH) measured at multiple time points [57].
  • Output Variable: The corresponding final product potency value from a validated, gold-standard bioassay (e.g., cytokine secretion, target cell killing) [55].
• Model Training: Employ a supervised machine learning algorithm (e.g., Random Forest, Support Vector Machine). Use a portion of the data (e.g., 70-80%) to train the model to predict final potency from the in-process data.
• Model Validation:
  • Performance: Test the model on the held-out dataset (20-30%). Evaluate using metrics like R², root mean square error (RMSE), and accuracy within a pre-defined potency range [15].
  • Robustness: Challenge the model with data from new, prospective batches to ensure predictive accuracy.
• Regulatory Strategy: As part of the regulatory engagement, propose the validated model as a part of a control strategy, potentially supporting RTRT as outlined in Annex 17 of EudraLex Volume 4 [25]. The model's development and validation should be documented per ICH Q9 principles [10].

The Scientist's Toolkit: Key Research Reagent Solutions

The successful development and testing of advanced manufacturing technologies rely on a suite of specialized reagents and materials. The following table details essential components for experiments related to process optimization and quality attribute monitoring.

Table 2: Essential Research Reagents and Materials for ATMP Process Development

Reagent/Material	Function in Experimental Protocols	Key Considerations
Characterized Cell Banks	Provides a consistent and qualified starting material for process development and comparability studies [55].	Documented donor history, testing for adventitious agents, and clear CQAs are essential for regulatory compliance [3] [55].
Serum-Free/Xeno-Free Media	Supports the expansion of cells in a defined, animal-component-free culture system, enhancing product safety and consistency [57].	Formulation must support cell growth and maintain critical quality attributes; batch-to-batch consistency is crucial [3].
Microcarriers	Provides a surface for cell attachment and growth in 3D bioreactor cultures, enabling scalable expansion of adherent cells [57].	Material composition, size, and sterility must be suitable for GMP-grade production and not interfere with cell harvest or function [57].
Flow Cytometry Antibody Panels	Used to characterize cell product identity and purity by detecting specific surface markers, a key CQA [57] [55].	Antibodies must be validated for specificity and reproducibility. Panels should align with accepted definitions (e.g., ISCT criteria for MSCs) [57].
Differentiation Induction Kits	Assesses the multilineage differentiation potential (osteogenic, adipogenic, chondrogenic) of stem/progenitor cells as a measure of potency [57].	Protocols must be standardized and yield quantifiable results (e.g., via staining or PCR) to demonstrate comparability between processes [57] [55].

Visualizing the Integrated Digital-Physical Workflow

The integration of digital and physical systems creates a cohesive data-driven manufacturing environment. The diagram below illustrates the logical flow of information and materials in an advanced ATMP production setup.

This workflow demonstrates a closed-loop system where PAT sensors continuously stream process data (CPPs) to a central data lake. This data serves as input for an AI/ML model, which has been trained on historical data linking CPPs to final product CQAs. The model can provide predictive control signals back to the automated bioreactor and flag potential deviations, enabling proactive quality management.

The integration of automation, closed systems, and digital/AI solutions is fundamentally transforming the landscape of ATMP manufacturing. These technologies directly address the core challenges of production reproducibility, scalability, and cost, which are essential for fulfilling the therapeutic promise of ATMPs for broader patient populations [15]. The successful adoption of these technologies, however, is inextricably linked to the evolving EU regulatory framework. The ongoing revision of GMP guidelines for ATMPs and strategic initiatives like the Horizon Europe program underscore the regulatory system's adaptation to these technological advancements [10] [56].

For researchers and developers, proactive engagement with regulatory bodies through scientific advice procedures is paramount. Demonstrating that a new technology maintains product quality, safety, and efficacy—supported by robust process characterization and comparability studies—is the foundation for successful manufacturing authorization [3] [55]. As the industry moves towards more decentralized and patient-centric manufacturing models, these technologies will be the enablers of robust, flexible, and quality-assured production, ultimately accelerating the delivery of these groundbreaking therapies to patients in the EU and beyond.

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic-cell therapies, and tissue-engineered products, represent a transformative approach to treating diseases [2]. In the European Union, the manufacture of these complex biological medicines is subject to a stringent authorization process where any legal entity must obtain a manufacturing authorization from the national competent authority of the Member State where the production activities occur [3]. This manufacturing authorization requires full compliance with EU Good Manufacturing Practice (GMP) standards, which ensure that medicines are consistently produced and controlled according to quality standards appropriate to their intended use [3].

The path to commercialization for ATMPs presents unique scalability challenges. These products often use substances of human origin composed of live cells with very short shelf lives, creating extreme logistical complexity from the collection of patient cells through to the administration of the final product [3]. Manufacturers must navigate two fundamental strategies for increasing production: scale-up, which involves increasing batch size using larger bioreactors, and scale-out, which involves running multiple small-scale production units in parallel [58]. The choice between these approaches has significant implications for regulatory compliance, facility design, and quality management within the constraints of the EU manufacturing authorization framework.

ATMP Manufacturing Authorization in the EU: Core Requirements

The EU regulatory framework for ATMP manufacturing establishes specific requirements that must be met to obtain and maintain a manufacturing authorization. Understanding these requirements is essential for designing scalable and flexible production systems that remain compliant.

Legal Framework and Key Actors

The manufacturing of ATMPs within the European Union is governed by Directive 2001/83/EC and the specific requirements outlined in Regulation (EC) No 1394/2007 for advanced therapy medicines [3] [32]. The key actors in this framework include:

• Manufacturing Authorisation Holder: The legal entity manufacturing ATMPs that must comply with EU quality standards (GMP and the European Pharmacopoeia) to obtain an authorization valid across the EU [3].
• National Competent Authorities: Assess applications for manufacturing authorizations, provide scientific advice, and conduct regular inspections to ensure ongoing GMP compliance [3].
• European Medicines Agency (EMA): Coordinates and harmonizes GMP activities across the EU, provides scientific assessment of ATMPs, and chairs the Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG) [3].
• Qualified Person (QP): Each manufacturing authorization holder must have a QP responsible for ensuring that all products are manufactured and tested in accordance with the authorization and applicable regulations [3].

GMP Requirements Specific to ATMPs

The European Commission has adopted detailed GMP guidelines specific to ATMPs that address their unique manufacturing challenges [3] [32]. These requirements are particularly critical given the biological nature of ATMPs, which often have limited shelf lives and require extreme precision throughout production. Key focus areas include:

• Quality Risk Management: Implementation of ICH Q9 principles to identify and control potential risks to product quality [10].
• Pharmaceutical Quality System: Establishment of a comprehensive quality system based on ICH Q10 that covers all aspects of production and quality control [10].
• Contamination Control: Development and implementation of a Contamination Control Strategy (CCS) aligned with the revised GMP Annex 1 requirements for sterile medicinal products [10].
• Starting Materials Management: Specific requirements for handling substances of human origin, including donor screening and testing protocols [3] [10].
• Environmental Controls: Clarified expectations for cleanroom classifications and the use of barrier systems such as isolators and Restricted Access Barrier Systems (RABS) [10].

The EMA is currently proposing revisions to Part IV of the EU GMP guidelines specific to ATMPs, with a public consultation period open until July 8, 2025 [10]. These revisions aim to better align ATMP requirements with updated Annex 1, incorporate ICH Q9 and Q10 concepts more explicitly, and adapt to technological advancements in ATMP manufacturing.

Scaling Strategies: Scale-Up vs. Scale-Out for ATMPs

Selecting the appropriate scaling strategy is a critical decision point in ATMP development that directly impacts manufacturing authorization requirements, facility design, and operational complexity. The table below compares the fundamental aspects of each approach.

Table 1: Key Differences Between Scale-Up and Scale-Out Strategies

Aspect	Scale-Up	Scale-Out
Definition	Increasing batch size using larger bioreactors [58]	Maintaining small volumes but increasing number of parallel units [58]
Best For	Allogeneic therapies, high-volume biologics [59] [58]	Autologous therapies, patient-specific treatments [59] [58]
Batch Size	Single, high-volume batches [58]	Multiple, small-volume batches [58]
Regulatory Validation	Complex process validation for large volumes [58]	Validation of parallel processes and consistency [3]
Facility Impact	Large, centralized facilities [60]	Distributed, modular facilities [60] [3]
Key Challenge	Maintaining homogeneous conditions in large volumes [58]	Managing multiple independent production runs [58]

Scale-Up Strategy for ATMPs

Scale-up involves increasing production volume by transitioning to larger bioreactors, typically used for allogeneic ATMPs where a single batch can treat multiple patients [59] [58]. This approach presents significant technical challenges, including maintaining homogeneous conditions across expanded culture volumes, controlling shear forces that can damage sensitive cells, and ensuring consistent oxygen transfer and nutrient distribution [58]. From a regulatory perspective, scale-up requires extensive process validation to demonstrate equivalence between small-scale clinical batches and large-scale commercial batches, which can be particularly challenging for complex biological products [58].

The regulatory framework requires that any significant scale-up activities must be assessed for impact on product quality, and variations to the manufacturing authorization may be necessary [3]. The EMA's Committee for Advanced Therapies (CAT) provides scientific recommendations that can help guide scale-up strategy while maintaining compliance with EU requirements [2].

Scale-Out Strategy for ATMPs

Scale-out maintains small batch sizes but increases capacity by running multiple production units in parallel, making it particularly suitable for autologous cell therapies where each batch is specific to an individual patient [59] [58]. This approach enables greater flexibility and allows production closer to patients, potentially reducing logistical challenges for products with limited shelf lives [58]. However, scale-out introduces significant operational complexities, including higher labor demands, increased facility footprint, and the need for sophisticated batch tracking systems [58].

The EU regulatory framework presents specific challenges for scale-out strategies, as each production site typically requires its own manufacturing authorization [3]. However, proposed reforms to EU pharmaceutical legislation may create exemptions for "decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site" [3]. This potential regulatory evolution could significantly facilitate scale-out implementation for ATMP manufacturers.

Implementing Flexible Manufacturing Systems for ATMPs

Flexible manufacturing approaches are essential for addressing the unique challenges of ATMP production while maintaining compliance with EU manufacturing authorization requirements. These approaches include multimodal facilities, decentralized manufacturing models, and digital integration.

Multimodal Facility Design

Multimodal facilities are designed to accommodate the production of multiple ATMP modalities within the same infrastructure, providing manufacturers with the flexibility to transition between different product types rapidly [59]. There are two primary approaches:

• Multimodal Flexible Suites: Single operating rooms designed to accommodate multiple modalities through careful scheduling and changeover procedures [59].
• Multimodal Flexible Facilities: Separate suites for specific modalities that leverage common facility infrastructure and support services [59].

Compatibility between different modalities is a critical consideration in multimodal design. Some modalities, such as gene therapy, viral vectors, and monoclonal antibodies, demonstrate high compatibility and can share equipment and infrastructure [59]. Others, like autologous CAR-T cell therapy and oligonucleotides, are largely incompatible due to fundamentally different equipment needs, room classification requirements, and containment considerations [59].

Table 2: Modality Compatibility in Flexible Manufacturing

Modality	Compatible With	Key Considerations
Gene Therapy & Viral Vectors	mAbs, some cell therapies	Same upstream equipment; requires BSL-2 containment [59]
Autologous CAR-T	Stem cell therapy, some allogeneic therapies	Grade C/B backgrounds with Grade A environments; similar bench-scale equipment [59]
mRNA/LNP	Certain cell therapies	Requires fume hoods for ethanol use; compatible scale [59]
Oligonucleotides	Limited compatibility	Heavy solvent use may require H-occupancy classification; different equipment [59]

Decentralized Manufacturing Models

Decentralized manufacturing distributes production processes across multiple locations rather than relying on a single centralized facility, offering significant advantages for ATMPs with limited shelf lives or specific patient proximity requirements [60] [3]. This approach can reduce lead times, lower shipping costs, and minimize environmental impact while improving responsiveness to regional market demands [60].

The EU regulatory framework currently presents challenges for decentralized manufacturing, as each production site typically requires its own manufacturing authorization [3]. However, the 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions that would create exemptions for decentralized sites operating under the responsibility of a central site's Qualified Person [3]. This potential regulatory evolution could significantly advance decentralized manufacturing implementation for ATMPs.

Digital Infrastructure and Industry 4.0 Technologies

Advanced digital technologies play a crucial role in enabling flexible ATMP manufacturing while maintaining GMP compliance and manufacturing authorization.

• Digital Twin Framework: A flexible digital twin framework specifically designed for ATMP biomanufacturing can digitalize, monitor, and manage physical production processes [61]. This approach uses a hierarchical architecture that organizes production into distinct abstraction levels: processes, tasks and skills, and microservices, allowing individual component updates without disrupting the overall system [61].

• Data Management Systems: Robust data management is essential for decentralized and flexible manufacturing, ensuring all production sites have access to the same up-to-date information [60]. Technical Data Package (TDP) solutions enable efficient creation and distribution of detailed manufacturing instructions, while collaborative platforms allow teams across different locations to access and work on the same engineering product data in real time [60].

• Automation and Process Control: Automated systems and closed single-use technologies are increasingly important for maintaining consistency across multiple small batches in scale-out scenarios [10] [58]. The revised GMP guidelines for ATMPs will provide additional clarifications on qualifying, controlling, and managing these technologies to ensure they do not detrimentally impact product quality [10].

Regulatory Strategy and Compliance in Flexible Operations

Navigating the EU regulatory landscape requires a strategic approach to maintaining manufacturing authorization while implementing flexible production systems.

Managing Manufacturing Authorization Across Multiple Sites

For companies implementing scale-out or decentralized manufacturing strategies, managing multiple manufacturing authorizations presents significant complexity. Under current EU requirements, each production site must hold its own manufacturing authorization and comply with ATMP-specific GMP standards [3]. This necessitates:

• Comprehensive quality systems that ensure consistency across all sites
• Robust change control processes that coordinate modifications across the manufacturing network
• Centralized oversight by Qualified Persons who maintain responsibility for product quality
• Regular internal and regulatory inspections to verify ongoing compliance

The proposed regulatory reforms that would exempt decentralized sites from individual manufacturing authorizations could substantially reduce this administrative burden, though the central site would maintain ultimate responsibility for GMP compliance [3].

Lifecycle Management and Process Changes

ATMP manufacturing processes inevitably evolve throughout their lifecycle, requiring careful management to maintain manufacturing authorization. The EU regulatory framework requires that any significant changes to manufacturing processes must be assessed for their potential impact on product quality, safety, and efficacy [3]. Manufacturers must:

• Establish rigorous comparability protocols to demonstrate that process changes do not adversely affect the product
• Implement effective change control procedures within their pharmaceutical quality systems
• Submit variations to their manufacturing authorization when required by the scope of changes
• Maintain comprehensive documentation to support the scientific justification for changes

The EMA's guideline on "Questions and answers on comparability considerations for advanced therapy medicinal products" provides specific guidance on managing process changes for ATMPs [31].

Optimizing scale-up and decentralized manufacturing strategies for ATMPs requires careful balancing of technical feasibility, regulatory compliance, and commercial objectives within the EU manufacturing authorization framework. The unique characteristics of ATMPs - including their biological complexity, limited shelf life, and frequently personalized nature - demand innovative approaches to manufacturing that can maintain product quality while achieving necessary production scale.

Successful implementation of flexible manufacturing strategies requires early and ongoing engagement with regulatory authorities, including utilization of scientific advice procedures offered by both national competent authorities and the EMA [2] [3]. The EMA's ongoing revisions to ATMP-specific GMP guidelines [10] and potential legislative reforms for decentralized manufacturing [3] signal an evolving regulatory landscape that may increasingly accommodate the flexible production models needed to bring these transformative therapies to patients.

As the ATMP field continues to mature, manufacturers who strategically integrate scalability considerations into their initial process development and facility design will be best positioned to navigate the complex EU manufacturing authorization process while efficiently delivering advanced therapies to patients in need.

The Scientist's Toolkit: Essential Technologies for Flexible ATMP Manufacturing

Table 3: Key Technologies for Implementing Flexible ATMP Manufacturing

Technology Category	Specific Solutions	Function in Flexible Manufacturing
Single-Use Bioreactor Systems	Small-scale (1-10L) single-use bioreactors	Enable parallel processing for scale-out; reduce cross-contamination risk [58]
Digital Twin Platform	Hierarchical modeling framework (Processes → Tasks → Microservices)	Digitalizes and optimizes both manual and automated operations; allows virtual commissioning [61]
Data Management Systems	Anark Collaborate, Technical Data Package (TDP) solutions	Ensure universal access to current engineering data across decentralized sites [60]
Automated Process Controls	SCADA, MES with ATMP-specific modules	Maintain consistency across multiple parallel batches; enable real-time release [10] [58]
Rapid Microbiology Testing	Portable mass spectrometry, nucleic acid-based systems	Accelerate quality control for products with short shelf lives [10]
Barrier Isolation Systems	Restricted Access Barrier Systems (RABS), isolators	Maintain sterility for open manipulations in Grade B/C backgrounds [10]

The development and manufacture of Advanced Therapy Medicinal Products (ATMPs) in the European Union represents one of the most complex challenges in modern therapeutics. These innovative medicines, which include gene therapies, somatic-cell therapies, and tissue-engineered products, require a sophisticated regulatory framework that ensures patient safety while encouraging innovation [2]. For researchers, scientists, and drug development professionals navigating this landscape, understanding the available support mechanisms is crucial for successful product development. The European medicines regulatory network offers substantial assistance through specialized procedures, particularly for micro, small, and medium-sized enterprises (SMEs) [2]. These include fee reductions, targeted scientific advice, and a formal SME certification process designed to make the regulatory pathway more accessible to organizations with limited resources. This guide examines these critical support mechanisms within the broader context of ATMP manufacturing authorization, providing a technical roadmap for developers seeking to bring innovative therapies to patients in the EU.

Understanding ATMP Manufacturing Authorization

In the EU, any legal entity manufacturing ATMPs must obtain a manufacturing authorization from the national competent authority of the Member State where the manufacturing activities occur [3]. This authorization requires full compliance with Good Manufacturing Practice (GMP) principles and guidelines, as well as the standards of the European Pharmacopoeia [3]. The manufacturing authorization is distinct from marketing authorization, though both are interconnected in the product development pathway.

The GMP framework for ATMPs presents unique challenges due to the complex nature of these products. These challenges include the use of substances of human origin composed of live cells with short shelf-lives, extreme logistical complexity in supply chains, difficulties in maintaining sterility throughout manufacturing, and the inherent variability of biological materials [3]. For autologous cell therapies, additional challenges emerge in scaling out production and potentially manufacturing at point-of-care locations [3]. Recognizing these special requirements, the European Commission has issued detailed guidelines on GMP specific to ATMPs, with the European Medicines Agency (EMA) currently proposing revisions to further align these guidelines with updated international standards [10] [3].

Table: Key Challenges in ATMP Manufacturing Authorization

Challenge Category	Specific Challenges	Potential Impact
Production Complexity	Use of live biological materials with short shelf-life; Substantial manipulation requirements; Maintaining sterility throughout process	Product consistency issues; Increased validation requirements; Higher risk of manufacturing failures
Regulatory Compliance	Meeting GMP standards for ATMPs; Demonstrating comparability between batches; Multiple site manufacturing complexities	Extended timelines; Need for specialized quality systems; Increased documentation burden
Economic Factors	High development and production costs; Specialized facilities and equipment; Need for highly skilled personnel	Significant capital investment required; Longer return on investment timeline; Particularly challenging for academic institutions and smaller companies
Logistical Management	Complex supply chains for autologous therapies; Temperature control and monitoring; Coordination between collection, manufacturing, and administration	Risk of product failure during transport; Need for sophisticated tracking systems; Requirement for seamless clinical-manufacturing integration

SME Certification Procedure

The EU offers a specific SME certification procedure through the EMA that provides significant regulatory support to smaller companies developing ATMPs. This status is particularly valuable for academic spin-offs and small biotechnology companies that are often at the forefront of ATMP innovation but have limited financial resources. The certification process enables eligible organizations to access fee reductions, regulatory assistance, and specialized support throughout the medicine development lifecycle [2].

The European Commission has recently adopted revised regulations that change how SME status is verified for regulatory procedures. While these changes specifically reference REACH regulations, they indicate a broader shift in approach to SME verification that may influence medicines regulation in the future. Under the new system, companies must obtain SME recognition before submitting their dossiers to benefit from reduced fees, moving from an ex-post to an ex-ante verification system [62] [63]. For REACH, this pre-verification must be completed at least two months before intended submission, with ECHA having two months to verify the SME status [62] [64]. Once granted, SME status remains valid for three years from the date of ECHA's decision [62] [65]. If a company's size remains unchanged, the first renewal can be accomplished through self-declaration initiated two months before the validity expires [62].

Table: SME Certification Benefits and Requirements

Aspect	Current System (Medicines)	New Verification Approach (From Feb 2027 for REACH)
Fee Reductions	Significant fee reductions for regulatory procedures [2]	Maintained fee reductions while standard fees increase for large companies [62] [63]
Application Timing	Can be applied for in conjunction with regulatory submissions	Must be applied for at least 2 months before submission [62] [64]
Validation Period	EMA does not specify validity period	3-year validity from decision date [62] [65]
Recognition Process	Evaluation as part of regulatory procedure	Ex-ante verification before submissions [63] [64]
Renewal Procedure	Not specified	Self-declaration possible if company size unchanged [62]

For ATMP developers, the SME certification with the EMA provides access to the ATMP pilot for academia and non-profit organizations launched in September 2022 [2]. This pilot offers dedicated regulatory support throughout the development process, including guidance on manufacturing best practices, clinical development strategies, and planning for efficacy and safety follow-up [2]. This targeted assistance is particularly valuable for addressing the specialized requirements of ATMP manufacturing authorization.

SME Certification Pathway

Scientific Advice and Protocol Assistance

Scientific advice and protocol assistance represent critical components of the regulatory support system for ATMP developers. These procedures allow medicine developers to obtain guidance from regulatory authorities on the appropriate tests and studies needed to generate robust data on a medicine's quality, safety, and efficacy [66]. For ATMP manufacturers navigating the complex authorization pathway, this advice can be invaluable in designing development programs that meet regulatory expectations while optimizing resources.

The EMA's scientific advice procedure is available at any stage of medicine development and is provided through the Committee for Medicinal Products for Human Use (CHMP), based on recommendations from its Scientific Advice Working Party (SAWP) [66]. For ATMPs, the Committee for Advanced Therapies (CAT) is routinely consulted, bringing specialized expertise to address the unique challenges of these products [2] [66]. The advice can cover quality aspects (manufacturing processes, testing), non-clinical aspects (toxicological tests), clinical aspects (study design, endpoints), methodological issues (statistical analysis), and overall development strategy [66].

For orphan medicines, which include many ATMPs targeting rare diseases, protocol assistance serves as a specialized form of scientific advice [66]. This procedure addresses not only general development questions but also specific aspects related to orphan drug designation, including demonstration of significant benefit and assessment of similarity or clinical superiority over existing orphan medicines [66].

The scientific advice process follows a structured pathway:

• Registration with EMA: Unless already registered, the medicine developer must register themselves, their organization, and the product in development with EMA [66].

• Formal Request and Validation: The developer submits a scientific advice request via the IRIS platform, including a briefing document with specific scientific questions and proposed development approaches [66].

• Appointment of Coordinators: For each validated procedure, two SAWP members with relevant expertise are appointed as coordinators [66].

• Assessment Team Formation: Each coordinator forms an assessment team with assessors from national agencies, preparing reports addressing the scientific questions [66].

• Meeting with Developer: If needed, the SAWP may organize a meeting with the developer, particularly when proposing alternative development plans [66].

• Expert Consultation: The SAWP consults relevant EMA committees (including CAT for ATMPs) and external experts, and often involves patients in the process [66].

• Final Response: The SAWP consolidates responses to the scientific questions, with final advice adopted by CHMP and sent to the medicine developer [66].

For ATMP developers, engaging with regulatory authorities through scientific advice is particularly valuable when developing innovative approaches where regulatory pathways may be less established, when deviating from existing scientific guidelines, or when dealing with the complex manufacturing and control strategies typical of ATMPs [66]. At the national level, institutions like the Paul-Ehrlich-Institut in Germany also offer scientific advice and regulatory guidance specific to ATMP development [67].

Fee Structures and Financial Incentives

Financial incentives, particularly fee reductions, constitute a significant component of the EU's support system for ATMP development. The EMA offers substantial fee reductions for SMEs, which is especially important given the high costs associated with ATMP development and manufacturing authorization [2]. These reductions apply to various regulatory procedures, including scientific advice, marketing authorization applications, and inspections.

The recent revision to the REACH Fee Regulation, while specific to chemicals, indicates a broader trend in EU fee structures that may influence medicine regulations in the future. This revision introduces a 19.5% increase in standard fees for large companies while protecting SMEs from this increase [62] [63] [64]. This approach reflects the EU's commitment to maintaining the competitiveness of smaller enterprises in regulated sectors.

For ATMP developers, the ATMP pilot for academia and non-profit organizations offers additional financial incentives, including fee reductions and waivers [2]. This pilot, launched in September 2022, provides increased regulatory support for promising ATMPs targeting unmet medical needs, recognizing the particular challenges faced by non-commercial developers in navigating the complex regulatory pathway [2].

Table: Regulatory Support Mechanisms for ATMP Developers

Support Mechanism	Key Features	Eligibility	Relevant Authority
SME Certification	Fee reductions; Regulatory assistance; Tailored support [2]	Micro, small, and medium-sized enterprises	EMA
Scientific Advice	Guidance on quality, non-clinical, and clinical development; Protocol assistance for orphan medicines [66]	All medicine developers	EMA (CHMP/CAT) and National Authorities
Protocol Assistance	Specialized advice for orphan medicines; Guidance on significant benefit and similarity assessment [66]	Developers of designated orphan medicines	EMA (CHMP/COMP)
ATMP Pilot	Dedicated regulatory support; Fee reductions and waivers [2]	Academic and non-profit organizations developing ATMPs	EMA
National Advice	Early scientific advice and regulatory guidance; Support for national authorization pathways [67]	All medicine developers	National Competent Authorities (e.g., Paul-Ehrlich-Institut)

• IRIS Platform: The EMA's online portal for submitting scientific advice requests and other regulatory applications [66]. This platform streamlines interactions with regulatory authorities and facilitates the formal request process for scientific guidance.

• EudraGMDP Database: A publicly accessible EU database containing manufacturing and import authorizations, GMP certificates, and non-compliance statements [3]. This resource is essential for verifying the compliance status of manufacturing sites and understanding regulatory expectations.

• TransMed Academy: Hosts online training modules to help ATMP developers navigate the regulatory environment, including topics such as ATMP classification, environmental risk assessment, and quality considerations in clinical development [2].

• EU Guidelines on GMP Specific to ATMPs: The detailed guidelines issued by the European Commission outlining GMP requirements tailored to the unique characteristics of ATMPs [3]. These are essential reference documents for establishing compliant manufacturing processes.

• EMA Scientific Guidelines: Comprehensive collection of guidelines covering various aspects of ATMP development, regularly updated based on experience gained through scientific advice procedures and emerging technologies [66].

Experimental Protocols for Regulatory Compliance

Protocol 1: Manufacturing Process Validation for ATMPs

Objective: To generate data demonstrating that the manufacturing process consistently produces ATMPs meeting predetermined quality attributes. This protocol is essential for both manufacturing authorization and marketing authorization applications.

Methodology:

• Define critical quality attributes (CQAs) based on intended mechanism of action
• Identify critical process parameters (CPPs) through risk assessment
• Execute process performance qualification (PPQ) using multiple batches
• Establish in-process controls and acceptance criteria
• Demonstrate comparability after process changes
• Implement continuous process verification

Regulatory Framework: Based on EU Guidelines on GMP specific to ATMPs and ICH Q9 Quality Risk Management principles [10] [3].

Protocol 2: Stability Testing Program for ATMPs

Objective: To establish shelf life and storage conditions for ATMPs, particularly challenging given the short shelf-life of many cellular products.

Methodology:

• Design real-time stability studies under recommended storage conditions
• Include accelerated and stress conditions where appropriate
• Test potency, viability, purity, and sterility at multiple time points
• Use worst-case batches representing actual production
• Include in-use stability testing where applicable
• Monitor transport validation under simulated conditions

Regulatory Framework: Aligned with requirements in Module 3 of the Marketing Authorisation Application dossier and ATMP-specific GMP guidelines [3].

The EU regulatory framework for ATMPs offers substantial support mechanisms designed to facilitate the development and authorization of these innovative therapies while maintaining high standards for quality, safety, and efficacy. For researchers and drug development professionals, understanding and utilizing these mechanisms—particularly the SME certification procedure, scientific advice protocols, and financial incentives—is essential for successfully navigating the complex pathway to ATMP manufacturing authorization. The specialized support available through the EMA's Committee for Advanced Therapies, the ATMP pilot for academia and non-profit organizations, and national competent authorities provides targeted assistance that addresses the unique challenges of ATMP development. As the regulatory landscape continues to evolve with proposed revisions to GMP guidelines and updated fee structures, engaging early and proactively with regulatory authorities remains the most effective strategy for optimizing ATMP development and accelerating patient access to these transformative therapies.

Securing Market Approval: From Manufacturing Compliance to Marketing Authorization

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of medicines in human healthcare, encompassing gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs that incorporate medical devices as integral components [2]. These therapies, often based on genes, cells, or tissues, introduce innovative approaches for treating, diagnosing, or preventing diseases by leveraging sophisticated biological mechanisms [2]. The development and authorization of these products in the European Union (EU) are governed by a specialized regulatory framework, recognizing their unique biological characteristics and complex manufacturing processes.

The European Medicines Agency (EMA) plays a central role in the scientific evaluation and supervision of ATMPs within the EU [2]. All ATMPs must be authorized via the centralized procedure, which provides a single evaluation and authorization process valid across all member states [2]. This procedure ensures consistent high standards of quality, safety, and efficacy for these innovative therapies. The Committee for Advanced Therapies (CAT), a dedicated committee within EMA, provides expert evaluation and guidance throughout the authorization process, working closely with the Committee for Medicinal Products for Human Use (CHMP) [2].

Crucially, the regulatory pathway for ATMPs involves two interconnected yet distinct authorizations: the manufacturing authorization and the marketing authorization. The manufacturing authorization, granted by national competent authorities, focuses specifically on compliance with Good Manufacturing Practice (GMP) standards at the production facilities [3]. The marketing authorization, granted via the EMA centralized procedure, provides the final approval to place the medicine on the market after comprehensive assessment of quality, safety, and efficacy data [2]. Understanding the intricate relationship between these two processes is essential for successful ATMP development and commercialization in the EU.

The Centralized Authorization Procedure for ATMPs

The centralized marketing authorization procedure is mandatory for all ATMPs within the European Union, providing a streamlined pathway for approval across all member states [2]. This process involves a single application submitted directly to the EMA, which then coordinates a comprehensive scientific assessment of the product's quality, safety, and efficacy. The procedure is designed to ensure that ATMPs meeting rigorous standards can efficiently reach patients throughout the EU market while maintaining consistent oversight.

The CAT is responsible for preparing a draft opinion on the ATMP application, which is then sent to the CHMP [2]. Based on this assessment, the CHMP adopts an opinion recommending or opposing the authorization to the European Commission [2]. The European Commission ultimately issues the final legally binding decision on the marketing authorization valid across the EU [2]. This collaborative assessment process leverages specialized expertise in advanced therapies while maintaining integration with the established regulatory framework for medicinal products.

Table 1: Key Committees in the EU ATMP Authorization Process

Committee	Acronym	Primary Role in ATMP Authorization
Committee for Advanced Therapies	CAT	Provides specialized expertise for ATMP evaluation; prepares draft opinion on quality, safety, and efficacy [2]
Committee for Medicinal Products for Human Use	CHMP	Adopts opinion on marketing authorization recommendation based on CAT assessment [2]
Good Manufacturing and Distribution Practice Inspectors Working Group	GMP/GDP IWG	Provides harmonized approach to GMP interpretation and inspection standards across member states [3]

Submission Timeline and Validation

The formal submission process for ATMP marketing authorization follows a structured timeline with specific validation requirements. Marketing authorization applications must be submitted in electronic Common Technical Document (eCTD) format, which provides a standardized structure for presenting comprehensive information on the medicinal product [35]. The EMA has established precise submission deadlines throughout the year, which are published in the "Human Medicines – Procedural Timetables/Submission dates" to facilitate planning for applicants.

Prior to formal submission, applicants are strongly encouraged to engage in early dialogue with regulatory authorities through scientific advice or protocol assistance procedures [2]. This preliminary engagement helps optimize development strategies and identify potential issues before the formal application process. The EMA's Innovation Task Force (ITF) provides a multidisciplinary forum for early dialogue with applicants developing emerging therapies and technologies, offering regulatory advice on eligibility and development plans [68].

Following submission, the EMA validates the application to ensure all required components are present and correctly formatted. The assessment procedure then proceeds through defined clock cycles, with the PRAC/CHMP assessment process taking up to 120 days of active evaluation time [35]. Throughout this process, the marketing authorization applicant maintains communication with regulatory authorities, responding to inquiries and providing additional information as requested by the assessment committees.

Manufacturing Authorization for ATMPs

GMP Requirements and Quality Standards

The manufacturing authorization for ATMPs represents a fundamental prerequisite within the overall regulatory pathway, focusing specifically on the production environment and quality control systems. According to EU regulations, any legal entity manufacturing medicinal products must hold a manufacturing authorization issued by the national competent authority of the member state where the manufacturing activities occur [3]. This authorization verifies that the manufacturing processes comply with stringent Good Manufacturing Practice (GMP) standards, which are particularly specialized for ATMPs due to their complex biological nature.

The GMP framework for ATMPs addresses the unique challenges associated with these products, including the use of substances of human origin, limited shelf life, and complex logistical requirements [3]. The European Commission has published detailed guidelines on GMP specific to ATMPs, which provide comprehensive requirements for specialized premises, equipment, and personnel qualifications [3]. Manufacturers must implement rigorous monitoring and quality control systems throughout the entire production process, from the collection of starting materials through to the final product release.

A critical requirement within the manufacturing authorization is the presence of a Qualified Person (QP), who carries legal responsibility for ensuring that each batch of the ATMP has been manufactured and tested in compliance with GMP standards and the marketing authorization [3]. The QP performs batch certification and release, providing the final quality assurance before the product reaches the patient. This role is particularly crucial for ATMPs given their often personalized nature and limited options for end-product testing.

Challenges in ATMP Manufacturing

ATMP manufacturing presents distinctive challenges that differentiate it from conventional pharmaceutical production. High production and development costs represent a significant barrier, driven by the need for specialized facilities, equipment, and highly skilled personnel [3]. The extreme logistical complexity of ATMPs, particularly autologous therapies involving patient-specific cells, requires sophisticated coordination between clinical collection sites, manufacturing facilities, and treatment centers while maintaining strict chain of identity and chain of custody.

The inherent variability of biological materials combined with complex manipulation steps creates significant challenges in demonstrating process consistency and product comparability between batches [3]. This variability is especially pronounced in autologous therapies, where the starting material differs for each batch. Additionally, the limited shelf life of many ATMPs creates stringent timelines for manufacturing, quality control testing, and transportation to patients, often requiring innovative approaches to logistics and stability management.

Table 2: Key Challenges in ATMP Manufacturing and Regulatory Considerations

Challenge Category	Specific Challenges	Regulatory Considerations
Production Complexity	High costs, specialized facilities and personnel, autologous scale-out needs, academic infrastructure limitations [3]	GMP guidelines specific to ATMPs; SME support with fee reductions; regulatory advice [68] [3]
Logistics & Supply Chain	Collection of patient cells, transportation to facility, sterile maintenance, limited shelf life, supply to healthcare provider [3]	Requirements for traceability, storage conditions, and transportation validation; point-of-care manufacturing considerations [3]
Product Consistency & Testing	Biological variability, complex manipulations, demonstrating comparability, validating process consistency with small batch sizes [3]	Process validation requirements; risk-based approaches to testing; platform technologies; potency assay development [3] [4]

For smaller companies and academic institutions, the transition to GMP-compliant manufacturing presents particular challenges, including lack of qualified personnel, infrastructure limitations, and insufficient capital for late-phase studies [3]. In response to these challenges, the EU regulatory system provides various support mechanisms, including the EMA's SME Office which offers administrative assistance, fee reductions, and regulatory guidance to help navigate the complex requirements [68].

The Common Technical Dossier (CTD) for ATMPs

Structure and Module Requirements

The Common Technical Dossier (CTD) provides the standardized format for presenting all quality, non-clinical, and clinical information required for ATMP marketing authorization applications in the EU. The CTD is organized into five modules, each serving a distinct purpose in the comprehensive documentation of the medicinal product's development and characterization [34]. This harmonized structure facilitates efficient regulatory review by presenting information in a consistent manner familiar to assessors across different regions.

Module 1 contains region-specific administrative information and documents, including the application form, product information (Summary of Product Characteristics, labeling, and package leaflet), and information about the experts responsible for the application [35]. For ATMPs, this module also includes specific details regarding the pharmacovigilance system and risk management plan, which are particularly important for monitoring potential long-term risks associated with advanced therapies [35].

Module 2 presents overview summaries and summaries of the quality, non-clinical, and clinical data, providing a high-level integrated analysis of the information presented in the detailed modules. These summaries should critically analyze the data and demonstrate how the information supports the quality, safety, and efficacy of the ATMP [35]. For renewal applications, addenda to the overviews are required to incorporate new data accumulated since the initial authorization or last renewal [35].

Modules 3, 4, and 5 contain the detailed reports on quality (pharmaceutical/chemical/biological documentation), non-clinical data, and clinical data respectively [34]. These modules provide the comprehensive experimental data and results that form the scientific foundation for the marketing authorization application. For ATMPs, specific considerations in these modules include extensive characterization of the manufacturing process, validation of analytical methods, and specialized non-clinical studies addressing potential unique risks such as tumorigenicity or biodistribution.

Quality Documentation (Module 3) Requirements

Module 3 of the CTD, covering quality documentation, is particularly critical for ATMP applications due to the complex relationship between manufacturing process and product characteristics. The EMA's guideline on clinical-stage ATMPs emphasizes that approximately 70% of the content addresses Chemistry, Manufacturing, and Controls (CMC) information, reflecting the importance of comprehensive quality documentation for these products [4]. The module follows the standard CTD organizational structure with specific adaptations for ATMPs.

Section 3.2.S (Active Substance/Drug Substance) for ATMPs requires detailed information on the starting materials, including cellular and tissue-based materials, their sourcing, qualification, and testing [4]. Comprehensive documentation of the manufacturing process includes description of all steps, in-process controls, and process validation data demonstrating consistency and reproducibility. For ATMPs with limited shelf lives, * stability data* must be provided to support the proposed storage conditions and expiration dating.

Section 3.2.P (Investigational Medicinal Product/Drug Product) covers the finished product formulation, composition, and specifications [4]. This includes detailed characterization of the final product, validation of analytical methods, and establishment of release specifications that ensure product quality. For ATMPs, particular emphasis is placed on potency assays, which must be scientifically justified and biologically relevant to the proposed mechanism of action [4]. The product specification file must include appropriate controls for safety, purity, potency, and identity.

Diagram 1: CTD Module Structure for ATMP Applications

Interconnection Between Manufacturing and Marketing Authorization

Regulatory Integration and Data Flow

The manufacturing authorization and marketing authorization processes for ATMPs are fundamentally interconnected, creating a continuous regulatory pathway from product development to commercial distribution. The manufacturing authorization focuses specifically on GMP compliance at the production facilities, while the marketing authorization provides comprehensive assessment of the product's quality, safety, and efficacy based on data generated from the GMP-compliant manufacturing processes [3]. This integrated approach ensures that the products reaching patients consistently meet the required quality standards.

The Common Technical Dossier serves as the critical bridge between these two authorization processes, with Module 3 (Quality Documentation) providing the comprehensive data that demonstrates the relationship between the manufacturing process and the resulting product characteristics [4]. This module includes detailed information on the manufacturing process validation, quality control testing, and batch analysis data that collectively demonstrate the ability to consistently produce ATMPs meeting their predefined quality attributes [4]. The manufacturing authorization provides the foundation for this data by ensuring the GMP compliance of the production environment.

Throughout the product lifecycle, the interconnection between manufacturing and marketing authorization is maintained through variation procedures and renewal processes. Any significant changes to the manufacturing process after initial authorization must be approved through variation submissions that demonstrate the changes do not adversely affect product quality, safety, or efficacy [35]. Similarly, during the renewal process conducted at five-year intervals, the marketing authorization holder must provide updated documentation including GMP compliance certificates for all manufacturing sites [35].

Practical Implementation and Compliance

The practical implementation of the interconnected authorization requirements demands careful planning and coordination between manufacturing authorization holders and marketing authorization applicants/holders [3]. These entities must maintain close collaboration to ensure that manufacturing sites, processes, and quality control procedures comply with both GMP standards and the specific details approved in the marketing authorization [3]. This collaboration is particularly important for ATMPs due to their complex manufacturing processes and often limited stability.

The national competent authorities and EMA provide coordinated oversight of this integrated system through a combination of manufacturing site inspections and regulatory assessment of marketing authorization applications and post-authorization changes [3]. The EMA chairs the GMP/GDP Inspectors Working Group (GMP/GDP IWG), which harmonizes GMP interpretation and inspection standards across member states, ensuring consistent application of requirements [3]. This coordination helps maintain the integrity of the regulatory system while addressing the unique challenges of ATMP manufacturing and control.

Diagram 2: Interconnection Between Manufacturing and Marketing Authorization Pathways

Recent Developments and Future Perspectives

Regulatory Advancements and Support Initiatives

The regulatory landscape for ATMPs in the EU continues to evolve rapidly, with several significant recent developments and support initiatives designed to streamline authorization processes while maintaining high standards for product quality and patient safety. In July 2025, the EMA's new Guideline on quality, non-clinical and clinical requirements for investigational ATMPs in clinical trials came into effect, providing consolidated multidisciplinary guidance for ATMP development [4]. This comprehensive document references over 40 separate guidelines and reflection papers, offering a primary-source reference for developers navigating the regulatory requirements.

The EMA has established specialized support mechanisms for ATMP developers, particularly targeting academia, non-profit organizations, and small and medium-sized enterprises (SMEs) [2] [68]. The ATMP pilot program launched in September 2022 provides dedicated regulatory assistance for developers targeting unmet medical needs, including guidance throughout the regulatory process and fee reductions or waivers [2]. Similarly, the EMA's SME Office offers specialized support with administrative and procedural assistance, fee reductions for scientific advice and inspections (90% reduction), and deferral of marketing authorization application fees [68].

The Horizon Europe funding program includes specific topics addressing ATMP manufacturing challenges, with the "Optimising the manufacturing of Advanced Therapy Medicinal Products (ATMPs)" call (HORIZON-HLTH-2025-01-IND-01) providing €40 million in funding to support manufacturing process improvements [56]. This initiative aims to address key challenges such as specialized equipment requirements, scaling-up, batch-to-batch reproducibility, and the transition from centralized to decentralized manufacturing models [56].

The Emerging EU Biotech Act and International Convergence

The forthcoming EU Biotech Act, expected to be adopted in the third quarter of 2026, represents a significant regulatory development with potential implications for ATMP authorization processes [69] [70]. This flagship initiative aims to strengthen Europe's capacity for biotechnology innovation and global competitiveness while translating advances into benefits for patients and society [69]. For the rare disease community, which represents a key target for many ATMPs, the Act presents opportunities to address specific challenges in development and accessibility.

The Biotech Act seeks to create a more cohesive regulatory framework across member states, addressing current fragmentation that creates complexity for companies navigating different national requirements [70]. It also aims to enhance access to risk-tolerant capital for biotechnology companies and improve coordination of biotechnology clusters across the EU [69] [70]. Additionally, the Act will address workforce skills development in biotechnology and promote the use of artificial intelligence and big data in biotech research and development [70].

Internationally, there is increasing emphasis on regulatory convergence between major regulatory authorities including the EU and U.S. FDA [4]. While significant convergence has already occurred in many areas, particularly in CMC requirements organized according to the CTD format, differences remain in specific areas such as allogeneic donor eligibility determination and the timing of GMP compliance verification [4]. Ongoing initiatives by professional organizations continue to promote further alignment, which could streamline global development of ATMPs while respecting regional regulatory specificities.

Table 3: Essential Research and Regulatory Tools for ATMP Development

Tool Category	Specific Tools/Resources	Application in ATMP Development
Regulatory Guidelines	EMA ATMP Guideline (2025), GMP Guidelines for ATMPs, Reflection Papers [4] [3]	Provide detailed requirements for quality, non-clinical, and clinical development; ensure compliance with regulatory standards
Support Mechanisms	SME Office, ATMP Pilot, Scientific Advice, Innovation Task Force [2] [68]	Offer regulatory guidance, fee reductions, and procedural assistance throughout development process
Funding Programs	Horizon Europe, JOIN4ATMP CSA Project [56]	Support manufacturing optimization, collaborative research, and infrastructure development
Quality Standards	European Pharmacopoeia, GMP Standards, EDQM Guidance [3]	Establish quality specifications and manufacturing standards for consistent product quality

The authorization pathway for Advanced Therapy Medicinal Products in the European Union represents a sophisticated regulatory framework that intricately connects manufacturing authorization with marketing authorization through the centralized procedure and CTD dossier requirements. This integrated approach ensures that these innovative therapies meet rigorous standards of quality, safety, and efficacy while addressing their unique scientific and technical challenges. The specialized evaluation by the Committee for Advanced Therapies, combined with the comprehensive assessment of manufacturing quality through GMP compliance, creates a robust system for overseeing these complex medicinal products.

The Common Technical Dossier serves as the critical conduit linking manufacturing and marketing authorizations, with particular emphasis on Module 3 quality documentation that demonstrates the relationship between manufacturing processes and product characteristics. The ongoing evolution of regulatory guidelines, including the recently implemented clinical-stage ATMP guideline and forthcoming EU Biotech Act, reflects the dynamic nature of this field and the commitment to streamlining authorization processes while maintaining appropriate oversight. For researchers, scientists, and drug development professionals working in this innovative field, understanding these interconnected regulatory pathways is essential for successfully navigating the journey from concept to clinic and ultimately delivering transformative therapies to patients in need.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of medicines for human use based on genes, cells, or tissues. In the European Union, the regulatory framework for these products is established by Regulation (EC) No 1394/2007, which recognizes their unique nature and the need for specialized oversight [2]. ATMPs are classified into three main categories: gene therapy medicines (contain genes for therapeutic, prophylactic or diagnostic effect), somatic-cell therapy medicines (contain manipulated cells or tissues), and tissue-engineered medicines (contain cells or tissues modified to repair, regenerate or replace human tissue) [2]. Some ATMPs may combine one or more medical devices as an integral part of the medicine, referred to as combined ATMPs [2].

The European Medicines Agency (EMA) plays a central role in the scientific evaluation of ATMPs through its Committee for Advanced Therapies (CAT), which provides the specialized expertise required to assess these complex products [2]. All ATMPs must be authorized centrally via the EMA, following a single evaluation and authorization procedure that applies across the European Union and European Economic Area [2]. For manufacturers, obtaining an ATMP manufacturing authorization requires compliance with EU quality standards, including Good Manufacturing Practice (GMP) principles and guidelines, and the European Pharmacopeia [3]. The manufacturing authorization is issued by the national competent authority of the Member State where the manufacturing activities take place [3].

Critical Quality Attributes (CQAs) in ATMP Development

Fundamental Concepts and Definitions

In the context of ATMPs, Critical Quality Attributes (CQAs) are defined as physical, chemical, biological, or microbiological properties or characteristics that must be maintained within an appropriate limit, range, or distribution to ensure the desired product quality [71]. CQAs represent the fundamental building blocks of quality for ATMPs and are directly linked to the Quality Target Product Profile (QTPP), which is a prospective summary of the quality characteristics that a drug product should possess to ensure the desired safety and efficacy [72]. The identification of CQAs forms the scientific basis for establishing a control strategy throughout the product lifecycle.

The determination of CQAs begins with a systematic analysis of the QTPP, which describes the design criteria for the product. As stated in ICH guidelines: "The QTPP forms the basis for development of the CQAs, CPPs, and control strategy" [72]. The criticality of a quality attribute is primarily based upon the severity of harm to the patient should the attribute fall outside the desired range, considering both safety and efficacy implications [72]. This distinguishes CQAs from other quality attributes that may have less impact on the final product's therapeutic performance.

Identification and Risk Assessment of CQAs

The process of identifying CQAs involves quality risk management and scientific rationale, considering factors such as the severity of harm (to safety and efficacy) before accounting for risk controls, the direct link to the patient as described in the QTPP, and the interdependencies between different CQAs [72]. The basis for establishing CQAs can include prior knowledge (from similar products or platforms), scientific first principles, and experimental data generated during product and process development [72].

For ATMPs, the risk assessment process must account for their unique characteristics, including the use of substances of human origin, limited shelf life, and inherent biological variability [3]. The criticality of quality attributes is based primarily on the severity of harm and does not change as a result of risk management, unlike process parameters whose criticality can evolve with increased process understanding [72]. This distinction is crucial for maintaining focus on attributes most vital to patient safety and product efficacy.

Common CQAs for Different ATMP Categories

Table 1: Typical CQAs for Different ATMP Categories

ATMP Category	Critical Quality Attributes	Rationale and Impact
Gene Therapy Medicines	Vector potency, vector genome titer, identity, purity, sterility	Directly impacts therapeutic efficacy and safety; insufficient potency or titer may render treatment ineffective [55]
Somatic-Cell Therapy Medicines	Cell viability, identity, potency, purity, sterility, dosage	Ensures functional cells are delivered in appropriate quantities without contamination; viability and identity are fundamental to mechanism of action [55] [73]
Tissue-Engineered Products	Cell number/viability, identity, purity, sterility, matrix characteristics	Critical for proper tissue integration and function; matrix properties directly impact delivery and engraftment [2] [55]

The complexity of ATMPs presents unique challenges in CQA identification and control. As highlighted in recent research: "Due to their complex characteristics, pharmacological properties of living cell products are, in contrast to classical biological drugs such as small molecules, more difficult to define" [73]. This complexity necessitates a thorough product development process to maintain consistent product characteristics and activity when transitioning from research-grade to clinical-grade manufacturing [73].

Process Validation in ATMP Manufacturing

The Lifecycle Approach to Process Validation

Modern process validation for ATMPs follows a lifecycle approach that links product and process development, validation of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production [74]. This paradigm has shifted from a retrospective, compliance-driven exercise to a proactive, science- and risk-based model encompassing three distinct stages: Process Design, Process Qualification, and Continued Process Verification [74]. The integrated approach ensures that quality is built into the manufacturing process from the earliest development stages rather than merely tested in the final product.

The lifecycle approach is universally structured around these three stages, all underpinned by Quality Risk Management (QRM) principles [74]. For ATMPs, this model is particularly important due to their biological complexity and the limited opportunities for end-product testing, especially for autologous products with short shelf lives [3]. The European Medicines Agency emphasizes that "the development approach should be adapted based on the complexity and specificity of product and process" [72], acknowledging that ATMPs require special consideration throughout the validation lifecycle.

Stage 1: Process Design

The Process Design stage represents the foundation of the validation lifecycle, where process knowledge is established and a control strategy is developed [74]. The objective is to "design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes" [74]. For ATMPs, this stage involves extensive characterization during all stages of process and analytical development to ensure that CQAs correlating with safety and efficacy are identified and that their specifications can be met during routine manufacturing [55].

The EU guideline explicitly links Stage 1 to the principles of pharmaceutical development as outlined in ICH Q8, recognizing two development pathways: a "traditional approach" where set points and operating ranges are defined, and an "enhanced approach" where scientific knowledge and risk management are used more extensively [74]. The enhanced approach, which employs tools such as Design of Experiment (DoE) and Quality by Design (QbD) principles, provides a deeper understanding of parameter relationships and typically offers greater regulatory flexibility in subsequent validation stages [74].

Stage 2: Process Qualification

Process Qualification constitutes the second stage of the validation lifecycle, serving as the bridge between process design and routine commercial production [74]. During this stage, the process design is evaluated to confirm that it is capable of reproducible commercial manufacturing [74]. The EU framework provides flexibility in validation approaches, permitting traditional validation (based on a predetermined number of consecutive successful batches), continuous process verification, or a hybrid of these methods [74].

A critical feature of the EU framework is the formal distinction between 'standard' and 'non-standard' manufacturing processes, with ATMPs universally classified as 'non-standard' due to their biological nature and complexity [74]. This classification requires the submission of full production-scale validation data in the marketing authorization dossier prior to approval [74]. For ATMPs, the Process Qualification stage must address unique challenges including maintaining sterility throughout manufacturing, managing biological variability in raw materials, and ensuring product consistency despite small batch sizes and limited opportunities for analytical testing [3].

Stage 3: Continued Process Verification

Continued Process Verification represents the third stage of the validation lifecycle, aimed at providing ongoing assurance that the manufacturing process remains in a state of control throughout the product's commercial life [74]. The FDA guidance emphasizes the need for "continual assurance that the process remains in a state of control" through an "ongoing program to collect and analyze product and process data that relate to product quality" [74]. For ATMPs, this stage is particularly challenging due to the limited number of batches produced, especially for orphan drugs or patient-specific autologous therapies.

The EU guideline recognizes that the control strategy can evolve throughout the product lifecycle, with consideration given to "improving the control strategy over the lifecycle in response to assessment of data trends over time and other knowledge gained" [72]. Continuous process verification enables manufacturers to monitor the process and make adjustments to the process and/or control strategy as appropriate [72]. For ATMPs, this ongoing verification must account for the potential need for process changes and the challenge of demonstrating comparability when using different manufacturing sites or technologies [3].

Methodologies and Experimental Protocols

Establishing the Quality Target Product Profile (QTPP)

The Quality Target Product Profile serves as the foundation for ATMP development and defines the target characteristics necessary to ensure the desired quality, safety, and efficacy. The QTPP should be established early in development and include consideration of the following elements: dosage form and route of administration, dosage strength, container closure system, pharmacokinetics, stability, and sterility [71]. For ATMPs, additional considerations include cell number/viability (for cell-based products), vector characteristics (for gene therapies), and scaffold properties (for tissue-engineered products) [55].

The experimental approach to defining the QTPP involves comprehensive analysis of target patient population, clinical objectives, and desired therapeutic outcomes. This includes literature review of disease pathophysiology, analysis of competitive products, and evaluation of preclinical proof-of-concept studies. The output is a comprehensive QTPP document that serves as the reference point for all subsequent development activities and provides the basis for identifying CQAs.

Risk Assessment and CQA Identification Protocol

A systematic methodology for risk assessment and CQA identification is essential for ATMP development. The protocol should include the following steps:

• Formation of a multidisciplinary team including experts in cell biology, process development, analytics, regulatory affairs, and clinical science
• Systematic analysis of each potential quality attribute against the QTPP using structured risk assessment tools
• Evaluation of severity should the attribute fall outside the desired range
• Prioritization of attributes based on their potential impact on safety and efficacy
• Documentation of rationale for classifying attributes as critical or non-critical

The risk assessment should employ established methodologies such as Failure Mode and Effects Analysis (FMEA) or Ishikawa diagrams to ensure a comprehensive evaluation. As noted in regulatory guidance: "Risk includes severity of harm, probability of occurrence, and detectability, and therefore the level of risk can change as a result of risk management. Quality attribute criticality is primarily based upon severity of harm and does not change as a result of risk management" [72]. This distinction is crucial for maintaining focus on attributes most critical to patient safety.

Process Characterization Study Design

Process characterization studies aim to establish the relationship between process parameters and CQAs, identifying which parameters are critical and defining their proven acceptable ranges. The recommended experimental approach includes:

• Screening studies using fractional factorial or Plackett-Burman designs to identify potentially significant parameters from a larger set
• Optimization studies using response surface methodologies (e.g., Central Composite Design, Box-Behnken Design) to characterize parameter interactions and establish optimal operating ranges
• Edge-of-failure studies to determine process boundaries and demonstrate robustness

For ATMPs, process characterization must account for the biological variability of starting materials and the potential for non-linear process responses. Studies should be designed using appropriate scale-down models that accurately represent the commercial manufacturing process. The output of these studies is a comprehensive process understanding that enables the establishment of a control strategy capable of consistently producing product that meets all CQAs.

Table 2: Essential Research Reagents and Analytical Tools for ATMP CQA Assessment

Reagent/Solution	Function in CQA Assessment	Specific Application Examples
Flow Cytometry Antibodies	Cell phenotype and identity characterization	Immunophenotyping of cell surface markers for identity CQA [55]
Cell Viability Assays	Determination of live cell percentage and potency	Trypan blue exclusion, fluorescent viability dyes [73]
Vector Titer Assays	Quantification of gene therapy vector concentration	qPCR for vector genome titer, functional titer assays [55]
Sterility Testing Media	Detection of microbial contamination	BacT/ALERT system, conventional sterility testing [3]
Potency Assay Reagents	Measurement of biological activity	Cytokine secretion assays, cytotoxicity assays, functional readouts [55] [73]
Process Analytical Technology (PAT)	Real-time monitoring of CPPs	In-line sensors for pH, dissolved oxygen, metabolite monitoring [71]

Regulatory Framework and Documentation Requirements

EU-Specific Regulatory Considerations for ATMPs

The regulatory framework for ATMPs in the European Union has specific requirements that manufacturers must address in their validation strategies. The Committee for Advanced Therapies (CAT) is responsible for the scientific assessment of ATMPs and prepares a draft opinion on quality, safety and efficacy that forms the basis for the CHMP's recommendation on authorization [2]. A crucial aspect of the EU framework is the requirement for manufacturing authorization issued by the national competent authority of the Member State where manufacturing occurs [3].

The European Commission has issued detailed guidelines on Good Manufacturing Practice (GMP) specific to ATMPs to address their unique characteristics and manufacturing challenges [3]. These include requirements for specialized premises and equipment, rigorous monitoring and quality control systems, and specific considerations for the use of substances of human origin [3]. Additionally, the EU framework includes incentives for ATMP developers, including fee reductions and waivers for academic and non-profit organizations, and the ATMP certification procedure for small and medium-sized enterprises [2].

Chemistry, Manufacturing, and Controls (CMC) Documentation

The Chemistry, Manufacturing, and Controls section of the marketing authorization application must comprehensively document the manufacturing process and control strategy. For ATMPs, the CMC documentation should include:

• Description of manufacturing process and process controls
• Control strategy for CQAs and CPPs
• Validation data for manufacturing process and analytical methods
• Stability data demonstrating product shelf-life
• Description of container closure system

The CMC documentation for ATMPs must address their specific characteristics, including the use of human cell or tissue-based starting materials, limited shelf life, and challenges with product characterization [3]. The level of detail required should be commensurate with the stage of development and the amount of available data, with the understanding that knowledge of the product and process will evolve throughout the lifecycle.

Addressing ATMP-Specific Challenges in Regulatory Submissions

ATMP manufacturers face unique challenges in preparing regulatory submissions that must be addressed through specific strategies:

• Limited shelf life: Implemented through accelerated stability studies and real-time stability protocols with frequent monitoring points [3]
• Small batch sizes: Addressed through statistical approaches appropriate for small sample sizes and use of historical data where justified [3]
• Biological variability: Controlled through rigorous donor screening, testing, and well-defined acceptance criteria for raw materials [73]
• Complex analytics: Justified through method validation data demonstrating specificity, accuracy, precision, and robustness despite complexity [55]
• Process changes: Managed through well-defined comparability protocols that may include analytical comparability, in vitro functional assays, and where necessary, non-clinical or clinical data [72]

The EU regulatory system recognizes these challenges and provides opportunities for interaction with regulators through scientific advice procedures, which are particularly valuable for addressing product-specific issues and discussing novel approaches to demonstrating product quality [2].

The successful development and authorization of ATMPs requires a systematic, science-based approach to defining Critical Quality Attributes and establishing a robust process validation strategy. The integration of these elements throughout the product lifecycle ensures that quality is built into the product from early development through commercial manufacturing. The EU regulatory framework provides specific pathways and requirements for ATMPs that acknowledge their unique characteristics while maintaining rigorous standards for quality, safety, and efficacy.

The future of ATMP manufacturing will likely see increased adoption of platform technologies, advanced analytics, and digital solutions to address current challenges in manufacturing and validation [56]. As noted in the Horizon Europe call for proposals, there is a focus on "optimising the manufacturing of Advanced Therapy Medicinal Products" through "computational modelling, automation, robotics or digital/Artificial Intelligence solutions" [56]. These advancements will enhance the ability to define and control CQAs, ultimately supporting the development of safe and effective ATMPs for patients with unmet medical needs.

In the European Union, any legal entity wishing to manufacture Advanced Therapy Medicinal Products (ATMPs) must obtain a manufacturing authorization from the national competent authority of the Member State where the manufacturing activities occur [3]. This authorization is a prerequisite for both clinical trial supplies and commercial marketing, ensuring that ATMPs are consistently produced and controlled in accordance with EU quality standards, particularly Good Manufacturing Practice (GMP) principles and guidelines [3].

The legal foundation for ATMP manufacturing lies in Regulation (EC) No 1394/2007, which established the regulatory framework for advanced therapies, and Directive 2001/83/EC, which outlines requirements for medicinal products for human use [75] [3]. For ATMPs specifically, the European Commission has issued detailed GMP guidelines that address the unique challenges presented by these complex biological medicines, with a recent 2025 proposal aiming to update these requirements further [5].

Regulatory Framework and Key Institutions

Legal Requirements for ATMP Manufacturing

• Manufacturing Authorization Mandate: Under Article 40 of Directive 2001/83/EC, no medicinal product can be manufactured in the EU without such authorization [3].
• GMP Compliance: The manufacturing process must adhere to EU GMP standards, defined as "the part of quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use" [3].
• Qualified Person (QP): Manufacturers must employ a Qualified Person responsible for certifying that each batch complies with requirements before release [3].
• Substances of Human Origin: ATMPs using human tissues or cells must comply with Directive 2004/23/EC, which sets quality and safety standards for donation, procurement, and testing [75].

Key Regulatory Bodies

Table: Key Regulatory Bodies in EU ATMP Manufacturing Oversight

Regulatory Body	Key Responsibilities	Relevance to GMP Inspections
National Competent Authorities (e.g., BfArM in Germany, ANSM in France)	Issue manufacturing authorizations; conduct regular on-site GMP inspections; assess applications [3].	Primary inspectors for on-site audits; evaluate compliance and issue GMP certificates [3].
European Medicines Agency (EMA)	Scientific evaluation of ATMPs; coordinates GMP harmonization; provides scientific advice [3] [2].	Maintains compilation of agreed GMP procedures; chairs GMP/GDP Inspectors Working Group [3].
Committee for Advanced Therapies (CAT)	Specialized committee for ATMP assessment; provides expertise on quality, safety, and efficacy [75] [2].	While not directly conducting inspections, informs quality expectations that inspectors assess [75].
GMP/GDP Inspectors Working Group (GMP/GDP IWG)	Comprises senior GMP inspectors from EEA; harmonizes interpretation of GMP requirements [3].	Ensures consistent application of GMP standards across EU member states [3].

Strategic Preparation for Pre-Approval GMP Inspections

Document Readiness and Quality Management Systems

A robust Pharmaceutical Quality System (PQS) aligned with ICH Q10 principles forms the foundation for GMP compliance. The upcoming revision to ATMP GMP guidelines emphasizes formal integration of these concepts [5]. Key documentation requirements include:

• Quality Management System (QMS) Documentation: Comprehensive standard operating procedures (SOPs) covering all manufacturing and control operations, change management, deviation handling, and corrective/preventive actions (CAPA) [3].
• Batch Documentation: Complete and accurate batch records demonstrating process consistency and control for every manufactured batch, including those for process validation [3].
• Validation Protocols and Reports: Extensive documentation of process validation, cleaning validation, analytical method validation, and facility/equipment qualification [55].
• Supplier Qualification Records: Comprehensive documentation evaluating and approving suppliers of critical raw materials and components, particularly those of human origin [3].

Facility and Equipment Control

ATMP manufacturing facilities require careful design and control to manage the unique risks associated with these products. The 2025 proposed GMP revisions emphasize cleanroom classifications and barrier systems such as isolators and Restricted Access Barrier Systems (RABS) [5]. Key preparation areas include:

• Contamination Control Strategy (CCS): A science-based approach to contamination prevention, aligning with the revised GMP Annex 1 requirements for sterile products [5].
• Environmental Monitoring Program: Comprehensive program demonstrating control of particulate and microbial levels in critical areas [5].
• Process Equipment Qualification: Installation, operational, and performance qualification (IQ/OQ/PQ) for all critical equipment, with emphasis on new technologies like automated systems and closed single-use systems [5].
• Facility Flow Design: Unidirectional material and personnel flows to prevent cross-contamination, particularly critical for products with short shelf lives [3].

Manufacturing Process Control and Validation

The inherently variable nature of biological materials in ATMPs presents significant validation challenges. Manufacturers must demonstrate thorough process characterization identifying Critical Process Parameters (CPPs) that impact Critical Quality Attributes (CQAs) [55]. Key aspects include:

• Process Robustness: Data demonstrating consistent production of ATMPs meeting predefined quality attributes despite biological variability [3] [55].
• In-Process Controls: Well-defined and validated controls at critical manufacturing steps to ensure process consistency [55].
• Analytical Method Validation: Comprehensive validation of methods used to assess CQAs, particularly challenging for autologous products with small batch sizes [3] [55].
• Comparability Protocols: Established protocols for demonstrating comparability after process changes [55].

The Inspection Process: Procedures and Focus Areas

Inspection Workflow and Methodology

Pre-approval GMP inspections follow a structured methodology to comprehensively assess compliance with regulatory requirements. Understanding this workflow enables effective preparation and interaction with inspectors.

ATMP-Specific Inspection Focus Areas

Table: Key ATMP-Specific GMP Inspection Focus Areas

Focus Area	Specific ATMP Considerations	Common Deficiencies
Starting Materials	Qualification of cell banks; viral safety; donor screening; traceability from donor to finished product [3] [55].	Inadequate characterization of cell banks; insufficient donor screening documentation; incomplete traceability [3].
Process Controls	Control of manual processes; aseptic processing validation; in-process testing; handling of individualized batches [3].	Lack of process validation for critical manual steps; inadequate environmental monitoring; insufficient in-process controls [3].
Facility & Equipment	Cleanroom classifications; use of isolators/RABS; prevention of cross-contamination; segregation of autologous batches [5].	Inadequate segregation between different product batches; insufficient cleanroom classification data [3].
Quality Control & Testing	Method validation for complex assays; product potency assays; stability testing; container closure integrity [3] [55].	Lack of validated potency assays; insufficient stability data; inadequate method validation for complex biological tests [55].
Personnel & Training	Specific training for aseptic techniques; handling of viable human cells; rapid microbiological methods [3].	Inadequate aseptic technique training records; insufficient competency assessment for critical operations [3].

Essential Tools and Reagent Solutions for ATMP Manufacturing

Successful GMP compliance requires appropriate technical solutions and quality reagents that meet regulatory standards. The following tools are essential for establishing and maintaining GMP-compliant ATMP manufacturing.

Table: Essential Research Reagent Solutions for ATMP Manufacturing

Reagent/Solution Category	Specific Function in ATMP Manufacturing	GMP Compliance Requirements
Cell Culture Media & Supplements	Ex vivo expansion and maintenance of therapeutic cells; must support consistent cell growth while maintaining critical quality attributes [55].	Qualified for human use; lot-to-lot consistency; full traceability and testing for adventitious agents [3] [55].
Growth Factors & Cytokines	Direct cell differentiation and expansion; critical for determining final product characteristics and potency [55].	Recombinant origin preferred; well-characterized and purified; concentration verified; endotoxin testing [55].
Vector Systems for Gene Therapy	Delivery of genetic material in GTMPs; critical determinant of product efficacy and safety [2] [55].	Fully characterized vector bank; demonstration of identity, purity, and potency; testing for replication-competent viruses [2] [55].
Critical Raw Materials	Materials contacting product during manufacturing (filters, single-use systems, reagents); potential impact on product quality [3].	Supplier qualification program; appropriate grade (GMP when possible); testing for biocompatibility and leachables [3].
Analytical Reference Standards	Qualification of critical quality attributes; calibration of equipment; validation of analytical methods [55].	Well-characterized and documented; appropriate storage and handling; established stability profile [55].

Addressing Common ATMP Manufacturing Challenges

Managing Biological Variability and Process Consistency

The inherent variability of biological starting materials presents significant challenges for GMP compliance. Manufacturers must implement robust strategies to manage this variability while ensuring process consistency:

• Donor Screening and Qualification: Implement rigorous donor screening protocols that account for biological factors impacting manufacturing success and product quality [3].
• In-process Controls and Specifications: Establish meaningful in-process controls and specifications that accommodate expected biological variability while maintaining critical quality attributes [55].
• Process Robustness Studies: Conduct studies demonstrating the manufacturing process can accommodate expected biological variability while consistently producing product meeting quality specifications [55].

Documentation Strategies for Autologous Products

For autologous ATMPs manufactured on a per-patient basis, documentation strategies must balance regulatory requirements with practical implementation:

• Master Batch Records with Patient-Specific Modifications: Develop comprehensive master batch records that allow for patient-specific information while maintaining process consistency [3].
• Electronic Batch Records: Implement electronic batch record systems to manage the complexity of individualized manufacturing while ensuring data integrity [3].
• Cross-Contamination Prevention: Document rigorous cleaning and segregation procedures between patient batches, particularly critical for autologous products [3].

Successful navigation of pre-approval GMP inspections requires systematic preparation, deep understanding of ATMP-specific challenges, and robust quality systems. The evolving regulatory landscape, including the proposed 2025 revisions to ATMP GMP guidelines, emphasizes quality risk management and technological adaptation [5]. By implementing the strategies outlined in this guide—from comprehensive document readiness to facility control and staff training—ATMP developers can establish a culture of quality that not only passes initial inspections but sustains compliance throughout the product lifecycle. The ultimate goal is ensuring that innovative ATMPs reach patients with demonstrated quality, safety, and efficacy, fulfilling their potential to address unmet medical needs.

In the European Union, the manufacturing of Advanced Therapy Medicinal Products (ATMPs) requires a manufacturing authorization issued by the national competent authority of the Member State where the activities are carried out [3]. This authorization mandates strict adherence to Good Manufacturing Practice (GMP) principles and guidelines, with the current ATMP-specific GMP guidelines (Part IV of Eudralex Volume 4) having been adopted in 2017 [10]. On May 8, 2025, the European Medicines Agency (EMA) released a concept paper proposing significant revisions to these guidelines, recognizing that the existing standalone document lacks references to other updated EU GMPs [10] [27]. This revision aims to harmonize ATMP manufacturing requirements with evolving regulatory standards and technological advancements, addressing critical challenges in this innovative field characterized by complex manufacturing processes, use of substances of human origin, and difficulties in ensuring batch-to-batch reproducibility with live biological samples [3].

The proposed revisions come at a pivotal time when ATMPs are transitioning from treating rare diseases to addressing more common conditions with larger patient populations, necessitating optimized manufacturing processes that balance scalability with the personalized nature of many therapies [15]. The public consultation period for these proposed changes remains open until July 8, 2025, allowing stakeholders to contribute to the evolving regulatory framework [10].

Key Drivers for the 2025 Revisions

Need for Regulatory Harmonization

The revision primarily addresses the regulatory misalignment created by Part IV's status as a standalone document. This structure means that changes to other GMP guidelines, such as the recently revised Annex 1 (effective August 2023) introducing modifications for sterile medicinal products, are not reflected in ATMP-specific requirements [10] [27]. The proposed changes seek to resolve this disconnect by ensuring consistent application of updated standards across all manufacturing contexts. Furthermore, the revision plans to incorporate fundamental ICH concepts, including Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System), promoting a systematic approach to quality risk management and robust pharmaceutical quality systems throughout ATMP development and manufacturing [10].

Technological Evolution in ATMP Manufacturing

The 2017 guidelines predate significant technological advancements that have emerged in ATMP manufacturing. The revision acknowledges the growing use of automated systems, closed single-use systems, and rapid microbiological testing methods, providing much-needed clarification on qualifying, controlling, and managing these technologies to prevent detrimental impacts on product quality [10]. Additionally, the proposed updates offer further clarification on expectations for cleanroom classifications and the use of barrier systems like isolators and Restricted Access Barrier Systems (RABS), while maintaining provisions for biosafety cabinets essential for manual manipulations in individualized ATMP batches [10].

Legal and Definition Updates

The revision will update legal references and definitions related to starting materials of human origin, incorporating new regulations on quality and safety standards for substances of human origin intended for human application [10]. This reflects the evolving regulatory landscape surrounding the biological starting materials that form the foundation of ATMP therapies.

Comprehensive Analysis of Proposed Technical Revisions

Integration of Contaminated Crossreference Control Strategy (CCS) and Annex 1 Alignment

The proposed guidelines emphasize the development and implementation of a comprehensive Contaminated Crossreference Control Strategy (CCS) as outlined in the updated Annex 1 [10]. For ATMP manufacturers, this represents a significant evolution in contamination control approaches, moving from traditional environmental monitoring to a holistic, risk-based strategy encompassing all potential contamination sources throughout the manufacturing process.

Table 1: Key Elements of Contamination Control Strategy in ATMP Manufacturing

Component	Current Emphasis	Proposed Enhancement
Environmental Monitoring	Cleanroom classification compliance	Risk-based monitoring with data-driven alert/action limits
Process Controls	Individual process parameters	Holistic assessment of contamination risks across unit operations
Microbial Controls	End-product testing	In-process controls & rapid microbial methods implementation
Quality Management	Documented procedures	CCS integrated into Pharmaceutical Quality System per ICH Q10
Personnel Training	GMP compliance	Contamination control behavior and aseptic technique validation

Quality Risk Management (ICH Q9) and Pharmaceutical Quality System (ICH Q10) Integration

The incorporation of ICH Q9 and ICH Q10 principles represents a fundamental shift toward proactive quality management in ATMP manufacturing. The revision mandates a systematic approach to quality risk management that addresses the unique characteristics of ATMPs, including their autologous nature, limited shelf life, and complex supply chains [3].

Table 2: Application of ICH Q9 and Q10 to ATMP-Specific Challenges

ATMP Challenge	Quality Risk Management Application	Pharmaceutical Quality System Enhancement
Short shelf life	Risk-based testing strategy with critical quality attribute identification	Knowledge management system for process understanding
Donor-to-donor variability	Risk assessment of starting material variability	Statistical process control for acceptable variability ranges
Limited batch size	Risk-based approach to process validation	Change management system accommodating process adaptations
Decentralized manufacturing	Risk assessment of multi-site operations	Quality system framework ensuring site-to-site consistency
Complex supply chain	Risk mapping of cold chain and logistics	Supplier management program for critical materials and services

Advanced Technologies and Manufacturing Systems

The proposed guidelines provide specific guidance on qualification approaches for emerging technologies particularly relevant to ATMPs. For automated systems and closed processing, the revision outlines expectations for validation protocols that demonstrate consistent product quality despite the complex manipulation steps involved in ATMP manufacturing [10] [3]. For single-use systems, the guidelines address extractables and leachables testing protocols specific to ATMP processes where product contact time may be shorter but product sensitivity higher. The revision also recognizes the value of rapid microbiological methods for products with short shelf lives, providing guidance on validation requirements compared to traditional methods.

Regulatory Relationships and Implementation Framework

The following diagram illustrates the regulatory ecosystem governing ATMP manufacturing authorization and the key relationships between different stakeholders:

Practical Implementation Roadmap

The following workflow outlines a systematic approach for implementing the proposed GMP revisions within an ATMP manufacturing organization:

Table 3: Key Research Reagent Solutions and Quality Management Tools for ATMP GMP Compliance

Tool/Resource	Function in ATMP Manufacturing	Regulatory Consideration
Platform Technologies	Standardized manufacturing processes across multiple ATMP products to enhance reproducibility [15]	Regulatory validity assessment for standardized assays including potency
Computational Modeling & AI	Process optimization, predictive analytics for quality attributes, and pattern recognition in manufacturing data [15]	Meaningful and measurable impact demonstration; alignment with proposed Annex 22 on AI
Automation & Robotics	Reduction of manual manipulations in aseptic processing, enhancement of batch consistency [15]	Qualification protocols addressing automated system impact on product quality
Digital Solutions & Advanced Sensors	Real-time monitoring of critical process parameters, data collection for continuous process verification [15]	Data governance implementation per revised Chapter 4 requirements [76]
Closed Single-Use Systems	Reduction of cross-contamination risk, elimination of cleaning validation for product-contact surfaces [10]	Extractables and leachables assessment specific to ATMP process conditions
Rapid Microbiological Methods	Faster assessment of microbial quality for products with short shelf lives [10]	Validation against traditional methods demonstrating equivalent or superior detection
ALCOA++ Principles	Framework for ensuring data integrity across paper and electronic systems [76]	Implementation of Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Traceable data

The proposed 2025 revisions to EU GMP Part IV represent a significant evolution in the regulatory expectations for ATMP manufacturing. For researchers, scientists, and drug development professionals, these changes necessitate a proactive approach to quality management that embraces risk-based principles, technological innovation, and integrated quality systems. The incorporation of ICH Q9 and Q10 frameworks, combined with alignment to updated Annex 1 requirements, creates a more robust foundation for manufacturing these complex therapies while addressing their unique challenges.

Successful implementation will require manufacturers to conduct thorough gap assessments of current quality systems against the proposed requirements, with particular attention to contamination control strategies, data integrity practices, and emerging technology qualification. As the July 8, 2025 consultation deadline approaches, stakeholders have a critical opportunity to shape the final guideline through comments submitted via the EU Survey tool [10]. The evolving regulatory landscape underscores the importance of early and continuous engagement with regulatory authorities throughout ATMP development, leveraging scientific advice and protocol assistance to navigate the complex requirements while advancing these innovative therapies to patients in need.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of medicines for human use based on genes, tissues, or cells, offering innovative treatments for diseases and injuries [2]. The European Medicines Agency (EMA) categorizes ATMPs into three main types: gene therapy medicines (containing recombinant genes for therapeutic effects), somatic-cell therapy medicines (containing manipulated cells or tissues), and tissue-engineered medicines (containing cells or tissues to repair, regenerate, or replace human tissue) [2]. Some ATMPs incorporate medical devices as integral components, classified as combined ATMPs [2].

The European regulatory framework for ATMPs, established under Regulation (EC) No 1394/2007, mandates that any company manufacturing ATMPs in the EU must hold a manufacturing authorization from the national competent authority of the Member State where activities occur [45]. All ATMPs marketed in the EU must be manufactured according to strict EU quality standards, including Good Manufacturing Practice (GMP) principles and guidelines specifically tailored for ATMPs, to ensure quality, safety, and efficacy for patients [45]. The manufacturing process is particularly challenging for ATMPs due to their complexity, the use of substances of human origin as starting materials, and reproducibility challenges when using live biological samples [45].

Table 1: Core Categories of Advanced Therapy Medicinal Products (ATMPs) in the EU

ATMP Category	Definition	Key Characteristics	Examples
Gene Therapy Medicines (GTMPs)	Contain genes that lead to therapeutic, prophylactic or diagnostic effect [2]	Work by inserting 'recombinant' genes into the body; often used for genetic disorders, cancer or long-term diseases [2]	Zolgensma (onasemnogene abeparvovec), Roctavian (valoctocogene roxaparvovec) [77]
Somatic-Cell Therapy Medicines (sCTMPs)	Contain cells or tissues that have been manipulated to change their biological characteristics [2]	Cells not intended for the same essential functions in the body; used to cure, diagnose or prevent diseases [2]	Alofisel, Ebvallo [78]
Tissue-Engineered Medicines (TEPs)	Contain cells or tissues that have been modified to repair, regenerate or replace human tissue [2]	Often involve cells or tissues engineered for structural repair functions [2]	Holoclar, Spherox [78]
Combined ATMPs	Contain one or more medical devices as an integral part of the medicine [2]	Combine biological components with structural or functional medical device components [2]	Cells embedded in a biodegradable matrix or scaffold [2]

ATMP Manufacturing Authorization: Framework and Fundamental Challenges

The Centralized Authorization Pathway

In the European Union, all ATMPs must be authorized centrally via the EMA, benefiting from a single evaluation and authorization procedure that is valid across all Member States [2] [78]. The Committee for Advanced Therapies (CAT) plays a pivotal role in the scientific assessment of ATMPs, preparing draft opinions on quality, safety, and efficacy for the Committee for Medicinal Products for Human Use (CHMP), which then adopts a final opinion for the European Commission's decision [2]. Despite this streamlined regulatory pathway, the transition from development to marketed product has proven challenging. As of 2025, only 19 ATMPs had received centralized marketing authorization in the EU, with 16 (84.2%) being gene therapies and only 3 being human cell and tissue products (HCTPs) [78].

Critical Manufacturing Challenges

ATMP developers face multidimensional challenges throughout the product lifecycle. A comprehensive survey-based cohort study among commercial ATMP developers revealed that 65% of developers are small- or medium-sized enterprises (SMEs), who particularly struggle with the complex regulatory and manufacturing requirements [79]. The most frequently cited challenges include:

• Manufacturing Complexity (15%): Difficulties maintaining costly technical specifications capable of guaranteeing reproducibility of medicine composition in accordance with GMP guidelines and specific marketing authorization requirements [79] [45].
• Country-Specific Requirements (16%): Heterogeneous national procedures at member state level create additional compliance burdens beyond the centralized authorization process [79].
• Quality Standards (5%): Implementing GMP specifically designed for cell and gene products, particularly for academic and hospital-based producers [79] [45].
• Supply Chain Management (2%): Ensuring integrity of starting materials and final products throughout complex logistics networks [79].

The "economic valley of death" between marketing authorization and patient access presents additional hurdles, as lengthy pricing and reimbursement negotiations with individual Member States can ultimately prevent product utilization despite regulatory approval [78].

ATMP Manufacturing Authorization Pathway & Challenges

Case Studies of Approved ATMP Manufacturing Pathways

Successful Manufacturing and Market Integration

Holoclar - Tissue Engineered Product

Product Description: Holoclar contains ex vivo expanded autologous human corneal epithelial cells containing stem cells for treating limbal stem cell deficiency [78]. This tissue-engineered product represents one of the few successfully authorized HCTPs in the EU.

Manufacturing Pathway: Holoclar's manufacturing process involves collecting a small biopsy of limbal tissue from the patient's healthy eye, followed by ex vivo expansion of epithelial cells containing stem cells under strict GMP conditions. The product was developed by Holostem, a spin-off from the University of Modena and Reggio Emilia, bridging academic research and commercial production.

Key Success Factors: The product was nearly discontinued until a government-sponsored investment fund intervened in 2022 after pressure on the Italian government [78]. This case highlights the vulnerability of ATMP manufacturing, even for authorized products, and the potential need for public intervention to sustain manufacturing capabilities for rare disease treatments.

CAR-T Cell Therapies (Kymriah & Yescarta)

Product Description: Chimeric antigen receptor (CAR) T-cell therapies represent a breakthrough in cancer treatment, involving genetic modification of a patient's own T-cells to target cancer cells [77].

Manufacturing and Reimbursement Strategy: These products successfully navigated manufacturing and reimbursement challenges through innovative approaches:

• England: Utilized the Cancer Drugs Fund (CDF) with confidential discounts and compulsory real-world evidence (RWE) collection, allowing near-immediate patient access while shielding NHS budgets until uncertainty of durability was resolved [77].
• Italy: Implemented registry-anchored national outcomes-based agreements (OBAs), with payments triggered at infusion, 6 months, and 12 months only if patients demonstrated durable response [77].
• Spain: Used the VALTERMED national outcomes platform, with approximately 50% of list price paid upfront and remaining instalments at 6, 12, or 18 months contingent on patient response [77].

Table 2: Manufacturing & Market Access Strategies of Approved ATMPs

ATMP Case Study	Therapy Type	Manufacturing Complexity	Market Access Strategy	Outcome
Holoclar [78]	Tissue-Engineered Product (TEP)	Ex vivo expansion of autologous limbal stem cells under GMP conditions	Government-sponsored investment fund to rescue production after near-discontinuation	Production sustained with conditions including commitment to attract private investors
CAR-T Therapies (Kymriah, Yescarta) [77]	Gene Therapy Medicinal Products (GTMPs)	Complex autologous cell collection, genetic modification, and reinfusion	Outcomes-based agreements across multiple EU countries; registry-anchored payment triggers	Successful market penetration despite ~£280,000-327,000 list price
Zolgensma [77]	Gene Therapy Medicinal Product (GTMP)	Single-dose gene replacement therapy for spinal muscular atrophy	"Pay-at-result" model with 5 annual payments contingent on survival and motor function	Broad reimbursement achieved despite €2.15 million list price
Zynteglo & Skysona [77]	Gene Therapies	Ex vivo lentiviral transduction of hematopoietic stem cells	Significant price disparity (€1.57M asking vs €0.77M German offer) with no early outcomes-based compromise	Stalled negotiations; limited patient access

Cautionary Tales: Manufacturing and Commercialization Failures

Strimvelis - Logistical Challenges

Product Description: Strimvelis is an autologous CD34+ cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) [77].

Manufacturing and Logistical Hurdles: The product faced critical challenges that limited its commercial success:

• Centralized Manufacturing: Manufacture and administration were confined to a single site in Milan, creating low throughput and significant travel burden for patients [77].
• Safety Concerns: A 2020 leukemia case raised safety concerns, pausing use and highlighting the inherent risks of gene therapy approaches [77].
• Economic Viability: Small patient volumes combined with a bespoke manufacturing process made cost recovery and multi-country rollout unviable [77].

This case demonstrates how manufacturing logistics and safety concerns can undermine even therapeutically effective ATMPs.

Alofisel - Market Withdrawal

Product Description: Alofisel (darvadstrocel) was a somatic cell therapy product containing expanded human allogeneic mesenchymal stem cells for treating complex perianal fistulas in Crohn's disease patients [78].

Market Discontinuance: Despite receiving marketing authorization, Alofisel was no longer authorized as of December 2024 [78]. The withdrawal highlights the commercial challenges facing ATMPs, even after successful navigation of the regulatory pathway. The case illustrates the "economic valley of death" where products achieve regulatory approval but fail to sustain commercial viability.

Essential Methodologies and Research Reagent Solutions

Core Technical Protocols for ATMP Manufacturing

The manufacturing of ATMPs requires specialized methodologies throughout the production process. Below are key experimental protocols and technical processes cited from successful ATMP case studies:

Protocol 1: Autologous Cell Collection and Expansion (Based on Holoclar & CAR-T Protocols)

• Biopsy Collection: Limbal tissue biopsy (1-2 mm²) collected under sterile conditions using corneal trephine for ocular applications, or leukapheresis for systemic therapies to collect peripheral blood mononuclear cells [78].
• Cell Separation: Density gradient centrifugation (Ficoll-Paque PLUS) at 800× g for 20 minutes at room temperature with minimal brake to separate mononuclear cells from other blood components.
• Activation and Expansion: Culture in GMP-compliant media supplemented with specific cytokine cocktails (e.g., IL-2 for T-cells) in gas-permeable cell culture bags or closed-system bioreactors.
• Genetic Modification (for GTMPs): Viral vector transduction (lentiviral or retroviral) at defined multiplicity of infection (MOI) in the presence of protamine sulfate or similar enhancing agents.
• Formulation and Cryopreservation: Resuspension in cryoprotectant medium (containing DMSO and human serum albumin) followed by controlled-rate freezing to -180°C for long-term storage.

Protocol 2: Quality Control Testing Suite

• Sterility Testing: Following European Pharmacopoeia methods 2.6.1 (bacterial) and 2.6.14 (fungal) with 14-day incubation period.
• Potency Assays: Flow cytometric analysis of target cell markers (CD3, CD4, CD8, CD19, etc.) with acceptance criteria >90% viability and >70% expression of target antigens.
• Vector Copy Number Assessment: Quantitative PCR analysis of integrated vector sequences with acceptance criteria of <5 copies per cell to minimize insertional mutagenesis risk.
• Endotoxin Testing: Limulus Amebocyte Lysate (LAL) testing with acceptance criteria of <5 EU/kg/hour for intravenous administration.

Protocol 3: Process Validation Requirements

• Validation Runs: Minimum of three consecutive successful manufacturing runs demonstrating process consistency and reproducibility.
• In-Process Controls: Defined critical process parameters (CPPs) including cell viability, doubling time, transduction efficiency, and identity testing at multiple manufacturing stages.
• Stability Studies: Real-time and accelerated stability studies to establish shelf-life and transport conditions.

The Scientist's Toolkit: Essential Research Reagent Solutions

Table 3: Essential Research Reagents and Materials for ATMP Development

Reagent/Material Category	Specific Examples	Function in ATMP Development	Application Notes
Cell Culture Media [79] [48]	X-VIVO 15, AIM-V, TexMACS, StemSpan	Serum-free media formulations supporting cell growth and maintenance while reducing contamination risks	Essential for GMP-compliant manufacturing; must be xeno-free for clinical applications
Cryopreservation Agents [48]	DMSO (Dimethyl sulfoxide), CryoStor, Hyaluronan-based CPA	Protect cells during freezing and thawing processes; maintain viability and functionality post-preservation	DMSO concentration typically 5-10%; requires controlled-rate freezing equipment
Cytokines/Growth Factors [77] [48]	IL-2, IL-7, IL-15, SCF, TPO, FGF	Direct cell differentiation, expansion, and maintenance of specific cell phenotypes	GMP-grade cytokines essential for manufacturing; concentration optimization critical
Viral Vectors [77] [78]	Lentiviral vectors, Retroviral vectors, AAV vectors	Gene delivery vehicles for genetic modification of target cells in gene therapy products	Must be produced under GMP; titer and purity critical parameters
Cell Separation Matrices [79]	Ficoll-Paque, CliniMACS, Lymphoprep	Isolation and purification of specific cell populations from heterogeneous mixtures	Closed systems preferred for GMP manufacturing to maintain sterility
Analytical Reagents [79] [45]	Flow cytometry antibodies, ELISA kits, PCR reagents	Quality control testing including identity, purity, potency, and safety assessments	Must be validated for intended use; reference standards essential for assay qualification

ATMP Manufacturing Technical Workflow & Quality Monitoring

The manufacturing pathways for approved ATMPs in the European Union demonstrate both remarkable scientific achievements and significant ongoing challenges. The analysis of successful case studies reveals several critical success factors: early engagement with regulators, innovative financing models, and robust manufacturing quality systems. The predominance of gene therapy products among authorized ATMPs (84.2%) compared to tissue-engineered and somatic cell therapy products highlights both the therapeutic potential of genetic approaches and the particular manufacturing challenges facing cell-based products [78].

Future development of the ATMP field will require addressing several key areas:

• Manufacturing Innovation: Continued advancement in automated, closed-system manufacturing technologies to improve reproducibility and reduce costs [79] [45].
• Regulatory Harmonization: Streamlining of country-specific requirements that currently complicate multi-national development and market access [79].
• Sustainable Business Models: Development of innovative financing and reimbursement approaches that recognize the potentially curative nature of ATMPs while ensuring healthcare system sustainability [77] [78].
• Academic-Industry Collaboration: Enhanced partnerships between public research institutions and commercial entities to bridge the "valley of death" between scientific discovery and commercial product [78].

The EU ATMP landscape continues to evolve, with ongoing regulatory refinements through initiatives like the EMA's ACT (Accelerating Clinical Trials) and the ATMP certification procedure for SMEs [2]. As manufacturing science advances and regulatory experience grows, the pathway from concept to clinically available ATMP is likely to become more efficient, potentially enabling broader patient access to these transformative therapies. However, sustainable success will require continued attention to the complex interplay between scientific innovation, manufacturing excellence, regulatory oversight, and economic viability.

Conclusion

Securing an ATMP manufacturing authorization in the EU is a multifaceted process that demands a deep understanding of a dynamic regulatory framework centered on GMP compliance and product quality. Success hinges on integrating quality by design from the earliest stages, proactively engaging with regulators through available support mechanisms, and adapting to technological advancements and guideline updates. The future of ATMP manufacturing will be shaped by increased automation, the maturation of decentralized models, and ongoing regulatory evolution, as seen in the 2025 GMP revisions. For researchers and developers, mastering this landscape is not merely a regulatory hurdle but a fundamental component of delivering transformative, safe, and effective therapies to patients across Europe.

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