Navigating ATMP Regulatory Requirements in 2025: A Strategic Guide for Developers

Abstract

This article provides a comprehensive overview of the current regulatory landscape for Advanced Therapy Medicinal Products (ATMPs), targeting researchers and drug development professionals. It covers the foundational EU and US frameworks, strategic pathways for marketing authorization, and practical guidance for navigating complex Chemistry, Manufacturing, and Controls (CMC) challenges. The content also explores emerging trends, including new 2025 EMA guidelines and the upcoming Substances of Human Origin (SoHO) Regulation, offering insights for optimizing development strategies and achieving regulatory success for these transformative therapies.

Understanding the ATMP Landscape: Definitions, Classifications, and Governing Bodies

Advanced Therapy Medicinal Products (ATMPs) represent a paradigm-shifting class of biopharmaceuticals that utilize genes, cells, or tissues to treat, prevent, or diagnose diseases [1]. These innovative therapies differ fundamentally from conventional pharmaceuticals by offering potential long-lasting or curative solutions for conditions previously considered untreatable, particularly in areas of high unmet medical need such as rare genetic disorders, oncology, and regenerative medicine [2] [3]. The European Union established a comprehensive regulatory framework for ATMPs under Regulation (EC) No 1394/2007 to support their development while ensuring safety, efficacy, and quality [4] [5]. These therapies are typically indicated for severe diseases and injuries where standard care is either unavailable or insufficient, positioning ATMPs at the forefront of personalized and precision medicine [6] [5].

The development and commercialization of ATMPs present unique challenges including manufacturing complexities, specialized delivery systems, high costs, and long-term safety considerations [2]. Regulatory bodies like the European Medicines Agency (EMA) provide specific pathways and support mechanisms to address these challenges while maintaining rigorous evaluation standards [4] [3]. As of 2024, the EMA had approved 27 ATMPs, with 52% receiving PRIME designation and 74% holding orphan medicine status, reflecting their focus on addressing serious and rare conditions [3]. This technical guide examines the four core ATMP categories, their regulatory framework, and the experimental approaches driving this rapidly evolving field.

The Four Core Categories of ATMPs

Gene Therapy Medicinal Products (GTMPs)

Gene Therapy Medicinal Products contain genes that lead to therapeutic, prophylactic, or diagnostic effects by inserting recombinant DNA into the body [4] [6]. These products work by introducing recombinant nucleic acids to regulate, repair, replace, add, or delete genetic sequences, with their effects relating directly to the recombinant nucleic acid sequence or the product of its genetic expression [2] [6]. GTMPs are primarily used to treat various diseases including genetic disorders, cancer, and long-term diseases [4]. A key characteristic of GTMPs is that they do not include vaccines against infectious diseases [6].

GTMPs can be administered through two primary approaches: in-vivo gene therapy, where the genetic material is delivered directly to the patient's cells inside the body, and ex-vivo gene therapy, where cells are removed from the patient, genetically modified outside the body, then reintroduced to the patient [1]. Notable examples include Luxturna (voretigene neparvovec), which treats inherited retinal dystrophy by delivering a healthy copy of the RPE65 gene, and oncolytic viral therapies designed to target melanoma cells [2] [6]. CAR-T cell therapies represent a hybrid approach that combines elements of both gene and cell therapy, where a patient's T-cells are genetically engineered to express chimeric antigen receptors that target cancer cells [2].

Somatic-Cell Therapy Medicinal Products

Somatic-Cell Therapy Medicinal Products consist of cells or tissues that have been manipulated to change their biological characteristics or are intended for use in different essential functions than they served in the donor [4] [6]. These products are used to cure, diagnose, or prevent diseases through pharmacological, immunological, or metabolic action of their cells or tissues [4] [6]. The key distinction from traditional transplants lies in the concept of "substantial manipulation" - when cells are processed in ways that alter their biological characteristics, physiological functions, or structural properties relevant for clinical application [4].

The regulation provides clarity on what does not constitute substantial manipulation, including processes such as cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, separation, concentration, purification, filtering, lyophilization, freezing, cryopreservation, and vitrification [6]. These products can be autologous (using the patient's own cells) or allogeneic (using donor cells) [1]. A prime example is the use of mesenchymal stromal cells (MSCs) for treating arthritis and fracture repair, where cells that originally served one function are applied to serve a different therapeutic purpose [6]. The same cells can be classified as an ATMP in one context but not in another, exemplified by bone marrow transplantation: when transplanted to serve the same function, it is not an ATMP, but when applied to heal cardiac tissue post-heart attack, it qualifies as an ATMP [1].

Tissue-Engineered Medicines

Tissue-Engineered Medicines contain engineered cells or tissues that are modified to repair, regenerate, or replace human tissue [4] [6]. These products are presented as having properties for, or are used in, regenerating, repairing, or replacing human tissue and may contain cells or tissues of human or animal origin (or both) in either viable or non-viable states [6]. The therapeutic effect must occur through pharmacological, immunological, or metabolic activity within the body [1].

Tissue engineering typically involves implanting cells, tissues, or organs to restore or replace impaired function, often utilizing additional substances such as scaffolds, chemicals, or molecules to support tissue development [6]. The field holds significant promise in orthopedics, cardiovascular medicine, and wound healing [2]. Well-established examples include lab-grown skin grafts for burn treatment and Carticel, which uses a patient's own cartilage cells to repair knee cartilage damage [2] [6]. Artificial skin and cartilage represent additional TEPs that have received regulatory approval, though their clinical application remains limited [1].

Combined Advanced Therapy Medicinal Products

Combined ATMPs incorporate one or more medical devices as an integral part of the medicine [4] [2]. These combination products typically feature cells or tissues combined with a structural component that serves a supportive function in the therapeutic application. For a product to be classified as a combined ATMP, it must contain viable cells or tissues OR be liable to act upon the human body with the primary action attributable to the medical device component [6].

The most common example is cells embedded in a biodegradable matrix or scaffold, where the scaffold provides structural support for cell attachment and subsequent tissue development [4] [1]. When developing combined ATMPs, manufacturers must adhere to both medicinal product legislation and medical device regulations, requiring collaboration with EU-notified bodies to certify compliance of the device component [5]. This dual regulatory oversight adds complexity to the development process but enables innovative approaches that leverage the advantages of both biological and engineering principles.

Table 1: Comparison of the Four Core ATMP Categories

ATMP Category	Key Components	Primary Mechanism of Action	Common Applications	Examples
Gene Therapy Medicinal Products (GTMPs)	Recombinant nucleic acids [4]	Inserting genes to regulate, repair, replace, add, or delete genetic sequences [2]	Genetic disorders, cancer, long-term diseases [4]	Luxturna, oncolytic viral therapies for melanoma [2] [6]
Somatic-Cell Therapy Medicinal Products	Manipulated cells or tissues [4]	Pharmacological, immunological, or metabolic action of cells [6]	Arthritis, fracture repair, cancer [2] [6]	Mesenchymal stromal cells (MSCs), CAR-T cells (as cell-based gene therapy) [2] [6]
Tissue-Engineered Medicines	Engineered cells or tissues [4]	Repair, regenerate, or replace human tissue [4]	Cartilage damage, burn treatment, orthopedics [2]	Lab-grown skin grafts, Carticel for knee cartilage repair [2] [6]
Combined ATMPs	Cells/tissues + medical device [4]	Combined action of biological component and device [1]	Tissue engineering requiring structural support [4]	Cells embedded in biodegradable matrices or scaffolds [4] [1]

ATMP Classification and Regulatory Framework

Regulatory Classification Criteria

The classification of a product as an ATMP follows specific criteria established in Regulation (EC) No 1394/2007 [5]. The fundamental distinction between ATMPs and traditional transplants hinges on two key concepts: substantial manipulation and different essential function. Substantial manipulation refers to processes that alter biological characteristics, physiological functions, or structural properties relevant for the intended clinical use [6]. The "different essential function" criterion applies when cells or tissues are intended for a different physiological purpose in the recipient than they served in the donor [1]. The EMA's Committee for Advanced Therapies (CAT) plays a pivotal role in classifying ATMPs and provides scientific recommendations on their quality, safety, and efficacy [4] [5].

The regulatory framework acknowledges that the same cells can be classified differently depending on their application. For example, bone marrow transplantation for hematopoietic reconstitution does not qualify as an ATMP since it serves the same essential function, while applying bone marrow-derived cells to repair cardiac tissue constitutes an ATMP because the cells are serving a different essential function [1]. This nuanced classification system requires developers to seek formal classification from regulatory authorities early in development to ensure appropriate regulatory pathways are followed [5].

Diagram 1: ATMP Classification Decision Tree. This flowchart illustrates the regulatory logic for categorizing products as Advanced Therapy Medicinal Products based on composition and intended function [4] [6] [1].

Regulatory Approval Pathways and Timelines

ATMPs in the European Union must undergo a centralized authorization procedure through the EMA, resulting in a single evaluation and marketing authorization valid across all EU and EEA member states [4] [5]. The standard optimal timeline for this procedure is approximately 277 days from submission to European Commission decision, comprising 210 days for EMA assessment (excluding clock stops) and 67 days for Commission approval [5]. The Committee for Advanced Therapies (CAT) provides draft opinions on ATMP quality, safety, and efficacy, which inform the final recommendation by the Committee for Medicinal Products for Human Use (CHMP) [4] [5].

Several regulatory mechanisms can accelerate ATMP development and approval. The PRIME (PRIority MEdicines) scheme, introduced in 2016, provides enhanced support for medicines addressing unmet medical needs through early regulatory engagement, appointing CHMP/CAT rapporteurs, and eligibility for accelerated assessment [3]. Analysis shows PRIME-designated ATMPs experience a 42.7% reduction in time to marketing authorization compared to non-PRIME products [3]. Additional pathways include conditional marketing authorization (used for 41% of approved ATMPs) and approval under exceptional circumstances (7% of ATMPs) [3]. Orphan designation, held by 74% of approved ATMPs, is associated with a 32.8% reduction in approval time [3].

Table 2: ATMP Regulatory Approval Timelines and Pathways (Based on EU Approvals 2008-2024)

Regulatory Aspect	Statistics	Impact on Timelines
Overall Median Approval Time	441 days (IQR 370-645) [3]	Baseline for comparison
PRIME Designation	52% of approved ATMPs [3]	42.7% reduction vs. non-PRIME (median 376 vs. 669 days) [3]
Orphan Designation	74% of approved ATMPs [3]	32.8% reduction vs. non-orphan [3]
Authorization Type	Conditional: 41%, Standard: 50%, Exceptional: 7% [3]	Conditional fastest (median 405 days) [3]
ATMP Type Timeline Differences	19 GTMPs, 4 CTMPs, 3 TEPs, 1 Combined approved [3]	GTMPs fastest (median 385 days), TEPs slowest (median 1174 days) [3]
Scientific Advice Impact	Varies by product development phase [3]	More SA interactions correlate with faster approval for PRIME products [3]

Experimental Protocols and Manufacturing Considerations

ATMP Manufacturing Workflows

ATMP manufacturing follows specialized protocols that differ significantly from conventional pharmaceutical production due to the biological nature of the starting materials and frequently personalized approach. All ATMP manufacturing must comply with Good Manufacturing Practice (GMP) standards, with recent guidelines emphasizing Contamination Control Strategy (CCS), Quality Risk Management (ICH Q9), and Pharmaceutical Quality System (ICH Q10) principles [7] [8]. The EMA is currently revising GMP guidelines for ATMPs to address technological advancements including automated systems, closed single-use systems, and rapid microbiological testing methods [7] [8].

Manufacturing processes differ substantially between autologous and allogeneic approaches. Autologous ATMPs use the patient's own cells as starting material, creating highly individualized products with complex logistics but reduced risk of immune rejection [5]. Allogeneic ATMPs use donor-derived cells to create "off-the-shelf" products that offer superior scalability and faster availability but require strict donor screening and traceability systems [5]. The world's first allogeneic CAR-T therapy (tabelecleucel) received European Commission approval in December 2022, representing a significant milestone in scalable ATMP manufacturing [5].

Diagram 2: ATMP Manufacturing Workflows. Comparison of autologous (patient-specific) and allogeneic (donor-derived) manufacturing approaches highlighting different scalability and logistical considerations [5] [8].

Essential Research Reagents and Materials

ATMP development and manufacturing require specialized reagents and materials that maintain the viability and functionality of biological components while ensuring final product quality and safety. The following table details key research reagent solutions essential for experimental and production activities in the ATMP field.

Table 3: Essential Research Reagent Solutions for ATMP Development

Research Reagent Category	Specific Examples	Function in ATMP Development	Quality Standards
Cell Culture Media	Serum-free media, cytokines, growth factors	Supports cell expansion, maintenance, and differentiation while minimizing contamination risk [2]	GMP-grade for manufacturing [6] [8]
Gene Delivery Vectors	Viral vectors (lentiviral, retroviral, AAV), non-viral methods	Facilitates genetic modification in GTMPs and cell-based gene therapies [2]	GMP-grade with appropriate biosafety testing [2] [8]
Cell Separation Reagents	Antibodies, magnetic beads, density gradient media	Enriches specific cell populations from starting materials [2]	Clinical-grade with documentation [6]
Scaffolding Materials	Biodegradable polymers, hydrogels, decellularized matrices	Provides structural support for tissue-engineered products and combined ATMPs [4] [1]	Biocompatibility testing per medical device standards [5]
Cryopreservation Solutions	DMSO, cryoprotectants, controlled-rate freezing media	Maintains cell viability during storage and transport [6]	GMP-grade with validated cooling protocols [8]
Quality Control Assays	Sterility tests, mycoplasma detection, potency assays	Ensures product safety, identity, purity, and potency [6] [8]	Validated methods per pharmacopoeial standards [8]

Current Regulatory Developments and Future Directions

The ATMP regulatory landscape continues to evolve rapidly to accommodate scientific advancements while maintaining appropriate oversight. Significant ongoing developments include the revision of Part IV of the EU GMP guidelines specific to ATMPs, with a concept paper released in May 2025 proposing alignment with updated Annex 1 requirements and integration of ICH Q9/Q10 principles [7] [8]. The implementation of Regulation (EU) 2021/2282 on health technology assessment beginning in January 2025 introduces harmonized EU-wide methods for evaluating ATMPs, particularly for oncology products [5].

Future regulatory considerations include addressing the challenges of genome-editing technologies like CRISPR-Cas9, with the EMA noting that guidelines will be updated as additional experience is gained with these products [9]. The increasing complexity of combination ATMPs incorporating device components requires ongoing coordination between medicinal product and medical device regulatory frameworks [5]. Additionally, regulatory bodies are developing approaches to manage the growing volume of ATMP applications while maintaining thorough evaluation standards, potentially requiring significant additional resources as the field expands [5].

The progressive alignment of regulatory requirements between major jurisdictions (regulatory convergence) represents another significant trend, with efforts underway to harmonize technical guidance, standards, and scientific principles to facilitate global ATMP development while respecting regional legal frameworks [9]. This convergence is particularly evident in chemistry, manufacturing, and controls (CMC) requirements, though differences remain in areas such as allogeneic donor eligibility determination and phase-appropriate GMP implementation [9].

The development and approval of Advanced Therapy Medicinal Products (ATMPs) are governed by sophisticated regulatory frameworks in major jurisdictions. The European Medicines Agency (EMA) and its Committee for Advanced Therapies (CAT), together with the U.S. Food and Drug Administration's Center for Biologics Evaluation and Research (CBER), constitute the principal regulatory authorities ensuring the safety, quality, and efficacy of these groundbreaking therapies. This technical guide examines the distinct yet complementary roles of these bodies, their regulatory pathways, and the evolving landscape of ATMP oversight. Understanding their requirements is crucial for researchers and drug development professionals navigating the path from laboratory discovery to clinical application and market approval.

Profiles of the Core Regulatory Authorities

European Medicines Agency (EMA) and the Committee for Advanced Therapies (CAT)

The EMA operates a centralized authorization procedure for ATMPs, providing a single evaluation and marketing authorization valid across the European Union (EU) and European Economic Area (EEA) [4]. The Committee for Advanced Therapies (CAT) is a cornerstone of this system, a dedicated committee within the EMA providing specific expertise on ATMPs [4]. The CAT's core responsibilities include [4]:

• Preparing draft opinions on the quality, safety, and efficacy of ATMPs for the Committee for Medicinal Products for Human Use (CHMP).
• Providing recommendations on the classification of borderline products as ATMPs.
• Contributing to scientific advice for ATMP developers.
• Evaluating applications for the certification of quality and non-clinical data for small and medium-sized enterprises (SMEs).

The CAT plays a pivotal role in the ATMP classification procedure, a voluntary process where developers can seek a formal scientific recommendation on whether their product meets the definition of an ATMP. This procedure, based on Article 17 of Regulation (EC) No 1394/2007, is free of charge and results in a recommendation within 60 days [10]. The CAT has adopted 675 out of 682 submitted classification recommendations by October 2024, highlighting its active role in the regulatory landscape [10].

U.S. FDA Center for Biologics Evaluation and Research (CBER)

Within the United States, the Center for Biologics Evaluation and Research (CBER) is the regulatory authority responsible for evaluating cellular and gene therapy products, which correspond closely to the EU's definition of ATMPs. CBER operates under different statutory authorities and regulatory frameworks but shares the common goal of ensuring that these innovative products are safe, pure, and potent before they reach patients [11] [12].

CBER oversees a robust approval pathway, as evidenced by the growing list of licensed cellular and gene therapy products [11]. The Office of Therapeutic Products (OTP) within CBER is directly responsible for this review process. Recent initiatives from CBER demonstrate a focus on adapting regulatory science to the unique challenges of ATMPs, particularly for rare and ultra-rare conditions [12].

Table: Core Functions and Legal Basis of Key Regulatory Authorities

Authority	Core Functions & Responsibilities	Governing Legislation / Legal Basis
EMA (EU)	- Centralized marketing authorization for ATMPs [13]- Scientific assessment via CHMP & CAT [4]- Post-authorization safety monitoring (Pharmacovigilance) [4]	- Regulation (EC) No 726/2004 [13]- Regulation (EC) No 1394/2007 (ATMP Regulation) [4]
CAT (EU)	- ATMP classification scientific recommendations [10]- Draft opinion on ATMP quality, safety, & efficacy [4]- ATMP certification for SMEs [4]	- Regulation (EC) No 1394/2007 [10]
CBER (U.S.)	- Regulatory oversight of cellular & gene therapy products [11]- Evaluates safety, purity, and potency of biologics [12]- Manages INDs, BLAs, and expedited programs (e.g., Accelerated Approval) [14]	- Public Health Service Act § 351 [12]- Federal Food, Drug, and Cosmetic Act [12]

ATMP Classifications and Regulatory Pathways

ATMP Classifications in the EU

The European regulatory framework defines four main types of ATMPs, based on the underlying science and technological approach [4]:

• Gene Therapy Medicinal Products (GTMPs): Contain genes that lead to a therapeutic, prophylactic, or diagnostic effect. They work by inserting 'recombinant' genes into the body [4].
• Somatic-Cell Therapy Medicinal Products (sCTMPs): Contain cells or tissues that have been manipulated to change their biological characteristics or are not intended for the same essential functions in the body [4].
• Tissue-Engineered Medicines: Contain cells or tissues that have been modified to repair, regenerate, or replace human tissue [4].
• Combined ATMPs: Incorporate one or more medical devices as an integral part of the medicine, such as cells embedded in a biodegradable matrix or scaffold [4].

Key Regulatory Pathways and Procedures

EU Marketing Authorisation Application

For an ATMP to be legally marketed in the EU, a Marketing Authorisation Application (MAA) must be submitted to the EMA under the centralized procedure [13]. The application dossier must comply with the Common Technical Document (CTD) format, a standardized structure comprising five modules [13]:

• Module 1: Regional Administrative Information
• Module 2: CTD Summaries (Overview of Quality, Non-Clinical, Clinical)
• Module 3: Quality Data (Chemical, Pharmaceutical, Biological)
• Module 4: Non-Clinical Safety (Toxico-pharmacological) Data
• Module 5: Clinical Efficacy Data

The scientific assessment is performed by the CAT and CHMP, culminating in an opinion sent to the European Commission, which grants the final marketing authorization [13].

FDA Approval Pathways for Cell and Gene Therapies

The FDA's CBER provides several pathways for the development and approval of cell and gene therapies. Accelerated Approval has become increasingly significant for therapies targeting serious rare diseases with unmet medical needs [14]. This pathway allows for approval based on a surrogate endpoint that is reasonably likely to predict clinical benefit, requiring post-approval confirmatory trials to verify the anticipated benefit [14].

A newly proposed "Plausible Mechanism Pathway" aims to further expedite treatments for ultra-rare conditions. This pathway, announced in late 2025, is designed for cases where randomized trials are not feasible and leverages successful outcomes from single-patient expanded access INDs as an evidentiary foundation for a marketing application [12]. Its five core elements are [12]:

• Identification of a specific molecular or cellular abnormality.
• The product targets the underlying biological alterations.
• The disease's natural history is well-characterized.
• Confirmation that the target was successfully "drugged" or edited.
• Demonstration of an improvement in clinical outcomes or disease course.

Diagram: Comparative Regulatory Pathways for ATMPs in the EU and U.S.

Technical and Regulatory Requirements for ATMP Development

Chemistry, Manufacturing, and Controls (CMC)

Robust CMC documentation is fundamental to any ATMP application. The EMA's new guideline on clinical-stage ATMPs, effective July 1, 2025, provides a consolidated multidisciplinary reference, drawing from over 40 separate guidelines [9]. While significant regulatory convergence has been achieved between EMA and FDA on CMC requirements, key differences remain that sponsors must manage [9].

Table: Key CMC Considerations and Regional Emphases for ATMPs

CMC Area	Core Requirement	EMA Emphasis	U.S. FDA (CBER) Emphasis
Starting Materials	Detailed characterization and control of cell lines, tissues, and vectors.	Compliance with EU and member state-specific legal requirements for human cell-based materials [9].	Prescriptive requirements for donor eligibility determination, including specific infectious disease tests and lab qualifications [9].
Manufacturing Process	A detailed, controlled, and validated description of the manufacturing process.	Mandatory GMP compliance for all clinical trial stages, verified through self-inspections [9].	Phase-appropriate, graduated GMP compliance; full compliance verified via pre-license inspection [9].
Product Characterization	In-depth analysis of Critical Quality Attributes (CQAs), including identity, purity, potency, and safety.	Extensive characterization of the active substance and finished product per CTD Module 3 [13].	Similar rigorous characterization expectations, aligned with CTD structure for BLA submission.
Potency Assay	A quantitative measure of the biological activity relevant to the claimed clinical effect.	A validated potency assay is critical for release and stability testing [15].	Similarly requires a validated potency assay that reflects the product's mechanism of action.

Preclinical and Clinical Development

The transition from non-clinical Good Laboratory Practice (GLP) studies to Good Manufacturing Practice (GMP)-compliant manufacturing presents a major challenge. The manufacturing process must be designed to consistently achieve the product's Critical Quality Attributes (CQAs) identified during development [15]. Key hurdles include securing GMP-grade raw materials, managing donor-to-donor variability, and developing scalable, automated cell expansion protocols like closed-system bioreactors [15].

Clinical development for ATMPs must address unique safety concerns, such as the risk of tumorigenesis. For pluripotent stem cell (PSC)-derived products, this involves in vivo teratoma formation assays. For somatic cell-based therapies, tumorigenicity is assessed using in vivo studies in immunocompromised models, with more sensitive in vitro methods like digital soft agar assays now recommended [15].

Current Regulatory Landscape and Future Directions

Sector Growth and Clinical Trial Activity

The ATMP sector demonstrated significant global activity in the first half of 2025. The table below summarizes key sector metrics, illustrating the substantial investment and research focus in North America and the Asia-Pacific region [16].

Table: Global ATMP Sector Metrics (H1 2025) [16]

Region	Number of Clinical Trials	Number of Developers	Investment (H1 2025)
North America	844	770	$4.4 Billion
Europe	304	453	$0.8 Billion
Asia-Pacific	838	750	$0.5 Billion
H1 2025 Total	1,905	2,070	$5.0 Billion

Regulatory approvals are also tracking upward. Europe is projected to achieve 5-6 ATMP approvals in 2025, exceeding the three approvals it saw in 2023 and 2024 combined. The U.S. ATMP sector is expecting a similar number of approvals (5-6) in 2025 [16].

Evolving Regulatory Policies

Recent policy shifts highlight the ongoing adaptation of regulatory frameworks:

• FDA's Plausible Mechanism Pathway: This new approach, unveiled in November 2025, is a significant shift for ultra-rare conditions, leveraging single-patient outcomes from expanded access INDs as evidence for marketing applications [12].
• EMA's Clinical Trial Guideline: The implementation of the new multidisciplinary guideline for investigational ATMPs in July 2025 aims to consolidate and clarify expectations for clinical trial applications [9].
• Divergence on Expedited Pathways: While the FDA is increasingly embracing Accelerated Approval for gene therapies based on surrogate endpoints, the EMA has been more cautious. Gene therapies granted accelerated approval in the U.S. (e.g., Skysona, Elevidys) have not yet received approval in the EU, whereas products with full U.S. approval (e.g., Beqvez, Hemgenix, Zolgensma) are typically also approved in the EU [14].

The Scientist's Toolkit: Essential Research Reagents and Materials

The development and quality control of ATMPs rely on a suite of critical reagents and materials. The following table details key components and their functions in the research and development pipeline.

Table: Key Research Reagent Solutions for ATMP Development

Reagent / Material	Core Function in ATMP Development
Cell Culture Media & Supplements	Provides essential nutrients, growth factors, and cytokines for the ex vivo expansion and maintenance of cellular starting materials (e.g., T-cells, stem cells). Formulations must often be xeno-free and GMP-grade for clinical use.
Viral Vectors (e.g., Lentivirus, AAV)	Serves as the primary delivery vehicle for gene therapy medicinal products (GTMPs), enabling the introduction of therapeutic genetic material into patient cells. Critical CQAs include titer, infectivity, and purity.
Cell Separation & Activation Reagents	Enables the isolation of specific cell populations (e.g., CD4+ T-cells) from a heterogeneous starting material (e.g., apheresis product) using technologies like magnetic-activated cell sorting (MACS).
Analytical Assay Kits	Used for in-process testing and lot release to characterize CQAs. Examples include flow cytometry kits for immunophenotyping, ELISA for cytokine detection, and qPCR assays for vector copy number and mycoplasma testing.
Cryopreservation Media	Allows for the long-term storage of cell-based drug substances and products by cooling them to very low temperatures (e.g., in liquid nitrogen) while maintaining cell viability and functionality upon thawing.
Biodegradable Matrices/Scaffolds	Acts as the device component in a Combined ATMP, providing a three-dimensional structure that supports cell attachment, growth, and tissue formation when implanting tissue-engineered products.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking class of biotherapeutics derived from genes, cells, or tissues, offering innovative treatments for diseases with limited therapeutic options [17]. The European Union and the United States have established sophisticated yet distinct legislative frameworks to govern the development, evaluation, and marketing of these complex products. The EU's approach is centralized under Regulation (EC) No 1394/2007, which specifically defines and regulates ATMPs [18] [19]. In contrast, the US regulatory system operates under a dual statutory framework: the Public Health Service Act (PHS Act) and the Federal Food, Drug, and Cosmetic Act (FD&C Act) [20] [21]. These legislative foundations aim to safeguard public health while fostering innovation and ensuring timely patient access to transformative therapies. Understanding the nuances of these systems is crucial for researchers, scientists, and drug development professionals navigating the global development of advanced therapies.

The European Union Framework: Regulation (EC) No 1394/2007

Legislative Foundation and Definitions

Regulation (EC) No 1394/2007, active since December 2008, establishes a comprehensive regulatory framework for ATMPs within the European Union [17]. This regulation operates as a lex specialis (special law), introducing additional provisions to the existing medicinal product legislation under Directive 2001/83/EC [18]. It was designed to overcome the scarcity of expertise in the Community, ensure a high level of scientific evaluation, and facilitate market access for these innovative technologies through a centralized authorization procedure [18] [19].

The Regulation categorizes ATMPs into four distinct classes, each with precise legal definitions [4] [17]:

• Gene Therapy Medicinal Products (GTMP): These contain genes that lead to a therapeutic, prophylactic, or diagnostic effect. They work by inserting 'recombinant' genes into the body, typically to treat genetic disorders, cancer, or long-term diseases [4].
• Somatic Cell Therapy Medicinal Products (SCTMP): These contain cells or tissues that have been manipulated to change their biological characteristics, or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose, or prevent diseases [4].
• Tissue-Engineered Products (TEP): These contain cells or tissues that have been modified so they can be used to repair, regenerate, or replace human tissue [4].
• Combined ATMPs (cATMPs): These incorporate one or more medical devices as an integral part of the medicine, such as cells embedded in a biodegradable matrix or scaffold [4].

A critical aspect of the EU framework is the clear differentiation between ATMPs and products falling under other legal frameworks, such as transplant laws or the blood system, where cells are not considered medicinal products and cannot be commercialized on an industrial scale for ethical and legal reasons [17].

Regulatory Bodies and Approval Pathways

The European Medicines Agency (EMA) plays a central role in the authorization and oversight of ATMPs. All ATMPs must be evaluated via the centralized procedure, ensuring a single evaluation and authorization applicable across the EU [4] [17]. Two key committees within EMA are responsible for the scientific evaluation:

• Committee for Advanced Therapies (CAT): Established specifically by Regulation (EC) No 1394/2007, the CAT gathers the best available expertise on ATMPs in the Community [18]. It is responsible for preparing a draft opinion on the quality, safety, and efficacy of each ATMP application, classifying ATMPs, and following scientific progress in the field [4].
• Committee for Medicinal Products for Human Use (CHMP): Based on the CAT's draft opinion, the CHMP adopts a final opinion recommending or not recommending the authorization of the medicine to the European Commission, which makes the final binding decision [4] [17].

Marketing authorization may be granted through three primary pathways [17]:

• Standard Marketing Authorization
• Conditional Marketing Authorization: Granted when an innovative medicine addresses an unmet medical need and demonstrates a positive benefit-risk balance, but comprehensive clinical data are not yet available.
• Marketing Authorization under Exceptional Circumstances: For situations where a disease is rare or a clinical endpoint is difficult to measure.

Table 1: Expedited Development and Approval Pathways in the EU

Pathway	Purpose	Key Features
PRIME (Priority Medicines)	For medicines offering a major therapeutic advantage over existing treatments or benefits for patients without treatment options [22].	Early dialogue and support; accelerated assessment (150 days) [23] [22].
Conditional Marketing Authorization	Early approval for medicines addressing unmet medical needs based on less comprehensive data [17].	Allows submission of final efficacy proof under specific post-authorization obligations [22].
Accelerated Assessment	Shortens the review timeline for medicines of major public health interest [23].	Reduces standard 210-day review to 150 days [23].

The United States Framework: PHS Act & FD&C Act

Legislative Foundation and Definitions

In the United States, advanced therapies, commonly referred to as Cell and Gene Therapies (CGTs), are regulated as biological products under a dual statutory framework [22] [17]. The FD&C Act provides the foundational authority for the FDA to regulate drugs and biological products, with biological products also subject to the provisions of the PHS Act [20] [17]. This combination ensures that CGTs meet standards for safety, purity, and potency.

The classification system in the US differs from the EU's multi-category approach. The primary categories for advanced therapies are [17]:

• Gene Therapy Products
• Cellular Therapy Products

A crucial regulatory distinction is made between these biological products and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). HCT/Ps are defined as "articles containing or consisting of human cells or tissues intended for implantation, transplantation, infusion, or transfer into a human recipient" and are not considered biological products if they meet specific criteria, such as being minimally manipulated and intended for homologous use only [17]. The 21st Century Cures Act, signed into law in 2016, further advanced this framework by establishing expedited programs like the Regenerative Medicine Advanced Therapy (RMAT) designation [17].

Regulatory Bodies and Approval Pathways

The Food and Drug Administration (FDA) holds the authority for approving biological products in the US. Within the FDA, the Center for Biologics Evaluation and Research (CBER) is specifically responsible for regulating cell and gene therapy products [22]. Unlike the EU, where the European Commission grants the final marketing authorization, the FDA has full approval authority for CGTs [23].

The standard pathway for market approval is the submission of a Biologics License Application (BLA) to CBER. The BLA must demonstrate that the biological product is safe, pure, and potent [24] [23]. The US employs a multi-faceted system of expedited programs to accelerate the development and review of promising therapies, particularly for serious conditions [24].

Table 2: Key Expedited Programs for Advanced Therapies in the US

Pathway/Designation	Purpose	Key Features
RMAT (Regenerative Medicine Advanced Therapy)	For regenerative medicine therapies (including cell and gene therapies) for serious diseases with preliminary clinical evidence addressing unmet needs [22] [17].	Similar to Breakthrough Therapy; intensive guidance, rolling review, potential for accelerated approval [23] [22].
Fast Track	To facilitate development and expedite review of drugs for serious conditions that address an unmet need [24].	Rolling review; more frequent interactions with FDA [24].
Breakthrough Therapy	For drugs intended to treat serious conditions where preliminary clinical evidence indicates substantial improvement over available therapies [24].	Intensive guidance on efficient drug development; organizational commitment [24].
Accelerated Approval	Allows approval for serious conditions based on a surrogate or intermediate endpoint likely to predict clinical benefit [24] [23].	Requires post-approval confirmatory trials [24].
Priority Review	For drugs that offer significant improvements in safety or effectiveness [24].	Shortens standard 10-month review clock to 6 months [24] [23].

Comparative Analysis: EU vs. US Regulatory Systems

Side-by-Side Comparison of Key Features

The regulatory frameworks for advanced therapies in the EU and US, while having the common goal of ensuring patient safety and product efficacy, exhibit significant differences in structure, process, and requirements.

Table 3: Comprehensive Comparison of EU and US Regulatory Frameworks for Advanced Therapies

Aspect	European Union (EU)	United States (US)
Governing Legislation	Regulation (EC) No 1394/2007, Directive 2001/83/EC [18] [17]	PHS Act, FD&C Act, 21st Century Cures Act [20] [17]
Product Categories	Gene Therapy, Somatic Cell Therapy, Tissue-Engineered, Combined ATMP [4]	Gene Therapy, Cellular Therapy [17]
Regulatory Authority	European Medicines Agency (EMA)	Food and Drug Administration (FDA)
Key Evaluation Committees	Committee for Advanced Therapies (CAT), CHMP [4]	Center for Biologics Evaluation and Research (CBER) [22]
Marketing Authorization Type	Centralized Marketing Authorization [4]	Biologics License Application (BLA) [23]
Standard Review Timeline	210 days [23]	10 months for standard BLA [24]
Expedited Review Timeline	150 days (Accelerated Assessment) [23]	6 months (Priority Review) [24]
Expedited Pathway for CGT/ATMP	PRIME Scheme [22]	RMAT Designation [22]
Clinical Trial Approval	Submission to National Competent Authorities (NCAs) via CTIS [23]	IND submission to FDA (30-day review) [23]
Post-Marketing Surveillance	EudraVigilance, Periodic Safety Update Reports (PSURs), Risk Management Plans (RMPs) [23]	FAERS, REMS, Long-Term Follow-up (LTFU) studies (15+ years for gene therapies) [23]
Final Decision Maker	European Commission [23]	FDA [23]

Strategic Implications for Drug Development Professionals

The divergent regulatory expectations between the EU and US have direct consequences on global development strategies for ATMPs [23]. A recent study highlighted that only 20% of clinical trial data submitted to both agencies matched, revealing major inconsistencies in regulatory expectations [23]. These differences manifest in several key areas:

• Clinical Trial Design and Data Requirements: The FDA often demonstrates greater flexibility in accepting real-world evidence and surrogate endpoints, particularly through accelerated approval pathways. In contrast, the EMA typically requires more comprehensive clinical data, emphasizing larger patient populations and long-term efficacy before granting approval [23]. This can result in therapies gaining market access more swiftly in the US, while facing delays or rejections in Europe due to more stringent data demands [23].
• Approval Timelines: Analyses of COVID-19 medicine approvals showed a median time to approval of 24 days for the EMA's conditional MAs and 36 days for the US FDA's Emergency Use Authorizations (EUAs) [24]. These accelerated timelines during a public health crisis demonstrate the functionality of expedited pathways, though standard reviews are considerably longer.
• Post-Marketing Requirements: The FDA mandates 15 or more years of long-term follow-up (LTFU) for gene therapies, while the EMA enforces a decentralized pharmacovigilance system with country-specific compliance requirements, though its LTFU requirements are generally considered less prescriptive than the FDA's [23].

Essential Protocols for Regulatory Strategy and ATMP Classification

Protocol for Developing an Integrated EU/US Regulatory Strategy

A proactive, risk-based regulatory strategy is essential for successfully navigating the complex landscape of advanced therapy development. The following protocol outlines a systematic approach for engaging with both the FDA and EMA.

Figure 1: Workflow for an Integrated EU/US Regulatory Strategy Development. This diagram outlines the sequential steps for building a combined regulatory strategy, emphasizing early engagement and parallel planning.

Methodology Details:

• Early Agency Engagement: Developers should initiate dialogue with regulators as early as possible. In the US, this can be done via INTERACT meetings with CBER, while in the EU, options include informal meetings with National Competent Authorities (NCAs) or through the EMA's Innovation Task Force (ITF) [22]. Following this with formal Pre-IND (FDA) and Scientific Advice (EMA) meetings is highly recommended to obtain binding feedback on development plans.
• Regulatory Risk Assessment: A thorough assessment should be conducted across three domains [22]:
  • Quality (CMC): Evaluate manufacturing process, characterization, and controls.
  • Non-Clinical: Assess the design of pharmacology and toxicology studies.
  • Clinical: Review clinical trial design, endpoint selection, and safety monitoring plans.
• Tailored Clinical Trial Design: Given the differing expectations, sponsors should design trials that incorporate adaptive elements and endpoints acceptable to the FDA, while also planning for the larger sample sizes and longer follow-up durations often requested by the EMA [23].
• Strategic Use of Expedited Pathways: Identify and apply for all relevant expedited programs (e.g., RMAT, PRIME, Orphan Drug Designation) early in development to access intensified regulatory guidance and potential accelerated reviews [22].
• Submission Preparation: Create a common core document for both agencies, then adapt it with region-specific modules to address divergent requirements for data presentation, trial design, and post-market commitments [22].

Protocol for ATMP Classification and Certification in the EU

For products developed in the EU, determining the correct classification is a critical first step. The Committee for Advanced Therapies (CAT) provides formal classification procedures.

Figure 2: Decision Logic for ATMP Classification in the European Union. This chart illustrates the logical process for determining whether a product qualifies as an ATMP and under which specific category it falls.

Methodology Details:

• Mode of Action Analysis: The primary criterion is whether the product's principal mode of action is pharmacological, immunological, or metabolic. Products acting primarily by physical means are excluded from the ATMP definition [18] [19].
• Level of Manipulation: For cell-based products, they must be substantially manipulated or be intended for a different essential function than their native role in the body to be classified as an ATMP [4] [17].
• Formal Classification Procedure: Sponsors can submit a request for a CAT classification to the EMA. The CAT will issue a formal opinion on whether the product meets the criteria to be classified as a GTMP, SCTMP, TEP, or cATMP. This step is crucial as it determines the entire regulatory pathway [4] [17].
• Certification for SMEs: The EMA offers an ATMP certification procedure for small and medium-sized enterprises (SMEs). This voluntary procedure allows the CAT to assess the quality and non-clinical data of a developing ATMP, identifying gaps that may hamper future marketing authorization. This certification can be requested at any development stage but provides the highest value before initiating pivotal non-clinical or clinical studies [22].

The Scientist's Toolkit: Essential Research Reagents and Materials

The development and manufacturing of ATMPs require specialized reagents and materials to ensure product safety, identity, purity, and potency. The following table details key components of a research toolkit for ATMP development.

Table 4: Essential Research Reagent Solutions for ATMP Development

Reagent/Material	Function	Key Considerations
Cell Culture Media & Supplements	Supports the expansion and maintenance of cellular starting materials and final products.	Defined, xeno-free formulations; growth factors and cytokines; compliance with Good Manufacturing Practice (GMP) for clinical lots [22].
Gene Delivery Vectors	Vehicles for introducing genetic material into target cells (e.g., viral vectors, plasmid DNA).	Viral vectors (Lentivirus, Retrovirus, AAV); non-viral methods (electroporation, transfection reagents); vector purity and titer [4].
Cell Separation & Selection Reagents	Isolates specific cell populations from heterogeneous mixtures (e.g., lymphocytes, stem cells).	Antibody-based magnetic beads (e.g., CD4+, CD34+); density gradient media; fluorescence-activated cell sorting (FACS) reagents [22].
Biocompatible Scaffolds/Matrices	Provides 3D structure for Tissue-Engineered Products (TEPs) and Combined ATMPs.	Biodegradable polymers (e.g., PLA, PGA); hydrogels; decellularized tissues; must support cell attachment and growth [4].
Critical Process Reagents	Used in manufacturing but not present in the final product (e.g., enzymes, cytokines).	Trypsin/accutase for cell detachment; recombinant proteins; serum-free replacements; rigorous quality control and sourcing [22].
Analytical Assays & Kits	Characterizes the final product and in-process materials (safety, identity, potency, purity).	Sterility, mycoplasma, and endotoxin testing kits; flow cytometry panels; PCR assays for vector copy number; functional potency assays [22].

The regulatory frameworks governing advanced therapies in the European Union and the United States, built upon the foundational pillars of Regulation (EC) No 1394/2007 and the U.S. PHS Act & FD&C Act respectively, are complex and evolving. While both systems share the ultimate goal of bringing safe and effective treatments to patients, their structural differences, approval pathways, and data expectations present significant challenges for global development. Success in this landscape requires a deep understanding of both systems, proactive regulatory engagement, and carefully tailored development strategies that accommodate divergent requirements from the earliest stages of research. As the science of advanced therapies continues to advance rapidly, these regulatory frameworks will undoubtedly adapt, requiring ongoing vigilance and education from researchers, scientists, and drug development professionals worldwide.

The European Union's regulatory framework for substances of human origin (SoHO) is undergoing its most significant transformation in two decades. The new SoHO Regulation (EU) 2024/1938, adopted by the Council on 27 May 2024 and published in the Official Journal on 17 July 2024, replaces the previous Blood and Tissues and Cells Directives with a directly applicable regulation that will be fully implemented by 7 August 2027 [25] [26]. This legislative evolution represents a paradigm shift in how human-derived biological materials are regulated, with profound implications for Advanced Therapy Medicinal Product (ATMP) research and development. The regulation emerges against a backdrop of rapid scientific advancement where the previous framework, established over 20 years ago, no longer adequately addressed emerging risks, global epidemiological changes, or the pace of innovation in biomedical technologies [26].

For researchers, scientists, and drug development professionals working with ATMPs, understanding this new framework is critical. The regulation fundamentally reshapes the regulatory environment for starting materials essential to ATMP development while introducing novel requirements for quality, safety, and efficacy demonstration. This technical guide provides a comprehensive overview of the SoHO Regulation's key provisions, its intricate interplay with the existing ATMP framework, and practical guidance for navigating this transformed landscape to ensure compliance and facilitate continued innovation in advanced therapy development.

Core Provisions of the SoHO Regulation

Expanded Scope and Key Definitions

The SoHO Regulation significantly expands the scope of regulated substances beyond the previous framework's coverage of blood, tissues, and cells. It now explicitly encompasses novel substances including breast milk, intestinal microbiota, and serum eye drops, while also creating a pathway for automatic inclusion of future human-derived substances used for human application [26] [27] [28]. This expanded scope addresses previous regulatory gaps and ensures that emerging therapies utilizing these substances will have a clear regulatory pathway from their inception.

The regulation introduces precise terminology that researchers must understand and correctly apply:

• SoHO Entities: Any organization legally established in Member States that carries out one or more SoHO activities, including donor recruitment, testing, collection, processing, storage, or distribution [26] [27].
• SoHO Establishments: A subset of SoHO entities that perform higher-risk activities including processing, storage, release, import, and export of SoHOs [26].
• SoHO Preparations: Substances of human origin that have undergone manufacturing processes intended for specific clinical indications [27].
• Critical SoHOs: Those substances "for which an insufficient supply will result in serious harm or risk of serious harm to recipients' health," which will be subject to enhanced controls and monitoring requirements [26] [27].

Key Objectives and Rationale for Reform

The SoHO Regulation was developed to address five key areas where the previous legal framework demonstrated significant shortcomings [26]:

• Patient protection from new risks arising from global epidemiological changes
• Donor protection, including offspring from medically assisted reproduction
• Harmonization of oversight activities across Member States to address unequal safety levels
• Inadequate capacity of previous legislation to deal with innovation
• Weakness in guaranteeing continuity of SoHO supply during emergencies

The regulation aims to create a future-proof framework that can more readily adapt to scientific and technical developments while maintaining high standards of quality and safety [25]. By establishing a regulation rather than a directive, it ensures direct applicability across all Member States, reducing the regulatory fragmentation that hampered cross-border exchange of materials under the previous directive-based system [29] [28].

Quality, Safety, and Oversight Requirements

The regulation introduces rigorous new requirements that will significantly impact research and development activities:

• SoHO Preparation Authorization: SoHO establishments must obtain authorization for preparation processes, including submission of dossiers containing a clinical outcome-monitoring plan to demonstrate safety and efficacy [26]. For preparations where scientific evidence is insufficient or risk is more than negligible, a preliminarily approved monitoring plan enables collection of further evidence to support benefit-risk assessment [26].

• Robust Oversight Framework: SoHO competent authorities will implement a risk-based inspection and authorization system, with SoHO establishments subject to formal authorization and routine inspections [26] [28]. The regulation mandates both announced and unannounced inspections, targeting specific activities as necessary [28].

• Enhanced Traceability and Vigilance: Comprehensive traceability systems must be maintained from donation to human application or disposal, with serious adverse reactions and events subject to a rapid alert procedure communicated through the EU SoHO Platform [26] [28].

Table 1: Key Implementation Timelines for the SoHO Regulation

Date	Milestone	Implications for Researchers
17 July 2024	Publication in Official Journal	Regulation enters into force
7 August 2027	General application date	Full compliance required for all SoHO activities [25]
7 August 2028	Additional year for certain provisions	Specific complex requirements become applicable [25]

Interplay Between SoHO Regulation and ATMP Framework

Navigating the Borderline Between SoHO and ATMP

A critical challenge addressed by the new regulation is the ambiguous classification boundary between products regulated as SoHOs versus those classified as ATMPs [30]. This distinction has significant consequences, as ATMPs are considered medicinal products requiring centralized marketing authorization by the European Medicines Agency (EMA), while SoHOs follow a different regulatory pathway managed through healthcare systems and regional transplant authorities [27]. The classification determines not only the regulatory pathway but also associated administrative burdens, costs, and evidence requirements for market access [31].

The boundary between these categories has been increasingly blurred, with several notable cases of products being reclassified from SoHO to ATMP status. Cultured limbal cells and cultured keratinocytes, previously regulated under the Tissues and Cells Directive, have been reclassified as ATMPs based on recommendations from the Committee for Advanced Therapies (CAT) [32]. Such reclassifications have imposed substantial costs on developers who must transition from SoHO requirements to the more stringent ATMP framework, including the need for marketing authorization [32].

New Consultation Procedure for Borderline Products

Article 14 of the SoHO Regulation establishes a formal consultation procedure to address regulatory uncertainty regarding classification of substances, products, or activities [32]. This mechanism requires SoHO competent authorities to consult with authorities governing alternative regulatory frameworks when qualification uncertainties arise. The procedure includes:

• Mandatory inter-authority consultation when regulatory status is uncertain
• Potential referral to the SoHO Coordination Board (SCB) for an opinion on regulatory status
• Compilation of decisions in a publicly available compendium to promote consistency [32]

Where consultations fail to yield a decision at the member state level, the European Commission may issue a final determination on regulatory status, providing a mechanism for resolving persistent classification disputes [28] [32].

Diagram 1: SoHO-ATMP Borderline Classification Procedure

Implications for ATMP Research and Development

The expanded scope of the SoHO Regulation significantly impacts ATMP developers, as the regulation now covers additional activities in the product development chain. Previously covering mainly donation collection and testing, the regulation now encompasses donor registration, storage, distribution, import, export, and distribution to the ATMP manufacturer [28]. This means all parties handling these activities – now classified as SoHO entities – must comply with the regulation's requirements, appointing responsible persons to ensure adherence [28].

For ATMPs developed under the hospital exemption (HE) pathway, the relationship with SoHO regulation is particularly important. The European Blood Alliance (EBA) has advocated for expanding rather than restricting the use of HE for ATMPs, suggesting that HE should become a "harmonized regular approach" for producing ATMPs [30]. The EBA further recommends modifying the ATMP framework to incorporate elements from the SoHO Regulation and reassessing classification of lower-risk cell-based ATMPs as SoHO products under specific conditions [30].

Implementation Framework and Institutional Architecture

New Governance Bodies and Coordination Mechanisms

The SoHO Regulation establishes new governance structures to support implementation and ongoing oversight:

• SoHO Coordination Board (SCB): An advisory body that supports Member States in implementing the regulation, developing common practices for inspection and vigilance, and providing advice on regulatory applicability [26]. The SCB also facilitates cross-sector coherence with other legal frameworks governing medical devices and pharmaceuticals [26].

• EU SoHO Platform: A central digital tool that serves as a hub for information exchange, providing access to data on SoHO entity registrations, authorizations, technical guidelines, and aggregated data on donations, clinical use, and adverse reactions [26]. This platform supports traceability, adverse event detection, and rapid alerts across the EU [27].

Technical Standards and Harmonization

The regulation leverages existing technical guidelines from the European Directorate for the Quality of Medicines and HealthCare (EDQM) and the European Centre for Disease Prevention and Control (ECDC), which will become the primary means for meeting EU quality and safety standards for SoHO [26]. This approach enables more rapid incorporation of new scientific and technical evidence without requiring amendment of the regulation itself, particularly for areas such as donor selection criteria and testing for infectious diseases [26].

Table 2: Key Regulatory Bodies and Their Roles in the SoHO-ATMP Ecosystem

Organization/Body	Role in SoHO Regulation	Role in ATMP Framework	Interplay Responsibilities
SoHO Coordination Board (SCB)	Develop common practices, advise on regulation applicability	Limited direct role	Provides opinions on borderline classification cases [26] [32]
Committee for Advanced Therapies (CAT)	Limited direct role	Scientific assessment of ATMPs; classification recommendations	Provides ATMP classification guidance; limited consultation in borderline cases [4] [32]
National Competent Authorities	Authorize SoHO establishments; oversee SoHO activities	Implement ATMP regulations at national level; approve hospital exemption	Participate in Article 14 consultation procedure for borderline products [28] [32]
European Medicines Agency (EMA)	Limited direct role	Centralized ATMP authorization; scientific support to developers	Collaboration with SoHO bodies on borderline products [4]
European Commission	Adopt implementing acts; final determination on borderline cases	Adopt marketing authorizations for ATMPs	Ultimate arbiter of regulatory status disputes [32]

Practical Implications for ATMP Researchers and Developers

Preparation and Compliance Strategies

With the regulation applying fully from 7 August 2027, ATMP researchers and developers should implement proactive preparation strategies:

• Comprehensive Gap Analysis: Conduct a thorough assessment of current practices against SoHO Regulation requirements, particularly focusing on expanded activity coverage including storage, distribution, and import/export activities [28].

• Documentation Systems: Develop robust systems for maintaining the required technical documentation for SoHO preparations, including detailed characterization of substances, manufacturing process descriptions, and clinical outcome monitoring plans [26] [27].

• Quality Management Enhancement: Strengthen quality management systems to address the regulation's emphasis on risk-based approaches to authorization and oversight, particularly for higher-risk activities [26].

• Personnel Designation: Appoint responsible persons to ensure compliance with SoHO Regulation requirements, particularly for entities handling multiple activities across the development chain [28].

Clinical Development Considerations

The SoHO Regulation introduces specific requirements for clinical development that researchers must incorporate into their development strategies:

• Clinical Outcome Monitoring: SoHO preparation authorization requires a clinical outcome-monitoring plan to demonstrate safety and efficacy, which must be approved beforehand when scientific evidence is insufficient or risk is more than negligible [26].

• Progressive Evidence Generation: The regulation enables a more flexible framework for initiating studies with SoHO products even without consolidated clinical evidence, allowing generation of useful data without immediately meeting strict medicinal product requirements [27].

• Benefit-Risk Assessment: Developers must implement systematic benefit-risk assessment frameworks that meet regulatory expectations, particularly for innovative SoHO preparations where established evidence may be limited [26].

Diagram 2: SoHO-ATMP Integrated Development Workflow

The Scientist's Toolkit: Essential Components for SoHO-Compliant ATMP Research

Table 3: Essential Research Components for SoHO-Compliant ATMP Development

Component Category	Specific Requirements	Function in SoHO-Compliant Research
Documentation Systems	Technical documentation for SoHO preparations; clinical outcome monitoring plans	Demonstrates safety, efficacy, and quality throughout development process [26] [27]
Traceability Platforms	EU SoHO Platform-compatible systems for donor-to-application tracking	Ensures comprehensive traceability and facilitates rapid alert procedures for adverse events [26] [28]
Quality Management	Risk-based quality systems; validated manufacturing methods	Supports authorization of SoHO establishments and preparation processes [26] [30]
Clinical Evidence Generation	Benefit-risk assessment frameworks; post-authorization monitoring plans	Enables demonstration of safety and efficacy for SoHO preparation authorization [26]
Regulatory Strategy Tools	Borderline classification assessment frameworks; consultation procedures	Facilitates navigation of SoHO-ATMP classification boundaries and regulatory requirements [28] [32]

The EU SoHO Regulation represents a transformative shift in the regulatory landscape for substances of human origin, with far-reaching implications for ATMP research and development. By establishing a comprehensive, directly applicable framework that expands beyond previous directives, the regulation addresses critical gaps in patient and donor protection while creating mechanisms to better accommodate scientific innovation. For researchers and developers, understanding the intricate interplay between SoHO and ATMP frameworks is essential, particularly the revised procedures for classifying borderline products that have previously created regulatory uncertainty and increased development costs.

The successful implementation of the SoHO Regulation will require substantial preparation from all stakeholders in the ATMP development ecosystem. By proactively adapting to the expanded activity coverage, enhanced oversight requirements, and novel clinical evidence expectations, researchers can not only ensure regulatory compliance but also leverage the regulation's mechanisms to support efficient development of innovative therapies. The creation of the SoHO Coordination Board and EU SoHO Platform offers promising opportunities for greater harmonization and information exchange that may ultimately facilitate cross-border research collaboration and improve patient access to advanced therapies across the European Union.

As the 2027 implementation deadline approaches, ATMP researchers and developers should prioritize understanding how their specific activities and product candidates intersect with the new regulatory requirements. Through strategic preparation and active engagement with the evolving regulatory landscape, the scientific community can harness the potential of the SoHO Regulation to support the development of safe, effective, and innovative therapies that address unmet patient needs while maintaining the highest standards of quality and safety.

The ATMP Development Pathway: From Clinical Trials to Market Authorization

The development of Advanced Therapy Medicinal Products (ATMPs)—encompassing gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs—represents the frontier of medical innovation [4]. For researchers and drug development professionals, navigating the regulatory pathway from first-in-human trials to market authorization is a critical component of product development. The regulatory funnel for ATMPs is characterized by increasing complexity and stringent oversight from major agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [9] [4]. Understanding the distinct yet occasionally converging requirements for Investigational New Drug (IND)/Clinical Trial Application (CTA) submissions through to Marketing Authorization Application (MAA)/Biologics License Application (BLA) is essential for efficiently advancing transformative therapies to patients.

ATMP Classification and Regulatory Framework

ATMP Categorization

ATMPs are classified based on their biological characteristics and mechanism of action [4]:

• Gene Therapy Medicines: Contain recombinant genes for therapeutic, prophylactic, or diagnostic effects, used for genetic disorders, cancer, or long-term diseases.
• Somatic-Cell Therapy Medicines: Contain manipulated cells or tissues with altered biological characteristics for curing, diagnosing, or preventing diseases.
• Tissue-Engineered Medicines: Contain cells or tissues modified to repair, regenerate, or replace human tissue.
• Combined ATMPs: Incorporate one or more medical devices as an integral part of the medicine, such as cells embedded in a biodegradable matrix or scaffold.

Regulatory Oversight and Convergence

The FDA and EMA maintain distinct regulatory frameworks but show increasing convergence in scientific principles [9] [33]. The FDA operates under the Federal Food, Drug, and Cosmetic Act with regulations in Title 21 of the Code of Federal Regulations, while the EMA functions under several key regulations including Regulation (EC) No 726/2004 and Directive 2001/83/EC [33]. A significant difference lies in approval authority: the FDA has centralized approval power, whereas the EMA provides scientific evaluation with final approval granted by the European Commission [33].

The Committee for Advanced Therapies (CAT) plays a central role in the EMA's scientific assessment of ATMPs, preparing draft opinions on quality, safety, and efficacy for the Committee for Medicinal Products for Human Use (CHMP) [4]. For the FDA, the Center for Biologics Evaluation and Research (CBER) oversees cell and gene therapy products, including ATMPs [9].

Table: Key Regulatory Bodies for ATMPs

Agency	Role in ATMP Regulation	Governing Regulations
FDA/CBER	Evaluates safety, efficacy, and quality of biological products including cell and gene therapies	Federal Food, Drug, and Cosmetic Act; 21 CFR
EMA/CAT	Provides scientific assessment of ATMPs; classifies ATMPs; advises on quality, non-clinical, and clinical requirements	Regulation (EC) No 726/2004; Directive 2001/83/EC
European Commission	Grants final marketing authorization for ATMPs in the EU based on EMA recommendation	EU Regulations and Directives

Phase 1: Pre-Submission Strategy and Planning

Early Regulatory Planning

Identifying the appropriate regulatory pathway early in development is crucial for ATMPs. Sponsors should [34] [9]:

• Determine ATMP Classification: Seek CAT classification for EU-bound products early to clarify regulatory status [4].
• Identify Expedited Pathways: Assess eligibility for programs like Fast Track, Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), Priority Medicines (PRIME), and Orphan Drug designations [34] [35].
• Plan for Global Development: Consider divergent requirements between regions, particularly for donor eligibility, GMP implementation, and comparability protocols [9].

Pre-IND and Pre-CTA Consultation

Formal regulatory consultations provide invaluable feedback before submission [36]:

• FDA Pre-IND Consultation: CDER's Pre-IND Consultation Program fosters early communication between sponsors and review divisions, providing guidance on data necessary to warrant IND submission [37].
• EMA Scientific Advice and CAT Classification: ATMP developers are encouraged to seek early guidance at either the national member state or European level to inform development [9]. The EMA also offers an ATMP Pilot for academia and non-profit organizations providing dedicated regulatory support [4].

A strategic pre-IND meeting requires [36]:

• A comprehensive briefing package (30-50 pages) with proposed clinical design, CMC strategy, and key nonclinical data
• Specific, targeted questions addressing potential concerns or ambiguities (5-7 key questions)
• Alternative approaches for discussion demonstrating flexibility
• A cross-functional team including regulatory affairs, clinical development, CMC, and toxicology experts

Phase 2: IND and CTA Submission Requirements

IND Application Components (FDA)

An IND application technically requests exemption from federal law prohibiting unapproved drugs from interstate commerce [37]. The IND must contain three broad areas of information [37]:

• Animal Pharmacology and Toxicology Studies: Preclinical data demonstrating reasonable safety for initial human testing, including any previous human experience.
• Manufacturing Information: Composition, manufacturer, stability, and controls for manufacturing drug substance and product.
• Clinical Protocols and Investigator Information: Detailed protocols for proposed clinical studies, investigator qualifications, and commitments to obtain informed consent and IRB review.

The FDA review period is 30 calendar days from IND submission before clinical trials may initiate [37].

Table: IND Types and Applications

IND Type	Purpose	Applicable Scenarios
Investigator IND	Submitted by a physician who initiates and conducts investigation	Research on unapproved drug or approved product for new indication/population
Emergency Use IND	Authorizes experimental drug use in emergency situations	Emergency cases without time for full IND submission; patients not meeting existing study criteria
Treatment IND	For promising drugs for serious/life-threatening conditions	Access during final clinical work and FDA review

CTA Requirements (EMA)

The EU's Clinical Trial Application process operates under the Clinical Trials Regulation (CTR) No. 536/2014, centralized through the Clinical Trials Information System (CTIS) since 2022 [33]. The CTA requires submission to both concerned Member States and Ethics Committees [33].

The EMA's guideline on clinical-stage ATMPs effective July 2025 provides a multidisciplinary reference document consolidating over 40 separate guidelines [9]. Key requirements include:

• Quality Documentation: Comprehensive Chemistry, Manufacturing, and Controls (CMC) information organized according to Common Technical Document (CTD) Module 3 headings [9].
• Risk-Based Approach: Sponsors should adopt risk-based evaluation of quality, non-clinical, and clinical data [9].
• Warning on Immature Quality Systems: Inadequate quality development may compromise use of clinical trial data to support marketing authorization [9].

Comparative Analysis: IND vs. CTA for ATMPs

Table: IND vs. CTA Requirements for ATMPs

Requirement	FDA IND	EMA CTA
Legal Basis	Federal Food, Drug, and Cosmetic Act; 21 CFR	Clinical Trials Regulation (EC) No 536/2014
Application System	Electronic Submissions Gateway	Clinical Trials Information System (CTIS)
Review Timeline	30-day review period before trial initiation [37]	Variable by Member State; coordinated assessment
CMC Emphasis	Phase-appropriate GMP with verification at BLA stage [9]	GMP compliance mandatory from early trials [9]
Donor Eligibility	Prescriptive requirements for screening and testing [9]	Compliance with EU and member state-specific legal requirements [9]
Primary Guideline	CBER-specific guidance for cell and gene therapies	EMA Guideline on clinical-stage ATMPs (effective July 2025) [9]

Technical Requirements for ATMP Applications

Chemistry, Manufacturing, and Controls (CMC)

The CMC section for ATMPs requires comprehensive documentation of manufacturing processes and quality controls. The EMA's clinical-stage ATMP guideline devotes approximately 70% of content to quality documentation [9]. Key elements include:

• Starting Materials: Detailed characterization of biological source materials, including donor screening and testing protocols [9].
• Manufacturing Process: Complete description of production methods, including all steps of manipulation, culture, and purification.
• Process Controls: In-process testing and acceptance criteria to ensure process consistency.
• Product Characterization: Comprehensive analysis of identity, purity, potency, and impurities.
• Specifications: Acceptance criteria for drug substance and drug product release.
• Stability Data: Real-time stability studies supporting proposed storage conditions and expiry dates.

Nonclinical Studies

Nonclinical development for ATMPs should establish proof-of-concept and initial safety profile [36]:

• Proof-of-Concept Studies: In vitro and in vivo models demonstrating biological activity.
• Pharmacology: Mechanism of action and dose-response relationships.
• Toxicology: Safety assessment including tumorigenicity, biodistribution, and integration sites (for gene therapies).
• Study Design Considerations: Use of relevant animal species, human equivalent dosing, and appropriate study duration.

Clinical Development Plan

ATMP clinical programs require careful consideration of [9]:

• Study Population: Selection of patients with serious or life-threatening conditions often without alternative treatments.
• Endpoint Selection: Clinically meaningful endpoints appropriate for the disease and product mechanism.
• Trial Design: Adaptive designs may be appropriate, with statistical justification.
• Safety Monitoring: Long-term follow-up plans for delayed adverse events, particularly for integrating gene therapies.

The Manufacturing and Quality Control Pathway

GMP Requirements for ATMPs

Good Manufacturing Practice requirements for ATMPs continue to evolve with technological advancements:

• EMA GMP Revisions: In May 2025, EMA released a concept paper proposing revisions to Part IV of EU GMP guidelines specific to ATMPs, focusing on alignment with revised Annex 1, integration of ICH Q9/Q10 principles, and adaptation to new technologies [7].
• FDA GMP Approach: Phase-appropriate GMP with attestation at early stages, transitioning to verified compliance at BLA stage [9].
• Technological Advancements: Guidelines address automated systems, closed single-use systems, and rapid microbiological methods [7].

Analytical Methods and Quality Control

A robust analytical toolbox is essential for ATMP characterization and quality control:

• Potency Assays: Quantitative measures of biological activity relevant to the proposed mechanism of action.
• Identity and Purity: Methods to confirm product identity and quantify impurities.
• Vector Copy Number and Integration Site Analysis: Critical for gene-modified products.
• Cell Phenotype and Viability: Characterization of cellular products.

Phase 3: Transition to Marketing Authorization

BLA Requirements (FDA)

The Biologics License Application represents the comprehensive submission for market approval [34]. Key components include:

• Complete Safety and Efficacy Data: Results from all clinical studies, with adequate demonstration of benefit-risk profile.
• Finalized CMC Information: Established manufacturing process with validated analytical methods.
• Proposed Labeling: Evidence-based prescribing information.
• Postmarket Safety Planning: Risk Evaluation and Mitigation Strategy (REMS) if required.

MAA Requirements (EMA)

The Marketing Authorization Application for ATMPs follows the centralized procedure with CAT involvement [4]. Requirements include:

• Module 1-5 of CTD: Comprehensive quality, nonclinical, and clinical data per Common Technical Document format.
• Risk Management Plan: Detailed pharmacovigilance and risk minimization activities.
• Product Information: Summary of Product Characteristics (SmPC), labeling, and package leaflet.
• Orphan Drug Considerations: Maintenance of orphan status if designated.

Expedited Pathways and Designations

Expedited programs have become standard for innovative therapies, with 57% of 2024 FDA applications having accelerated designations [35]. These include:

• Breakthrough Therapy Designation (FDA): 38.7% success rate for requests with 54% of designated products achieving full approval [35].
• PRIME Scheme (EMA): Enhanced support for promising medicines targeting unmet medical needs.
• Orphan Drug Designation: 52% of 2024 approvals targeted orphan diseases, reflecting market evolution [35].

Table: Expedited Pathway Comparison

Pathway	Agency	Criteria	Benefits
Breakthrough Therapy	FDA	Preliminary evidence of substantial improvement over available therapies	Intensive guidance, organizational commitment, rolling review
Fast Track	FDA	Addresses unmet medical need	Early and frequent FDA communication, rolling review
Priority Review	FDA	Significant improvement in safety or efficacy	Shorter review timeline (6 vs 10 months)
PRIME	EMA	Promising therapy for unmet medical need	Enhanced EMA support, accelerated assessment
Accelerated Assessment	EMA	Major public health interest	Reduced review timeline (150 vs 210 days)

The Scientist's Toolkit: Essential Research Reagents and Materials

Table: Key Research Reagent Solutions for ATMP Development

Reagent/Material	Function	Application in ATMP Development
AAV Vectors	Gene delivery vehicle	Gene therapy product development; in vivo gene transfer
Lentiviral Vectors	Gene delivery with genomic integration	Ex vivo gene-modified cell therapies (e.g., CAR-T cells)
Cell Separation Media	Isolation of specific cell populations	Preparation of starting materials for cell-based therapies
Cell Culture Media	Support cell growth and maintenance	Expansion and differentiation of cellular products
Cryopreservation Media	Long-term cell storage	Preservation of cell-based products for distribution
Cytokines/Growth Factors	Direct cell differentiation and expansion	Ex vivo manipulation of cellular products
Flow Cytometry Antibodies	Cell phenotype characterization	Quality control and potency assessment
PCR/qPCR Reagents	Genetic analysis	Vector copy number, mycoplasma testing, sterility testing
ELISA Kits	Protein quantification	Potency assays, impurity detection
Endotoxin Testing Kits	Detection of bacterial endotoxins	Product safety testing

Post-Approval Considerations

Pharmacovigilance and Risk Management

ATMPs require robust post-approval safety monitoring [4]:

• Specific Pharmacovigilance Plans: Tailored to ATMP-specific risks, including long-term follow-up for delayed adverse events.
• Risk Management Systems: Implementation of additional monitoring activities for identified and potential risks.
• Regulatory Reporting: Adherence to periodic safety update report (PSUR) requirements.

Lifecycle Management

Post-approval changes require careful management:

• Manufacturing Changes: Comparability protocols to demonstrate that changes do not adversely affect product quality.
• Labeling Updates: Revisions based on postmarket experience and additional clinical data.
• Additional Indications: Supplemental applications for new patient populations or disease indications.

Navigating the regulatory funnel from CTA/IND to MAA/BLA for ATMPs demands strategic planning, scientific rigor, and meticulous attention to evolving regulatory expectations. The increasing convergence between FDA and EMA requirements offers opportunities for streamlined global development, while remaining differences necessitate careful navigation. Success in this complex landscape requires [9]:

• Early and Ongoing Regulatory Engagement: Proactive consultation with regulatory agencies throughout development.
• Robust CMC Development: Implementation of phase-appropriate yet rigorous manufacturing and quality systems.
• Strategic Use of Expedited Pathways: Leveraging available designations to accelerate development without compromising scientific standards.

As regulatory frameworks continue to evolve with technological advancements, maintaining awareness of current guidelines and emerging trends remains essential for successfully bringing innovative ATMPs to patients in need.

The development of Advanced Therapy Medicinal Products represents one of the most innovative yet challenging frontiers in medical science. These therapies, which include gene therapies, somatic-cell therapies, and tissue-engineered products, offer potential cures for conditions with high unmet medical needs. For academic researchers and developers, navigating the complex regulatory pathways to bring these treatments from bench to bedside can be particularly daunting. Recognizing these challenges, regulatory agencies in the European Union and United States have established specialized support mechanisms: the PRIority MEdicines (PRIME) scheme, the Regenerative Medicine Advanced Therapy (RMAT) designation, and the ATMP Pilot for academic and non-profit organizations. These initiatives provide tailored regulatory guidance, accelerated assessment procedures, and enhanced support throughout the development lifecycle. This technical guide examines these regulatory support mechanisms within the broader context of ATMP development, providing researchers with strategic approaches to leverage these pathways effectively. By understanding and utilizing these frameworks, academic developers can significantly enhance their ability to translate groundbreaking research into approved therapies for patients.

EU PRIME Scheme: Enhanced Support for Promising Medicines

The PRIME scheme, launched by the European Medicines Agency in 2016, is a regulatory support mechanism designed to optimize development and accelerate assessment of medicines that target unmet medical needs [38]. The scheme focuses on medicines still in development that are not yet authorized in the EU, with particular emphasis on those demonstrating potential to address unmet medical needs to a significant extent [38]. To be accepted for PRIME, a medicine must show promising activity based on preliminary clinical evidence and the potential to offer a major therapeutic advantage over existing treatments [38]. This can mean introducing new therapeutic methods or substantially improving existing ones, with meaningful improvement in clinical outcomes such as impacting disease prevention, onset, and duration, or improving morbidity and mortality [38].

Key Benefits and Support Features

PRIME provides enhanced, proactive support to medicine developers, with benefits that include early appointment of CHMP or CAT rapporteurs, kick-off meetings with multidisciplinary expert groups, and dedicated EMA coordination [38]. The scheme employs an iterative approach to scientific advice throughout development stages, expedited follow-up scientific advice with shortened timelines, and submission readiness meetings approximately one year ahead of marketing authorisation application [38]. A significant advantage is the confirmation of potential accelerated assessment at the time of marketing authorisation application, providing greater certainty regarding assessment timelines [38]. The scheme was enhanced in March 2023 with new features based on a review of its first five years of operation [38].

Table 1: Key Benefits of PRIME Scheme for Applicants [38]

Benefit	Stage	Details
Early appointment of CHMP or CAT rapporteur	One month after PRIME eligibility is granted	Discussion on technical and scientific preparatory aspects of the marketing authorisation application
Kick-off meeting with rapporteur and multidisciplinary expert group	Three-four months after PRIME eligibility is granted	Guidance on overall development plan, future scientific advice and regulatory strategy
Iterative scientific advice	At any stage, and at major development milestones	Opportunity to involve health technology assessment bodies, patients, and US FDA
Expedited follow-up scientific advice	At any stage	Increased flexibility and shortened timeline for related procedures
Submission readiness meeting	~One year ahead of marketing authorisation application	Discussion on development status, dossier maturity, and potential regulatory challenges
Confirmation of potential accelerated assessment	At time of marketing authorisation application	Increased certainty of assessment timelines

Special Provisions for Academia and SMEs

The PRIME scheme offers specific advantages for small and medium-sized enterprises and academic applicants through Early Entry PRIME status [38]. This provision allows these developers to submit eligibility requests based on compelling non-clinical data in a relevant model that provides early evidence of promising activity (proof of principle), or when first-in-human studies indicate adequate exposure for desired pharmacotherapeutic effects and tolerability [38]. Benefits include immediate appointment of an EMA product team to advise on generating proof of concept data, introductory meetings to raise awareness of regulatory requirements, and total fee exemption for scientific advice to applicants from the European Economic Area [38]. This tailored support is particularly valuable for academic researchers who may have less experience with regulatory processes.

Application Process and Strategic Timing

Medicine developers must submit PRIME eligibility requests through EMA's secure online IRIS platform [38]. The ideal timing for application is during the exploratory clinical trial phase, when preliminary clinical evidence demonstrates promising activity and potential to address unmet medical need [38]. EMA offers pre-submission support, including virtual pre-submission meetings to discuss PRIME eligibility [38]. For academic developers, understanding this timeline is critical, as PRIME is not appropriate for products in advanced development stages, pre-submission phase of marketing authorisation, or for new indications of already authorized medicines [38].

US RMAT Designation: Expediting Regenerative Medicine

The Regenerative Medicine Advanced Therapy designation was established in the United States under the 21st Century Cures Act in 2016 [39]. RMAT shares many features with the breakthrough therapy designation but is specifically tailored for regenerative medicine products. An investigational drug is eligible for RMAT designation if it meets three key criteria: it qualifies as a regenerative medicine therapy (defined as including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products); it is intended to treat, modify, reverse, or cure a serious condition; and preliminary clinical evidence indicates the potential to address unmet medical needs for that condition [39]. The designation can be requested at the time of IND submission or as an amendment to an existing IND.

Benefits and Program Features

RMAT designation provides developers with several key benefits similar to breakthrough therapy designation, including more frequent FDA interactions, early agreement on surrogate endpoints, and potential rolling review of the Biologics License Application [39]. Additionally, RMAT includes distinctive features such as early discussions on potential surrogate or intermediate endpoints to support accelerated approval, and flexibility regarding the amount of clinical data necessary for demonstrating "preliminary clinical evidence" [39]. The designation facilitates an efficient development program through intensive FDA guidance and commitment to streamlined review processes.

Strategic Considerations for Academic Developers

For academic researchers pursuing RMAT designation, several strategic considerations are essential. The INTERACT meeting provides an opportunity for early, non-binding discussions with FDA's Center for Biologics Evaluation and Research before IND submission, though these meetings are granted based on CBER's availability and resources [39]. Following this with a pre-IND meeting is highly recommended to obtain more formal guidance on toxicology study designs and safety monitoring protocols [39]. Academic developers should note that while INTERACT meetings involve no fee, they do not replace pre-IND and other formal meetings for products regulated under the Prescription Drug User Fee Act [39].

Table 2: Comparison of PRIME and RMAT Designations

Feature	EU PRIME Scheme	US RMAT Designation
Year Established	2016 [3]	2016 [39]
Eligibility Basis	Potential for major therapeutic advantage/unmet medical need [38]	Preliminary clinical evidence for serious conditions [39]
Application Timing	Exploratory clinical trial phase [38]	IND submission or amendment [39]
Key Benefits	Early rapporteur, iterative advice, accelerated assessment [38]	Frequent interactions, endpoint agreement, rolling review [39]
Special Provisions	Early Entry for SMEs/academia with proof of principle [38]	Flexibility in clinical evidence requirements [39]
Fee Structures	Fee exemptions for scientific advice (EEA applicants) [38]	No PDUFA fee for INTERACT meetings [39]

EMA ATMP Pilot for Academia and Non-Profit Organizations

Objectives and Scope

In September 2022, the EMA launched a dedicated pilot program to support academic and non-profit organizations in developing advanced therapy medicinal products [4] [40]. This initiative aims to address the specific challenges faced by these developers in navigating regulatory requirements while advancing promising therapies for unmet medical needs. The pilot provides dedicated assistance for ATMP developers targeting unmet clinical needs, with guidance throughout the regulatory process—from manufacturing best practice to clinical development and follow-up planning on efficacy or safety issues [4]. The program includes fee reductions and waivers to make regulatory support more accessible to non-commercial developers [40].

Implementation and Expected Outcomes

The pilot program selected five academic and non-profit organizations to receive enhanced regulatory support [40]. The first beneficiary was The Hospital Clinic in Barcelona, which developed ARI-0001—an autologous chimeric antigen receptor T-cell product that had also joined the PRIME scheme in December 2021 [40]. This selection demonstrates how different regulatory support mechanisms can be complementary rather than mutually exclusive. The pilot is expected to run for three to four years, after which a report will be issued and a workshop with relevant stakeholders will discuss lessons learned and potential future support measures or regulatory changes [40]. The primary goal is to assess the level of regulatory support needed to boost the number of advanced therapy medicines that reach patients in the EU and European Economic Area [4].

Quantitative Impact Analysis of Regulatory Support Mechanisms

Measurable Benefits of PRIME Designation

Recent research provides compelling quantitative evidence of PRIME's impact on ATMP development timelines. A 2025 retrospective analysis of all EMA-approved ATMPs revealed that PRIME participation was associated with a 42.7% reduction in time to marketing authorization (p = 0.001) [3]. The study analyzed 27 approved ATMPs, 52% of which had received PRIME designation [3]. The median time from the start of the marketing authorization procedure to final approval by the European Commission was 376 days for PRIME-designated products compared to 669 days for non-PRIME products [3]. Additionally, PRIME-designated products experienced fewer and shorter clock stops during evaluation and engaged in more frequent scientific advice interactions with regulators [3].

Comparative Analysis of Regulatory Pathways

The same study provided detailed insights into how different regulatory pathways affect ATMP approval timelines. Conditional approvals showed the shortest median authorization time at 405 days, followed by standard approvals at 462 days, and approvals under exceptional circumstances at 644 days [3]. Orphan designation, which applied to 74% of approved ATMPs, was associated with a 32.8% reduction in time to marketing authorization (p = 0.021) [3]. These findings demonstrate the significant time savings achievable through strategic use of available regulatory mechanisms, with the combined benefit of multiple designations potentially accelerating development by over a year.

Table 3: Impact of Regulatory Measures on ATMP Approval Timelines [3]

Regulatory Attribute	Number of Products	Median Time to MA (Days)	Interquartile Range (Days)
PRIME Designation	14 (52%)	376	324-426
Non-PRIME Products	13 (48%)	669	459-848
Orphan Designation	20 (74%)	405	352-509
Non-Orphan Products	7 (26%)	660	539-766
Authorization Type
- Standard	13 (50%)	462	371-645
- Conditional	11 (42%)	405	352-509
- Exceptional Circumstances	2 (7.7%)	644	515-773

Integrated Regulatory Strategy Development

Building a Cross-Regional Development Plan

For academic developers planning multi-regional development, creating an integrated regulatory strategy that leverages both EU and US support mechanisms is essential. Developers can prepare a common core document with an overview of the ATMP development plan and adapt it according to specific regional regulatory guidelines [39]. This approach is particularly valuable when seeking joint advice from EMA and FDA, which is especially useful for advanced programs at End-of-Phase 2 or before finalizing pivotal clinical study designs [39]. While the joint nature of such meetings does not guarantee identical advice from both agencies, it helps identify regional requirements early and facilitates more efficient global development.

Sequential Engagement Approach

A strategic sequential approach to regulatory engagement often proves effective for academic developers. Early development may benefit from informal meetings with national competent authorities in the EU or INTERACT meetings with FDA, followed by more formal scientific advice procedures as development advances [39]. For SMEs developing ATMPs, the EMA offers additional services including classification and certification of quality and non-clinical data, which can help identify gaps that might hamper product authorization [39]. The certification review conducted by CAT can be requested at any development stage but provides highest value before initiating non-clinical or clinical studies [39].

Key Research and Regulatory Reagents

Successfully navigating ATMP regulatory pathways requires utilizing specific tools and resources. The IRIS platform serves as EMA's secure online system for PRIME eligibility requests and related communications, providing a single space for applicants and EMA to submit requests, communicate, share information and deliver documents [38]. Research Product Identifiers are essential for tracking medicines through pre-authorization procedures, replacing the previously used unique product identifiers [38]. For quality and manufacturing development, the Toolbox guidance on developing robust PRIME quality data packages summarizes scientific and regulatory approaches medicine developers can use in applications targeting unmet medical needs [38]. Additionally, the joint EMA/FDA Q&A guidance addresses quality development and GMP challenges when developing medicines under early access schemes [38].

Analytical and Assessment Tools

The PRIME development tracker and regulatory roadmap enables developers to monitor progress and maintain alignment with regulatory requirements throughout the development lifecycle [38]. EMA's training materials, including online training modules available through the TransMed Academy, help ATMP developers navigate the regulatory environment covering subjects such as ATMP classification, environmental risk assessment, scientific advice for ATMPs, ATMP certification, and quality in clinical development [4]. For US regulatory strategy, FDA's INTERACT meetings provide early, non-binding feedback, while pre-IND meetings offer more formal guidance before initiating clinical trials [39].

Table 4: Essential Regulatory Tools for ATMP Developers

Tool/Resource	Function	Applicable Stage
EMA IRIS Platform	Secure portal for PRIME applications and regulatory communications [38]	All development stages
Research Product Identifier (RPI)	Tracking product through pre-authorization procedures [38]	Early development through authorization
PRIME Quality Toolbox	Guidance on generating robust quality data packages [38]	Manufacturing and quality development
EMA/FDA Joint Q&A	Addresses quality and GMP challenges for early access schemes [38]	Chemistry, manufacturing, and controls
EMA Training Modules	Education on regulatory requirements for ATMPs [4]	Early planning stages
INTERACT/Pre-IND Meetings	Early FDA feedback on development plans [39]	Pre-IND through clinical development

The strategic application of regulatory support mechanisms—PRIME, RMAT, and the ATMP Pilot—provides academic developers with powerful tools to navigate the complex pathway from laboratory research to approved therapies. Quantitative evidence demonstrates that these initiatives significantly reduce development timelines, with PRIME designation associated with approval acceleration of approximately one year [3]. As the ATMP field continues to evolve, regulatory frameworks are also adapting, with proposed reforms to EU pharmaceutical legislation potentially affecting the roles of specialized committees like CAT [41]. Academic researchers should monitor these developments while leveraging current opportunities. The integration of these regulatory strategies—combining early engagement, targeted designation applications, and continuous dialogue with regulators—represents a best practice approach for translating innovative ATMP research into treatments for patients with unmet medical needs. By proactively utilizing these specialized pathways, academic developers can enhance their regulatory competence, optimize development efficiency, and ultimately accelerate patient access to transformative advanced therapies.

For developers of Advanced Therapy Medicinal Products (ATMPs), navigating the Chemistry, Manufacturing, and Controls (CMC) requirements for Investigational New Drug (IND) applications and Investigational Medicinal Product Dossiers (IMPD) presents unique challenges. A phase-appropriate approach to CMC is a strategic, risk-based framework that aligns the depth and rigor of manufacturing and quality control data with the stage of clinical development [42]. This methodology acknowledges that product and process understanding evolves throughout the clinical trial lifecycle, from initial Phase 1 safety studies to pivotal Phase 3 trials supporting marketing authorization.

The fundamental principle of phase-appropriate CMC is to ensure patient safety and product reliability while enabling timely clinical development without imposing non-critical requirements prematurely. For ATMPs—including gene therapies, cell therapies, and tissue-engineered products—this approach is particularly crucial due to their inherent biological complexity, often limited starting material, and individualized manufacturing paradigms [43]. This technical guide examines the core CMC considerations for ATMPs across development phases within the broader context of regulatory requirements for advanced therapy research.

Core CMC Principles for ATMPs

Foundational Regulatory Requirements

All CMC programs for ATMPs must address several foundational elements, regardless of development phase. The U.S. Food and Drug Administration (FDA) guidance focuses on SISPQ—Safety, Identity, Strength, Purity, and Quality—as core principles [44]. These attributes form the basis for establishing Critical Quality Attributes (CQAs) and implementing comprehensive risk assessment throughout product development.

Table 1: Foundational CMC Requirements for ATMPs

CMC Element	Key Considerations	Regulatory Reference
Starting Materials	Detailed characterization of cells, vectors, and tissues; donor screening and testing; documentation of source and history [44] [43]	FDA 2020 CMC Guidance
Manufacturing Process	Process description with flow diagrams; in-process controls; critical process parameters; vector production details [44] [45]	EMA ATMP Regulation
Product Testing	Identity, purity, potency, viability, and safety testing; adventitious agent testing; sterility [44]	ICH Q5A(R1), Ph. Eur.
Container Closure	Compatibility studies; leaching and adsorption assessments; container integrity [44]	FDA Guidance on Container Closure
Stability	Preliminary stability data; storage conditions; in-use stability [46]	ICH Q1A-Q1F

The Risk-Based Approach in ATMP Development

A risk-based approach is central to ATMP development and is formally recognized in regulatory frameworks globally [43] [47]. This approach determines the extent of quality, non-clinical, and clinical data required in regulatory submissions by evaluating product-specific risks. For ATMPs, risks differ significantly based on product type (autologous vs. allogeneic), biological characteristics of starting materials, and complexity of manufacturing processes [43].

The European Union's Directive 2009/120/EC formally introduced the risk-based approach for ATMPs, providing flexibility while maintaining focus on patient safety [43]. Manufacturers must identify and mitigate risks related to:

• Quality: Disease transmission, tumorigenicity, cold chain management
• Patient Factors: Underlying disease, parallel treatments, genetic modifications
• Administration: Dosing errors, surgical procedures, medical devices
• Persistence: Late complications, rescue procedures, malignancies
• Third Parties: Dissemination risks to healthcare professionals and environment

Figure 1: Quality Risk Management Process for ATMPs

Phase-Appropriate CMC Strategies

Phase 1 CMC Considerations

The primary goal during Phase 1 is to ensure patient safety while providing sufficient product characterization to support initial clinical testing. CMC requirements at this stage are focused rather than comprehensive, with an emphasis on critical quality attributes directly linked to safety [42].

For Phase 1 INDs, the FDA encourages analytical methods that are "fit for their intended purpose" rather than fully validated [42]. This phase-appropriate approach recognizes that extensive method validation may be premature when manufacturing processes are still evolving. Key considerations include:

• Manufacturing Process: A defined and controlled manufacturing process with basic in-process controls
• Product Characterization: Demonstration of identity, purity, sterility, and potency relative to a reference standard
• Safety Testing: Adventitious agent testing, endotoxin, and mycoplasma testing as applicable
• Stability: Preliminary stability data to support the proposed clinical trial duration

For cell therapy products, the FDA recommends a minimum viability of 70% for ex vivo genetically modified cells, though manufacturers can submit data to support lower viability if justified [44].

Phase 2 CMC Considerations

As development progresses to Phase 2, CMC requirements expand to include more comprehensive product and process characterization. The focus shifts toward ensuring consistency and reproducibility of manufacturing, with increased attention to quantifying process-related impurities.

Critical activities during Phase 2 include:

• Process Optimization: Scaling up and optimizing manufacturing processes, which may result in new impurity profiles
• Analytical Validation: Generating appropriate validation data for analytical methods
• Reference Standards: Establishing well-characterized reference standards for potency assays
• Extended Stability: More comprehensive stability studies to support longer clinical trials

The Phase 2 CMC package should demonstrate increased process understanding and control, with preliminary definition of critical process parameters and their impact on critical quality attributes [42].

Phase 3 and Commercialization CMC Considerations

Phase 3 CMC activities focus on establishing a validated manufacturing process and comprehensive control strategy suitable for marketing application. The level of rigor and documentation at this stage should be consistent with commercial requirements, as Phase 3 typically supports regulatory approval.

Table 2: Evolution of CMC Requirements Across Clinical Phases

CMC Element	Phase 1	Phase 2	Phase 3
Manufacturing Process	Defined and controlled	Optimized and scaled	Validated and locked
Process Controls	Basic parameters	Expanded controls	Comprehensive control strategy
Analytical Methods	Fit-for-purpose	Partial validation	Fully validated
Product Characterization	Basic attributes (identity, purity, safety)	Additional characterization	Comprehensive profile
Stability	Preliminary data	Supporting clinical trial duration	Commercial shelf-life
Potency Assay	Mechanism-relevant	Quantitative	Validated and correlated to clinical outcome
Impurity Profile	Identified and limited	Characterized and controlled	Fully defined with specifications

For ATMPs, potency assays present particular challenges across all phases. By Phase 3, potency assays should be established and validated, representing the mode of action of the drug and being quantitative in nature [44]. These assays should measure the expressed product rather than just the vector for gene therapies.

Global Regulatory Landscape for ATMPs

Comparative Analysis of Regional Requirements

Global development of ATMPs requires understanding regional differences in CMC regulatory requirements. While major markets follow ICH guidelines, significant differences exist in content, format, and review processes [46].

Table 3: Comparative CMC Requirements Across Major Regions

Geography	US	EU	Canada
Clinical Application	IND	CTA (Q-IMPD)	CTA (QOS-CE or Q-IMPD)
Submission Format	eCTD per ICH M4Q	IMPD format per EU guidance	QOS-CE per HC template or IMPD format
Module 2.3 QOS	Optional	Required (in Q-IMPD format)	Required (QOS-CE)
Drug Substance Information	May cross-reference DMF	May cross-reference ASMF or CEP	May cross-reference Canadian DMF
Process Validation	Not applicable for investigational product	Not applicable (except non-standard sterilization)	Not applicable for investigational product
Stability Commitment	Not applicable	Shelf-life extension plan required	Summary of stability protocol required

Regional Regulatory Innovations

Different regions have implemented innovative regulatory pathways to accelerate ATMP development:

• United States: The FDA's INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER Products) meetings provide early-stage guidance for innovative products [47]
• European Union: The Priority Medicines (PRIME) scheme offers enhanced support for promising medicines [47]
• China: NMPA has implemented expedited programs including Priority Review, Breakthrough Therapy Designation, and Conditional Approval Pathway [47]

China's regulatory framework has evolved significantly, with the NMPA issuing a series of technical guidance documents specific to ATMP categories including immune cell therapy, gene therapy, and stem cell products [47]. The IND review time has been reduced from 90 to 60 days through an implied license system [47].

Implementation Strategies and Documentation

The Scientist's Toolkit: Essential Research Reagent Solutions

Successful ATMP development requires careful selection and control of critical materials throughout manufacturing. The materials below represent essential components with specific quality considerations.

Table 4: Essential Research Reagent Solutions for ATMP Development

Material Category	Key Functions	Critical Quality Considerations
Viral Vectors	Gene delivery vehicles for genetic modification	Identity, titer, purity, replication competence, absence of adventitious agents [44]
Cell Culture Media	Support cell growth, expansion, and differentiation	Composition, growth factor concentration, absence of animal components, endotoxin levels [44]
Cell Separation Reagents	Isolation and selection of target cell populations	Purity, efficiency, viability impact, clearance demonstration [44]
Cryopreservation Media	Maintain cell viability during frozen storage	DMSO quality, composition, sterility, post-thaw viability and recovery [44]
Gene Editing Tools	CRISPR-Cas systems, nucleases for genetic modification	Specificity, efficiency, off-target risk, delivery mechanism [47]
Ancillary Materials	Reagents not intended in final product (e.g., cytokines, growth factors)	Purity, functionality, demonstration of clearance during manufacturing [44] [45]

Manufacturing Process and Documentation

Comprehensive documentation of the manufacturing process is essential across all phases. For viral vectors, the FDA requires thorough description of all manufacturing steps, including cell culture, harvesting, vector purification, and in-process testing [44]. For vectors less than 40 kilobases, the entire vector must be sequenced; for larger vectors, minimum sequencing should include the gene insert, flanking regions, and any modified region [44].

For genetically modified cell production, documentation must include [44]:

• Source material and collection procedures
• Cell selection, isolation, and enrichment steps
• Cell expansion conditions, hold times, and transfer steps
• Cell harvest and purification procedures
• Shipping and handling procedures

Figure 2: ATMP Manufacturing Process Workflow

Control Strategy and Testing Requirements

A robust control strategy evolves throughout development, with testing requirements becoming more comprehensive at each phase. For ATMPs, key testing categories include:

• Microbial Testing: Sterility testing at various manufacturing steps; mycoplasma testing using culture or PCR methods; adventitious agent testing including in vitro and in vivo viral testing [44]
• Identity Testing: For ex vivo genetically modified cells, an assay to measure presence of vector material plus cell surface markers or other specific identifiers [44]
• Purity Testing: Assessment of pyrogenicity, endotoxins, residual contaminants, antibodies, serum, and solvents with standard acceptance limits based on dosing [44]
• Potency Testing: Quantitative assays representing the product's mechanism of action, with validated methods required by Phase 3 [44]

Successful CMC strategy for ATMPs requires balancing regulatory expectations, development drivers, and resource constraints through a phase-appropriate approach. This framework enables efficient advancement of promising therapies while maintaining focus on patient safety and product quality. As highlighted throughout this guide, the key principles include:

• Early Engagement: Utilizing pre-IND meetings and regulatory feedback opportunities to align on CMC strategies
• Risk-Based Approach: Focusing resources on critical quality attributes that impact safety and efficacy
• Evolutionary Development: Progressively increasing product and process understanding throughout clinical development
• Global Perspective: Understanding regional differences in CMC requirements for international development programs

For ATMP developers, implementing a well-designed phase-appropriate CMC program is not merely a regulatory requirement but a strategic imperative that can significantly impact development timelines, costs, and ultimate success in bringing transformative therapies to patients.

The development of Advanced Therapy Medicinal Products (ATMPs) represents one of the most innovative yet complex frontiers in modern medicine. These therapies, which include gene therapies, somatic cell therapies, tissue-engineered products, and combined ATMPs, offer revolutionary potential for treating serious diseases with high unmet medical need. However, their sophisticated biological nature and novel mechanisms of action create unique regulatory challenges that developers must navigate successfully. Within the European Union framework, early regulatory dialogue and specifically the ATMP classification procedure serve as critical foundational steps that can significantly de-risk development pathways and accelerate patient access to breakthrough therapies.

The European regulatory environment for ATMPs is established under Regulation (EC) No 1394/2007, which defines these products as biological medicines based on genes, cells, or tissue engineering [48] [4]. The legislation created the Committee for Advanced Therapies (CAT) within the European Medicines Agency (EMA) as the dedicated expert committee responsible for ATMP evaluation, classification, and certification [48] [4]. For developers, engaging with this framework through early dialogue is not merely administrative but represents a strategic imperative that shapes every subsequent development decision, from manufacturing to clinical trial design.

The ATMP Classification Procedure: A Foundation for Development

Understanding the ATMP Classification Request

The ATMP classification procedure is a formal mechanism for developers to obtain a scientific recommendation on whether their product falls within the definition of an ATMP and, if so, which specific category it belongs to [10] [49]. This voluntary procedure is established under Article 17 of Regulation (EC) No 1394/2007 and delivers significant value by addressing borderline classification issues early in development [50] [10]. The CAT provides these scientific recommendations after consultation with the European Commission within 60 days after receipt of a valid request [50] [10].

The procedure is designed to resolve uncertainties about product classification that could otherwise lead to costly development missteps. Between its establishment and October 2024, the CAT had adopted 675 recommendations out of 682 submitted, demonstrating both the high utilization and essential clarity this procedure provides to developers [10]. The outcome is published as a summary report on the EMA website, with the list of medicines assessed since March 2019 updated quarterly [49].

ATMP Categories and Definitions

ATMPs are categorized into four distinct types based on their composition and mechanism of action, each with specific legal definitions [48] [4]:

Table: Advanced Therapy Medicinal Product (ATMP) Categories and Definitions

ATMP Category	Legal Definition	Key Characteristics	Examples
Gene Therapy Medicinal Products (GTMPs)	Contains genes that lead to therapeutic, prophylactic or diagnostic effects	Works by inserting 'recombinant' genes into the body; based on recombinant DNA technology	CAR-T cells [49], viral vectors for retinal disease [48]
Somatic Cell Therapy Medicinal Products (sCTMPs)	Contains cells or tissues that have been manipulated to change biological characteristics or used for non-homologous functions	Cells substantially manipulated or used for different essential functions; not immunomodulation-only	Ex-vivo expanded allogeneic bone marrow derived mesenchymal stromal cells for graft-versus-host disease [49]
Tissue-Engineered Products (TEPs)	Contains cells or tissues that have been modified to repair, regenerate or replace human tissue	Cells or tissues substantially manipulated with regeneration/repair primary mode of action	Cultured autologous cells for urinary diversion [49], cartilage products [48]
Combined ATMPs	Contains one or more medical devices as integral part of the medicine	Combined with medical device (e.g., scaffold, matrix) where action is primary to cells	Autologous skeletal muscle derived cells attached to microparticles [49]

A critical concept in ATMP classification is "substantial manipulation," which refers to processing that alters biological characteristics, physiological functions, or structural properties of cells or tissues in ways relevant to their intended clinical function [4]. Products that are not substantially manipulated and are used for the same essential function typically fall outside ATMP classification and may be regulated under different frameworks such as the Substances of Human Origin (SoHO) legislation [51].

Procedural Guide: Navigating the ATMP Classification Request

Application Timeline and Process

The ATMP classification procedure follows a structured timeline with specific submission deadlines throughout the year. Understanding this timeline is essential for efficient regulatory planning [50]:

Table: ATMP Classification Request Timetable for 2025-2026

Deadline for Request Submission	Start of Procedure	CAT Discussion	CAT Adoption
9 Jan 2025	24 Jan 2025	21 Feb 2025	21 Mar 2025
6 Feb 2025	21 Feb 2025	21 Mar 2025	16 Apr 2025
5 Feb 2026	20 Feb 2026	20 Mar 2026	17 Apr 2026
5 Mar 2026	20 Mar 2026	17 Apr 2026	13 May 2026

The classification process begins with submission of two key forms: one covering administrative information and another containing the classification request and briefing information [10] [52]. These documents must be submitted via email to the EMA by the published deadlines. The CAT Chair and Co-chair supervise the process to ensure regulatory and scientific consistency [10]. Within 60 days of receipt, the CAT delivers its scientific recommendation after consultation with the European Commission [50] [10].

Experimental Protocols and Documentation Requirements

Successful classification requests require comprehensive documentation that clearly characterizes the product's properties and manufacturing process. The following experimental protocols and data are typically essential:

1. Product Characterization and Manufacturing Protocol

• Detailed description of starting materials (cells, tissues, genetic materials)
• Complete manufacturing process flow diagram with all critical steps
• Description of all reagents, materials, and equipment used
• Definition of critical quality attributes (CQAs) and critical process parameters (CPPs)
• Demonstration of phase-appropriate process controls and specifications

2. Substantial Manipulation Assessment

• Comparative analysis of pre- and post-manipulation cell/tissue characteristics
• Data demonstrating changes to biological characteristics, physiological functions, or structural properties
• Justification for the extent of manipulation relative to the intended function
• Assessment of whether manipulation alters the original characteristics relevant to the intended function

3. Mechanism of Action Studies

• In vitro and/or in vivo data supporting the proposed primary mechanism of action
• Evidence differentiating pharmacological, immunological, or metabolic action from structural or mechanical function
• For TEPs, data demonstrating repair, regeneration or replacement of human tissue
• For GTMPs, evidence of gene transfer and expression

4. Non-clinical Proof-of-Concept

• Pharmacodynamics studies demonstrating biological activity
• Biodistribution and persistence data where relevant
• Safety pharmacology assessments
• For combined ATMPs, device component testing and integration data

The CAT emphasizes the importance of orthogonal methods (using different scientific principles to measure the same attribute) for analytical testing to ensure robustness and reliability of product quality data, particularly when reference standards or validated methods are lacking [51].

Strategic Advantages of Early Classification

Regulatory Certainty and Development Planning

Obtaining formal ATMP classification early in development provides crucial regulatory certainty that informs the entire development pathway. This certainty is particularly valuable for borderline products where classification may not be immediately obvious [10] [52]. The scientific recommendation, while not legally binding, is generally followed by National Medicines Agencies across the EU and provides a solid foundation for subsequent regulatory interactions [10].

The classification directly impacts which regulatory guidance documents apply, what evidence will be required for marketing authorization, and whether the product might qualify for specific regulatory pathways such as the hospital exemption [10]. For example, CAR-T cell products are consistently classified as gene therapy medicinal products rather than somatic cell therapy products, which determines the specific quality, non-clinical, and clinical requirements that must be met [51].

Access to Regulatory and Financial Incentives

Early ATMP classification opens doors to numerous regulatory and financial incentives designed to support innovative therapy development:

Table: Regulatory and Financial Incentives for ATMP Developers

Incentive Type	Target Applicants	Key Benefits	Legal Basis
Scientific Advice	All ATMP developers	65% fee reduction (90% for SMEs) for protocol endorsement	[53]
ATMP Certification	SMEs only	90% fee reduction for quality/non-clinical data assessment	Article 18, Regulation 1394/2007 [52]
PRIME Scheme	Products addressing unmet medical need	Accelerated assessment, conditional approval pathways	[48]
ATMP Pilot	Academia & non-profit organizations	Enhanced regulatory support, fee reductions/waivers	[4] [52]

These incentives significantly reduce the financial burden on developers while providing enhanced regulatory support. The PRIME scheme, introduced in 2016, has been particularly impactful, with 19 ATMPs granted eligibility as of Q4 2018, including CAR-T therapies Yescarta and Kymriah that successfully completed their journeys to Marketing Authorisation [48].

The Scientist's Toolkit: Essential Research Reagent Solutions

ATMP development requires specialized reagents and materials that meet rigorous quality standards. The following table details key research reagent solutions essential for generating robust data for regulatory submissions:

Table: Essential Research Reagent Solutions for ATMP Development

Reagent Category	Specific Examples	Function in ATMP Development	Quality Requirements
Cell Culture Media	Serum-free media, cytokines, growth factors	Ex vivo cell expansion and differentiation	GMP-grade for clinical studies; defined composition with certificates of analysis [51]
Gene Delivery Systems	Viral vectors (lentiviral, AAV), plasmid DNA, mRNA, electroporation systems	Genetic modification of cells (GTMPs)	GMP-grade with full characterization; appropriate biosafety testing [51]
Cell Separation Reagents	Antibody conjugates, magnetic beads, density gradient media	Isolation of specific cell populations	Clinical-grade with minimal lot-to-lot variability; validation of separation efficiency
Scaffolds/Matrices	Biodegradable polymers, hydrogels, decellularized tissues	Structural support for tissue-engineered products (TEPs)	Medical device-grade materials with biocompatibility testing [4]
Analytical Reagents	Flow cytometry antibodies, PCR reagents, ELISA kits	Product characterization and quality control	Qualified/validated for intended use; orthogonal methods recommended [51]

Regulators expect increasing quality of materials as development progresses, with GMP-grade manufacturing required for investigational medicinal products in first-in-human studies in the EU [51]. The FDA does not allow research-grade excipients or starting materials for CGTs due to potential patient risks [51].

Integration with Broader Regulatory Strategy

ATMP Classification in the Development Workflow

The ATMP classification request should be integrated into a comprehensive regulatory strategy rather than treated as an isolated activity. The following diagram illustrates the logical relationship between ATMP classification and subsequent development activities:

Future Regulatory Developments

The EU pharmaceutical legislation governing ATMPs is evolving, with proposed changes that could impact classification procedures. The European Commission's proposal for a full reform of the EU pharmaceutical legislation suggests replacing the CAT scientific recommendation on ATMP classification with a general procedure of EMA's scientific recommendation on regulatory status that would cover all medicines, not just ATMPs [10]. However, this remains a proposal subject to change during the legislative process.

Additionally, the new EU legislation for substances of human origin (SoHOs), revised in 2024, extends activities covered to include donor registration, collection, testing, storage, distribution, import, and export [51]. All parties handling SoHO activities must comply with the new regulation by 7 August 2027, which has significant implications for ATMP developers using human-derived materials [51].

Early regulatory engagement through the ATMP classification procedure represents a strategic investment that pays dividends throughout the product development lifecycle. By obtaining regulatory clarity at the outset, developers can design more efficient development pathways, access financial incentives, and avoid costly missteps. The procedure provides a structured mechanism to resolve classification uncertainties while fostering dialogue with regulators.

As the ATMP landscape continues to evolve with scientific advancements and regulatory changes, maintaining early and proactive engagement with regulatory authorities remains essential. The classification request serves not only to clarify regulatory status but also to establish relationships with regulators that can support successful product development and ultimately accelerate patient access to transformative advanced therapies.

Overcoming Common ATMP Hurdles: CMC, Manufacturing, and Scalability

The manufacture of Advanced Therapy Medicinal Products (ATMPs) represents a frontier in modern medicine, offering groundbreaking treatments for a range of severe illnesses. However, the biological nature of these living therapies introduces unique and complex manufacturing challenges that differ significantly from those of conventional pharmaceuticals. Within the European Union and other regulated markets, ATMPs are strictly classified and must be manufactured in accordance with Good Manufacturing Practice (GMP) standards and relevant pharmacopoeia to ensure quality, safety, and efficacy for patients [54]. The core challenges of this manufacturing process can be categorized into three critical areas: contamination control, tumorigenicity, and efficacy. A failure to adequately address any of these areas can result in product loss, patient harm, and regulatory action. This technical guide provides an in-depth analysis of these challenges, framed within current regulatory requirements, and offers detailed strategies and methodologies for the scientific and drug development community to navigate this complex landscape.

Contamination Control in ATMP Manufacturing

The Criticality of a Holistic Contamination Control Strategy (CCS)

For ATMPs, which are often administered parenterally and cannot be terminally sterilized, contamination control is not merely a best practice but a fundamental regulatory expectation. A Contamination Control Strategy (CCS) is a documented, proactive system that compiles the approaches adopted by an organization to ensure the control of microbial contamination across all product manufacturing stages [55]. The development of a proper CCS is a frequently recurring challenge in ATMP manufacturing, and its lack can lead to recalls, regulatory scrutiny, and the temporary revoking of manufacturing licenses [56]. By 2025, inspectors are focusing heavily on the integration of the CCS throughout the entire product lifecycle, not only in aseptic processing but across facility design, raw material handling, personnel behavior, and process validation [56].

The risks are magnified for cell therapies due to the time-criticality of manufacturing, particularly for autologous products like CAR-T cells, which are often the last treatment option for very sick patients. A contamination event here necessitates discarding the product and starting manufacturing anew, with significant additional costs and critical delays for the patient [57]. The sources of contamination are multifaceted, including human operators, water, material surfaces, air, and the raw materials themselves [57].

Advanced Protocols and System Design for Contamination Prevention

A robust CCS requires a multi-pronged approach that leverages advanced technologies and rigorous protocols.

1. Closed Systems and Automated Decontamination: Transitioning from open biosafety cabinets to fully closed systems like isolators or Restricted Access Barrier Systems (RABS) is a cornerstone of modern contamination control. These systems provide a physical barrier between the operator and the process, significantly reducing risk [56] [57]. Similarly, automated decontamination using technologies like Vaporized Hydrogen Peroxide (VHP) is more robust and reliable than manual methods. VHP offers excellent distribution, material compatibility, and provides a validated, repeatable process with full traceability, unlike variable manual cleaning [57].

2. Process-Enabled Controls: The use of single-use, sterile connectors and tube welding are preferred choices for maintaining a closed process in ATMP manufacturing. This strategy allows for production in a ballroom Grade C cleanroom, enabling multiple products to be produced side-by-side instead of maintaining many small, campaign-specific Grade B cleanrooms, a approach encouraged by the updated Annex 1 [56].

3. Real-Time Environmental Monitoring: Reactive, periodic environmental monitoring is becoming insufficient. The 2025 regulatory expectation is for systems that provide continuous monitoring of particles, temperature, humidity, and pressure differentials with real-time alerts and automated data collection for trending analysis [58].

Table 1: Comparison of Automated Decontamination Methods for Rooms and Enclosures

Contamination Control Method	Key Advantages	Key Disadvantages
UV Irradiation	Speed; no requirement to seal enclosure	Prone to shadowing; may not kill spores; efficacy decreases with distance from source [57]
Chlorine Dioxide	Highly effective at killing microbes	Highly corrosive, damaging equipment; high toxicity requires building evacuation [57]
Aerosolized Hydrogen Peroxide	Good material compatibility	Liquid droplets prone to gravity; relies on direct line of sight; longer cycle times [57]
Vaporized Hydrogen Peroxide (VHP)	Excellent distribution & efficacy; good material compatibility; quick cycle times with active aeration; safe with low-level sensors [57]	-

The following diagram illustrates the interconnected components of a comprehensive Contamination Control Strategy, from foundational elements to continuous improvement cycles.

Tumorigenicity Risk Assessment

Understanding the Safety Concern

Tumorigenesis is a critical safety concern in regenerative medicine, referring to the potential transformation of cells, particularly stem cells, into neoplastic (tumor) cells during therapy [15]. This risk is a double-edged sword; the very regenerative potential that makes these cells therapeutic also carries the possibility of inducing tumor formation. The genetic instability of cells caused by successive cultures in manufacturing further compounds this risk [15]. Consequently, rigorous tumorigenicity testing is a non-negotiable requirement for regulatory approval of many ATMPs.

Methodologies for Tumorigenicity Assessment

The assessment approach depends on the cell type used in the ATMP. For pluripotent stem cell (PSC)-derived products, the in vivo teratoma formation assay is a standard method used both to validate the pluripotency of the starting PSCs and to detect residual undifferentiated PSCs in the final drug product [15]. For somatic cell-based therapies, tumorigenicity is assessed using in vivo studies in immunocompromised models such as NOG/NSG mice, rather than the teratoma test [15].

In vitro safety testing has evolved beyond conventional methods. The traditional soft agar colony formation assay has limited sensitivity for detecting rare transformed cells in a therapeutic product. Current recommendations favor more sensitive methods such as digital soft agar assays or detailed cell proliferation characterization tests [15]. Karyotype analysis is also essential to monitor for genetic instability during cell culture and to select genetically stable cells for production [15].

The workflow below outlines the decision-making process and methodologies for assessing tumorigenicity risk in ATMPs.

Demonstrating Product Efficacy and Potency

The Challenge of Proving Clinical Benefit

Proving the efficacy of regenerative medicine products is one of the most critical issues in translational medicine [15]. A central challenge is demonstrating long-term clinical benefit through well-structured clinical trials, which is particularly difficult for ATMPs that often target rare diseases with limited patient populations [15]. This limited availability of clinical samples, combined with complexities in trial design and endpoint selection, raises concerns about the reliability and durability of therapeutic outcomes. Furthermore, difficulties in clearly defining and assessing the mechanism of action (MoA) and potency pose significant obstacles to confirming clinical effectiveness [15].

The Role of Potency Assays and Advanced Models

Potency assays are a fundamental aspect of quality control for the final cell product and are increasingly seen as potential biomarkers for in vivo efficacy [59]. These assays must demonstrate the consistent biological activity of the product. For gene therapies, this includes the ability of a transgene to introduce a desired effect to a target cell, while for cell-based therapies, it involves measuring specific secretory, immunomodulatory, or differentiation functions [56] [59].

The revised European Pharmacopoeia provides more refined guidance on critical quality testing methods, supporting the need for precision and product consistency [56]. These updated methods include:

• Flow cytometry (2.7.24) for viability and cell count.
• BET using recombinant Factor C (2.6.14) for endotoxin testing.
• Microbiological examination of cell-based preparations (2.6.27).
• Nucleated cell count and viability (2.7.29) [56].

To better predict clinical efficacy, the field is moving towards more physiologically relevant 3D in vitro models. For example, 3D bioprinted co-culture models within microfluidic chips can create controlled tumor heterogeneity to study cell migration and drug response in a way that bridges the gap between conventional 2D cultures and in vivo studies [60]. These models allow for precise control over the position and arrangement of different cell types in a hydrogel matrix, enabling the design of various tumor architectures that more accurately represent the in vivo tumor microenvironment [60].

Table 2: Key Analytical Methods for ATMP Efficacy and Quality Testing

Method Category	Specific Technique	Primary Application in ATMPs
Cell Characterization	Flow Cytometry (Ph. Eur. 2.7.24)	Viability, cell count, and surface marker phenotyping [56]
Impurity/Safety Testing	Recombinant Factor C BET (Ph. Eur. 2.6.14)	Endotoxin testing, a critical safety release criterion [56]
Potency Assay	Droplet Digital PCR (ddPCR)	Quantification of viral vector copies or genetic impurities; cited as a flexible alternative to qPCR per Ph. Eur. [56]
Microbiological Control	Microbiological Examination of Cell-Based Preps (Ph. Eur. 2.6.27)	Monitoring sterility and bioburden in cell-based products [56]
Advanced Modeling	3D Bioprinted Co-culture Models	Creating physiologically relevant tumor models for drug screening and mechanism of action studies [60]

The Scientist's Toolkit: Essential Research Reagents and Materials

The following table details key reagents, materials, and systems critical for addressing the core challenges in ATMP manufacturing, as cited in the research.

Table 3: Essential Research Reagents and Materials for ATMP Manufacturing Challenges

Item Name / System	Function / Application	Relevance to ATMP Challenges
Alginate-Gelatin Hydrogel	Serves as a bioink for 3D bioprinting, providing a scaffold that mimics the native tumor extracellular matrix (ECM) [60].	Efficacy: Used to create advanced 3D in vitro models for studying tumor heterogeneity, cell migration, and drug response [60].
Vaporized Hydrogen Peroxide (VHP) System	An automated decontamination method for rooms and isolators. Vapor provides excellent distribution and condensation on surfaces for effective microbial kill [57].	Contamination Control: Provides a validated, repeatable, and traceable method for facility and equipment decontamination, superior to manual methods [57].
Closed System (Isolators/RABS)	A physical barrier system that fully separates the operator from the aseptic manufacturing process [56] [57].	Contamination Control: Fundamental for reducing risk from human-borne contamination, enabling production in lower-grade cleanrooms [56].
Recombinant Factor C Assay	A photometric, enzymatic method for bacterial endotoxin testing (BET) that replaces the traditional horseshoe crab-derived LAL test [56].	Efficacy & Safety: A critical quality control and release test for parenteral products, ensuring patient safety from pyrogenic reactions [56].
Droplet Digital PCR (ddPCR)	A sensitive PCR method used for quantification of viral vector copies or genetic impurities without the need for a standard curve [56].	Efficacy & Tumorigenicity: Supports a risk-based approach to impurity testing, as endorsed by the updated Ph. Eur., ensuring product quality and genetic stability [56].
Specialized Cleanroom Garments	Gowns, hoods, and boots designed for high-grade (e.g., Grade B) environments to control human-borne particulate and microbial contamination [58].	Contamination Control: A critical control point; requires validated laundering and lifecycle management to ensure effectiveness [58].

The manufacturing of ATMPs demands a paradigm shift from traditional pharmaceutical production. The challenges of contamination control, tumorigenicity, and efficacy are interconnected and must be addressed through a combination of advanced technologies, rigorous scientific methodologies, and a proactive regulatory strategy. The evolving frameworks of Annex 1, the USP, and the Ph. Eur. demonstrate that while regulatory expectations are tightening, there is a parallel push for science-based flexibility and innovation. Success in this field will belong to those who can effectively design holistic control strategies, implement and validate sensitive analytical methods, and leverage advanced models to de-risk product development. By doing so, the promise of these advanced therapies can be safely and effectively translated from the laboratory to the patients who need them most.

The development of Advanced Therapy Medicinal Products (ATMPs) represents one of the most innovative frontiers in modern medicine, offering groundbreaking treatments for serious diseases through gene therapies, somatic-cell therapies, and tissue-engineered products [4]. Unlike conventional pharmaceuticals, ATMPs are biological medicines that rely on living cells, tissues, and genetic materials as their active substances, making the sourcing of starting materials a fundamental component of both product efficacy and regulatory compliance [61] [17]. The integrity of these raw materials directly impacts the safety profile and therapeutic potential of the final product, establishing a chain of quality that begins at the very origin of the supply chain.

The Good Manufacturing Practice (GMP) framework for ATMPs extends beyond traditional pharmaceutical regulations to encompass the entire biological supply chain [62]. Current Good Manufacturing Practice (CGMP) regulations contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product to ensure it is safe for use and has the ingredients and strength it claims to have [62]. For ATMP developers, this means implementing rigorous control strategies over highly complex supply chains where the raw materials are often biological entities with limited stability windows [61]. The strategic sourcing of GMP-compliant materials therefore becomes not merely an operational concern but a critical determinant of both developmental success and regulatory approval.

Regulatory Framework for ATMP Starting Materials

EU Classification and Requirements

In the European Union, ATMPs are classified into three main categories: gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines, with an additional category for combined ATMPs that incorporate medical devices as integral components [4]. The overall regulatory framework is established by Regulation (EC) No 1394/2007, with detailed requirements provided in Directive 2009/120/EC [63]. The Committee for Advanced Therapies (CAT) is responsible for assessing the quality, safety, and efficacy of ATMPs, playing a pivotal role in their scientific evaluation and classification [63] [4].

A distinctive aspect of ATMP regulation in the EU is the requirement that human tissues and cells used as starting materials must be procured in accordance with the Tissues & Cells Directives (2004/23/EC, 2006/17/EC, 2006/86/EC) [61] [63]. This requires procurement from licensed establishments compliant with these directives, applying to both allogeneic and autologous donations [61]. Donors must be screened for statutory infectious disease markers (IDM), with testing performed in accredited facilities [61]. This regulatory structure creates a multi-layered compliance environment where ATMP manufacturers must demonstrate control over biological starting materials from the moment of procurement through final product administration.

Comparative US Regulatory Approach

The United States regulates advanced therapies as cellular and gene therapy products (CGTs) under the broader category of biological products [17]. A significant distinction exists between these products and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), with the latter not being classified as biological products unless they meet specific criteria [17]. The 21st Century Cures Act established the Regenerative Medicine Advanced Therapy (RMAT) designation to expedite product development, creating an additional regulatory pathway for promising therapies addressing unmet medical needs [17].

Table 1: Key Regulatory Differences Between EU and US for Advanced Therapies

Aspect	European Union	United States
Product Categories	Gene therapy, Somatic cell therapy, Tissue-engineered, Combined ATMPs	Cellular therapy, Gene therapy
Starting Material Regulation	Tissues & Cells Directives	HCT/P regulations
Procurement Site Requirements	Licensed establishments under Tissues & Cells Directives	No equivalent licensing requirement
Committee for Evaluation	Committee for Advanced Therapies (CAT)	Center for Biologics Evaluation and Research (CBER)
Expedited Pathway	Conditional Marketing Authorization	RMAT designation

Unique Sourcing Challenges in ATMP Development

Biological Starting Material Complexities

The foundational challenge in ATMP raw material sourcing stems from the biological nature of the starting materials, which are primarily cells or tissues from patients or volunteer donors [61]. This introduces inherent variability and complex handling requirements that traditional pharmaceutical supply chains are not designed to accommodate. For autologous products, each manufacturing batch serves a single patient, creating what is essentially a "batch size of one" paradigm that multiplies the complexity of quality control and documentation [64]. The supply chain must therefore manage not just materials but also associated data throughout the complete "vein-to-vein" journey [64].

The stability limitations of biological starting materials present another critical challenge. Unlike chemical compounds, cells and tissues have narrow viability windows that dictate the entire supply chain architecture [61]. For fresh products, the manufacturing and delivery process may be constrained to mere hours, while even cryopreserved materials face strict timelines for processing and infusion [61]. This time sensitivity necessitates specialized logistics capabilities and contingency planning for potential disruptions that could compromise product viability.

Documentation and Compliance Hurdles

Sourcing GMP-compliant materials for ATMP development demands exhaustive documentation that exceeds conventional pharmaceutical requirements. As evidenced by challenges in sourcing amino acid derivatives for peptide synthesis—relevant to some ATMP components—common documentation gaps include incomplete audit trails, missing TSE/BSE certifications, and fragmented change control processes [65]. These documentation shortcomings can delay regulatory approvals by months and create significant audit risks [65].

The multi-jurisdictional nature of ATMP development introduces additional complexity, as materials may be sourced globally while complying with region-specific regulations [66]. The European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have distinct though overlapping requirements, with differences in how combination products are classified and regulated [17]. This regulatory divergence necessitates careful planning for manufacturers targeting global markets, often requiring parallel compliance strategies and documentation approaches.

Diagram 1: ATMP Supply Chain from Procurement to Patient. The vein-to-vein supply chain involves multiple critical transfer points where temperature control and timing must be rigorously maintained.

Strategic Sourcing Frameworks for GMP-Compliant Materials

Supplier Qualification and Risk Mitigation

A robust supplier qualification program forms the cornerstone of effective raw material sourcing for ATMP development. This process should extend beyond basic documentation review to include comprehensive audits of supplier facilities, quality systems, and manufacturing processes [62] [67]. Regulatory bodies like the FDA and EMA require documented supplier qualification under GMP standards, holding companies accountable for vendor compliance even when activities are outsourced [66]. A risk-based audit approach is recommended, prioritizing suppliers whose materials impact critical manufacturing pathways [67].

Supply chain resilience requires deliberate strategies to avoid single-source dependencies. The limited availability of specialized ATMP supply partners makes it essential to pre-qualify alternative suppliers who can be quickly activated if primary suppliers become unavailable [64]. As noted in challenges specific to amino acid derivative sourcing, "single-source exposure" creates vulnerability to geopolitical issues, tariff fluctuations, and capacity limitations [65]. Implementing dual or multiple sourcing strategies builds resilience, though this approach requires careful management to ensure consistency between different suppliers [67].

Comprehensive Documentation Management

Mastering GMP documentation is essential for regulatory success. The documentation package for ATMP raw materials should include Certificates of Analysis (CoA) with comprehensive analytical data, TSE/BSE certifications, and complete change control records [65]. These documents must be audit-ready and available before materials are ordered, as incomplete documentation is a leading cause of regulatory delays [67]. The implementation of electronic document management systems can streamline this process while ensuring version control and accessibility.

A proactive approach to documentation should also include material traceability systems that follow materials throughout the supply chain. In the EU, specific traceability requirements are established by Directive 2006/86/EC, which sets standards for the coding of human tissues and cells [63]. These systems must be able to track materials from origin through final product administration, creating a complete chain of identity that is particularly critical for autologous products [64]. Advanced cell orchestration platforms are increasingly being deployed to manage this complex data load and ensure audit-ready documentation throughout the product lifecycle [64].

Table 2: Essential Documentation for GMP-Compliant Raw Materials

Document Type	Purpose	Regulatory Reference
Certificate of Analysis (CoA)	Provides batch-specific quality data including purity, potency, and testing methods	21 CFR Part 211 [62]
TSE/BSE Declaration	Certifies materials are free from transmissible spongiform encephalopathy agents	EMA/CAT recommendations [65]
Material Safety Data Sheet	Details handling, storage, and safety information for hazardous materials	REACH Regulation
Drug Master File	Contains confidential detailed information about facilities, processes, and articles used in manufacturing	FDA Guidance [67]
Audit Reports	Documents supplier qualification and compliance status	GMP requirements [66]
Change Notification Records	Tracks process deviations and manufacturing changes	Quality System Requirements [65]

Implementation of Quality Control and Testing Protocols

Analytical Methodologies for Raw Material Qualification

Implementing rigorous quality control protocols for ATMP raw materials requires sophisticated analytical methodologies capable of detecting subtle variations in biological materials. Standard analytical techniques often prove insufficient for detecting sub-percent contaminants that could significantly impact product safety or efficacy [65]. Advanced methods such as validated UHPLC and orthogonal testing techniques are increasingly necessary to ensure the high purity standards demanded by modern ATMP development [65].

The evolving nature of ATMPs necessitates continuous refinement of quality benchmarks. Where purity levels of ~98% were once considered acceptable for some biological materials, current expectations often demand higher standards with more sophisticated characterization [65]. This is particularly true for critical raw materials such as amino acid derivatives used in peptide synthesis, where inadequate analytical rigor can lead to batch-to-batch variability that compromises manufacturing consistency [65]. Quality control strategies should be developed during process validation and include testing of materials from multiple suppliers to ensure robustness [61].

Experimental Protocol: Raw Material Qualification Testing

Objective: To establish the quality, purity, and functionality of critical raw materials used in ATMP manufacturing through a comprehensive testing protocol.

Materials and Equipment:

• Test material sample (from qualified batch)
• Reference standards (USP/EP where available)
• UHPLC system with validated method
• Cell-based bioassay components (if applicable)
• Sterility testing media
• Endotoxin testing reagents (LAL)

Procedure:

• Identity Testing:

  • Perform comparative analysis against reference standard using UHPLC with photodiode array detection
  • Confirm identity through retention time matching (±2% of reference standard) and spectral comparison
  • For biological materials, include additional identity confirmation through cell surface marker analysis (flow cytometry) or functional assays

• Purity and Impurity Profile:

  • Execute validated UHPLC method with appropriate detection system
  • Quantify known and unknown impurities against qualified reference standards
  • Calculate purity percentage based on area normalization, with acceptance criteria typically ≥98.0% for critical materials
  • Document all impurities above reporting threshold (typically 0.1%)

• Potency/Functionality Assessment:

  • For biologically active materials, perform cell-based bioassay to confirm functional activity
  • Compare activity to reference standard, with acceptance criteria typically 80-120% of reference
  • For growth factors and cytokines, establish dose-response curve and calculate EC50 value

• Safety Testing:

  • Perform bacterial endotoxin testing using LAL method
  • Conduct sterility testing according to Ph. Eur. 2.6.1 or USP <71>
  • For materials of animal origin, include mycoplasma testing and specific virus testing

• Documentation and Release:

  • Compile all testing data in comprehensive report
  • Obtain quality unit review and approval
  • Issue final certificate of analysis for released material

Acceptance Criteria: All testing must meet pre-defined specifications established during method validation and process development. Any deviations must be investigated through a formal deviation management process before material release.

Diagram 2: Raw Material Testing and Release Workflow. All materials must undergo comprehensive testing and quality review before release to manufacturing.

Supply Chain Architecture and Logistics Management

Temperature Control and Distribution Practices

Maintaining product integrity throughout the supply chain requires rigorous temperature control systems tailored to the specific stability profiles of ATMP raw materials. Temperature fluctuations can significantly impact material stability, necessitating facilities with precise temperature control that maintain materials within designated ranges specified by stability data [62]. Different materials require different handling conditions—some are sensitive to ambient temperature changes, others require cryogenic preservation, and some need protection from light exposure [62].

The implementation of Good Distribution Practices (GDP) is essential for protecting material quality during transit [67]. Logistics providers must have validated processes for temperature monitoring, contingency planning for deviations, and security protocols to prevent unauthorized access [62] [68]. For critical biological materials, advanced monitoring technologies including Internet of Things (IoT) sensors and real-time tracking systems provide enhanced visibility and faster response times when deviations occur [68]. These systems should generate complete temperature logs that are available to both manufacturers and end users as part of the quality documentation [61].

Supply Chain Models for ATMP Development

The unique requirements of ATMP materials have led to the emergence of specialized supply chain architectures designed to address time sensitivity and geographical constraints. Three primary models have evolved:

• Centralized Manufacturing: Donor materials are shipped from multiple geographical sites to a global or regional manufacturing facility. This model offers security and reduced complexity but requires materials with sufficient stability for extended transport times [61].

• Distributed Pre-processing with Central Manufacture: Time-sensitive donor materials undergo initial processing at regional hubs to create more stable intermediate products (e.g., cryopreserved mononuclear cells) before shipment to central manufacturing facilities. This approach can be cost-effective but requires careful quality control at multiple sites [61].

• Regionally Distributed Manufacturing: Complete manufacturing processes are established in regional facilities to minimize transport times for highly labile materials. While this reduces transport risks, it requires significant capital investment and creates challenges for maintaining consistent quality across sites [61].

Table 3: Comparative Analysis of ATMP Supply Chain Models

Model	Key Advantage	Key Challenge	Ideal Use Case
Centralized Manufacturing	Enhanced security and consistency	Limited by material stability	Stable raw materials with global sourcing
Distributed Pre-processing	Balances cost and time efficiency	Requires quality control at multiple sites	Time-sensitive starting materials with moderate stability
Regionally Distributed Manufacturing	Minimizes transport time for labile materials	High capital investment and quality consistency challenges	Highly labile materials with very short stability windows

Emerging Trends and Future Directions

Technological Innovations in Supply Chain Management

The growing complexity of ATMP supply chains is driving adoption of digital integration platforms that provide end-to-end visibility and control. Cell orchestration solutions are increasingly being implemented as central components of supply chain ecosystems, overseeing critical information, automating complex processes, and securely sharing data across stakeholders [64]. These platforms help manage the extensive data generated by personalized medicine approaches, where each patient treatment represents a complete supply chain cycle [64].

Artificial intelligence and predictive analytics are transforming sourcing strategies through demand forecasting and risk anticipation [67]. AI tools can analyze multiple data streams—including sales patterns, lead times, and external factors like weather and geopolitical events—to identify potential shortages before they occur [67]. This enables proactive mitigation strategies and more dynamic safety stock management. When combined with IoT-enabled monitoring devices, these systems can automatically trigger contingency plans in response to supply chain disruptions [68].

Sustainability and Regulatory Evolution

Environmental sustainability is becoming an increasingly important consideration in raw material sourcing decisions. Pharmaceutical manufacturing involves chemicals and processes that affect the environment, requiring companies to balance GMP compliance with environmental regulations [66]. Forward-thinking organizations are investing in green chemistry approaches, waste reduction initiatives, and sustainable sourcing practices that minimize environmental impact while maintaining quality standards [65].

The regulatory landscape continues to evolve in response to ATMP innovations. Agencies are intensifying enforcement of GMP standards while simultaneously creating expedited pathways for promising therapies [66]. The EU's ATMP pilot program for academia and non-profit organizations provides dedicated regulatory support and fee reductions to encourage development of treatments for unmet medical needs [4]. Similar initiatives exist in the US through the RMAT designation program [17]. These regulatory developments highlight the importance of maintaining flexible quality systems that can adapt to changing requirements while ensuring consistent compliance.

Sourcing GMP-compliant raw materials for ATMP development requires a strategic approach that integrates regulatory expertise, robust quality systems, and sophisticated supply chain management. The unique challenges posed by biological starting materials—from their limited stability to their complex regulatory status—demand specialized strategies that go beyond traditional pharmaceutical sourcing. Success in this arena depends on building collaborative relationships with qualified suppliers, implementing comprehensive documentation practices, and developing contingency plans for supply chain disruptions.

As the ATMP field continues to mature, the companies that thrive will be those that treat material sourcing not as a procurement function but as a strategic capability fundamental to product quality and patient safety. By adopting the frameworks and best practices outlined in this guide, ATMP developers can build resilient supply chains capable of supporting the innovative therapies of tomorrow while maintaining the rigorous quality standards that these life-changing treatments demand.

The transition of Advanced Therapy Medicinal Products (ATMPs) from research laboratories to commercial manufacturing represents one of the most significant challenges in modern biopharmaceutical development. Scale-up and technology transfer are systematic processes that bridge the gap between R&D and commercial manufacturing of biological products, involving the translation of small-scale production methods to larger manufacturing scales while maintaining product quality, safety, and efficacy [69]. For ATMPs—which include gene therapies, somatic cell therapies, and tissue-engineered products—these processes are particularly complex due to the inherent biological variability of starting materials, the living nature of the products, and stringent regulatory requirements [15] [70].

A central component of successful scale-up and tech transfer is demonstrating product comparability—proving that the product manufactured at commercial scale is equivalent to the product used in earlier development phases that established safety and efficacy [15]. This requirement is complicated by the dynamic nature of ATMPs, where seemingly minor changes in process parameters, equipment, or manufacturing environments can significantly impact critical quality attributes (CQAs) [69]. The biopharmaceutical industry's adoption of AI-enabled, automation-rich environments has further magnified demand for specialized mathematical expertise to address these challenges, necessitating interdisciplinary education and strong collaboration between academia and industry [69].

Regulatory Framework and Requirements

Global Regulatory Landscape

ATMPs must navigate a complex global regulatory landscape with distinct pathways in major markets. In the European Union, ATMPs are formally classified under Regulation (EC) No 1394/2007 and overseen by the Committee for Advanced Therapies (CAT), which provides scientific recommendations for quality, safety, and efficacy assessment [4] [71]. The EMA has recently implemented updated guidelines, including the "Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials" effective July 2025, which consolidates information from over 40 separate guidelines and reflection papers [9].

In the United States, the FDA's Center for Biologics Evaluation and Research (CBER) regulates these products as cellular and gene therapies under the Public Health Service Act and Federal Food, Drug, and Cosmetic Act [71]. While there is significant regulatory convergence emerging between FDA and EMA approaches, particularly regarding Chemistry, Manufacturing, and Controls (CMC) documentation, important differences remain in areas such as allogeneic donor eligibility determination and GMP compliance expectations [9] [51].

Table 1: Key Regulatory Differences in ATMP Development Between Major Markets

Aspect	European Medicines Agency (EMA)	U.S. Food and Drug Administration (FDA)
Product Terminology	Advanced Therapy Medicinal Products (ATMPs)	Cellular and Gene Therapy Products (CGTs)
Classification Body	Committee for Advanced Therapies (CAT)	Office of Therapeutic Products (OTP) within CBER
GMP Compliance	Mandatory for clinical trial materials	Phase-appropriate approach with full compliance verified at BLA stage
Donor Eligibility	Member state-specific legal requirements	Prescriptive requirements for screening and testing
Key 2025 Guidelines	Guideline on clinical-stage ATMPs (effective July 2025)	Ongoing alignment with ICH guidelines

The Comparability Challenge

Regulatory authorities in the US, EU, and Japan have issued tailored guidance to address the critical challenge of demonstrating product comparability after manufacturing process changes [15]. These documents emphasize risk-based comparability assessments, extended analytical characterization, and staged testing to ensure changes do not impact safety or efficacy. The FDA recommends a tiered approach for reporting changes, while the EMA highlights the need to identify CQAs most susceptible to process variations [15].

For ATMPs, comparability exercises must account for the products' complex mode of action and frequently limited characterization. The EMA's guideline emphasizes that orthogonal methods should be considered for analytical testing to ensure robustness and reliability of results related to product quality, particularly when reference standards or validated methods are lacking [51]. This approach aligns with the broader move toward regulatory convergence with the FDA in analytical and comparability principles [51].

Implementation Strategy: A Risk-Based Framework

Process Risk Assessment

A systematic risk assessment provides the foundation for science-based decision making throughout the product lifecycle. Effective risk management for ATMP scale-up incorporates several methodological approaches [72]:

• Failure Mode and Effects Analysis (FMEA): A systematic method for identifying potential failure modes, their causes, and effects, assigning risk priority numbers based on severity, occurrence, and detectability ratings.
• Fault Tree Analysis (FTA): A top-down approach that starts with a potential failure and works backward to identify root causes, particularly useful for complex systems with multiple interdependencies.
• Hazard Analysis and Critical Control Points (HACCP): Originally developed for food safety, HACCP has applications in biomanufacturing for identifying and controlling biological and chemical hazards.

An implementation example from sterile manufacturing illustrates this approach: a biopharmaceutical company experiencing multiple sterility failures conducted an FMEA that identified inadequate vial inspection techniques and environmental monitoring program gaps as high-risk failure modes. Mitigation strategies included enhanced personnel training, automated visual inspection systems, and upgraded facility monitoring, resulting in elimination of sterility failures and regulatory acknowledgement as industry best practice [72].

Critical Quality Attributes (CQAs) and Process Parameters

Establishing and controlling CQAs is fundamental to ATMP development. According to regulatory concept of medicinal product quality, CQAs are those defining characteristics of the specification that correlate with safety and efficacy [70]. For ATMPs, CQAs typically include identity, purity, potency, viability, and safety parameters, each with associated analytical methods that must be phase-appropriately validated.

Table 2: Typical Critical Quality Attributes for Different ATMP Categories

ATMP Category	Key CQAs	Common Analytical Methods	Special Considerations
Gene Therapy Medicinal Products (GTMPs)	Vector genome titer, infectivity, potency, purity, identity	qPCR, plaque assay, cell-based potency assays, HPLC, sequencing	Genetic stability, insertional mutagenesis risk, vector shedding [73]
Somatic Cell Therapy Medicinal Products (sCTMPs)	Viability, identity, potency, purity, sterility	Flow cytometry, cell counting, functional assays, microbiological testing	Tumorigenicity, phenotypic stability, process-related impurities [73] [15]
Tissue-Engineered Products (TEPs)	Viability, identity, potency, matrix characteristics, sterility	Histology, immunohistochemistry, functional assays, ELISA, biomechanical testing	Scaffold integrity, cell-matrix interactions, biodegradation profile [73]

The following workflow diagram illustrates the integrated approach to risk assessment and control strategy development for ATMP manufacturing processes:

Figure 1: Risk-Based Process Development Workflow for ATMP Manufacturing

Experimental Protocols for Process Validation

Process Performance Qualification (PPQ)

Process Performance Qualification represents the second stage of process validation, designed to demonstrate that the manufacturing process can consistently produce product meeting predetermined specifications under routine operating conditions [72]. For ATMPs, PPQ planning must address unique challenges including limited product stability, complex analytical methods, and often limited manufacturing experience and process understanding [72].

A gene therapy case example illustrates PPQ strategy for an adeno-associated virus (AAV) vector: the company developed an enhanced protocol with intensified in-process controls, additional sampling points, and extended analytical testing beyond commercial requirements. Initial PPQ batches (1-3) showed inconsistent full/empty capsid ratios, triggering process optimization before successful confirmation batches (4-6) demonstrated process capability with Cpk >1.33 for all CQAs [72].

Continued Process Verification (CPV)

Continued Process Verification represents the third stage of process validation, focusing on ongoing monitoring and evaluation of process performance [72]. Regulatory agencies increasingly expect manufacturers to demonstrate continuous process control through:

• Statistical Process Control: Using control charts and statistical methods to monitor process parameters and product quality attributes over time to identify trends and variations that may indicate process drift.
• Periodic Review: Regular evaluation of process performance data to assess process capability and identify improvement opportunities.
• Risk-Based Monitoring: Focusing CPV activities on parameters and attributes with the highest risk to product quality.

An insulin manufacturing case study demonstrates CPV implementation: after establishing a statistical baseline from 30 historical batches, the company implemented control charts for 35 CPPs across fermentation, purification, and formulation. An automated data collection system with statistical analysis tools enabled real-time monitoring, with a monthly quality review board evaluating process performance. This program detected upward trends in fermentation pH and correlations between ambient temperature and purification performance, allowing proactive process adjustments [72].

Technology Transfer Methodologies

Strategic Transfer Planning

Technology transfer is the systematic process of moving a manufacturing process from one location to another, typically from development to commercial manufacturing sites [72]. Successful technology transfer ensures process robustness, product quality, and regulatory compliance through comprehensive planning:

• Facility Assessment: Evaluating receiving facility capabilities, including equipment, utilities, personnel, and quality systems to identify gaps that must be addressed before transfer.
• Process Adaptation: Modifying the manufacturing process as needed to accommodate facility-specific constraints while maintaining product quality and regulatory compliance.
• Documentation Package: Preparing complete documentation including process descriptions, specifications, procedures, analytical methods, and quality standards.

A therapeutic protein transfer example highlights the complexity: a company transferring manufacturing from a pilot facility in the USA to a commercial facility in Ireland conducted a comprehensive facility gap analysis identifying 25 significant gaps requiring resolution. The transfer was executed in three phases over 15 months: documentation transfer (months 1-3), equipment qualification (months 4-8), and process validation (months 9-15), ultimately achieving 10% higher productivity with 30% reduced operational costs [72].

The "Fit to Facility" Concept

The "fit to facility" concept involves adapting the manufacturing process to the specific constraints and capabilities of the receiving facility while maintaining product quality and regulatory compliance [72]. This requires thorough understanding of both the process and the facility through:

• Equipment Qualification: Ensuring all equipment at the receiving facility is properly installed, operational, and qualified for the intended use.
• Process Adaptation Studies: Conducting studies to confirm process performance with facility-specific equipment and utilities.
• Comparability Protocol: Developing a comprehensive protocol to demonstrate product comparability between sending and receiving sites.

The following diagram illustrates the multi-stage technology transfer process with key decision points:

Figure 2: Technology Transfer Process with Key Activities

The Scientist's Toolkit: Essential Research Reagent Solutions

Successful scale-up and tech transfer of ATMPs requires carefully selected reagents and materials that meet regulatory standards and ensure process consistency. The following table details essential research reagent solutions and their functions in ATMP process development and validation:

Table 3: Essential Research Reagent Solutions for ATMP Process Development

Reagent Category	Specific Examples	Function in ATMP Development	Regulatory Considerations
Cell Culture Media	Serum-free media, Xeno-free supplements, Defined growth factors	Support cell expansion while maintaining phenotypic stability and functionality	Must transition from RUO to GMP-grade; composition must be fully defined; raw materials must meet GMP standards [69] [51]
Gene Delivery Systems	Lentiviral vectors, AAV vectors, Plasmid DNA, Transfection reagents	Facilitate genetic modification of cells for gene therapies and genetically-modified cell therapies	Vectors must be produced under GMP; testing for replication-competent viruses; full characterization of vector design [73] [70]
Separation Matrices	Chromatography resins, Ficoll density gradient media, Magnetic bead separation systems	Purify target cell populations, remove impurities, and isolate drug substance	Must demonstrate lot-to-lot consistency; leachables and extractables testing; validation of separation efficiency [72]
Analytical Standards	Reference standards, Process impurities, Vector standards	Qualify and validate analytical methods; demonstrate method suitability	Must be fully characterized and qualified; stability data required; traceability to international standards [73] [51]
Cryopreservation Solutions	DMSO, Formulated cryoprotectants, Cell storage media	Maintain cell viability and functionality during frozen storage	Must be GMP-grade; container closure compatibility; validation of cooling rate protocols [15]

The successful scale-up and technology transfer of ATMPs requires a systematic, science-based approach that prioritizes product comparability and process validation. By implementing robust risk assessment methodologies, establishing meaningful CQAs, and following structured technology transfer processes, developers can navigate the complex regulatory landscape and bring these transformative therapies to patients in need. The evolving regulatory environment, with its increasing convergence between major markets and emphasis on risk-based approaches, provides a framework for efficient development while ensuring product quality and patient safety.

As the field advances, emerging technologies such as artificial intelligence, organoid systems, and advanced analytical methods offer promising opportunities to enhance the consistency, scalability, and precision of ATMP production [15]. By adopting the strategies and methodologies outlined in this technical guide, researchers, scientists, and drug development professionals can overcome the unique challenges presented by these sophisticated therapeutic modalities and fulfill their potential to treat previously untreatable diseases.

Implementing Robust Pharmacovigilance and Risk Management Plans for ATMPs

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic-cell therapies, and tissue-engineered medicines, represent a transformative approach in modern medicine for treating genetic disorders, cancers, and other serious conditions [4]. Unlike conventional pharmaceuticals, ATMPs often involve living cells, complex biological structures, and permanent modifications to human biological systems, resulting in unique safety profiles and risk-benefit considerations. The European Medicines Agency (EMA) mandates that all relevant EU legislation and guidelines regarding pharmacovigilance apply to ATMPs, requiring specialized approaches to safety monitoring and risk management [74].

The implementation of robust pharmacovigilance (PV) systems for ATMPs is critical due to their novel mechanisms of action, potential for long-term effects, and unique safety concerns such as immunogenicity, tumorigenicity, and off-target effects. In February 2018, EMA released a draft revised guideline specifically addressing the safety and efficacy follow-up and risk management of ATMPs, focusing on their unique characteristics in line with Article 14(4) of Regulation (EC) No 1394/2007 [74]. This guideline encourages developers to plan timely interactions with regulatory authorities to ensure efficient development processes and appropriate risk management strategies.

Regulatory Framework for ATMP Pharmacovigilance

International Regulatory Landscape

The regulatory framework for ATMP pharmacovigilance encompasses guidelines from major international authorities including the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA), and the International Council for Harmonisation (ICH). While general pharmacovigilance principles apply to ATMPs, regulatory bodies have recognized the need for product-specific guidance to address their unique challenges [74] [75].

The EMA's Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs, providing expertise for evaluating these complex products and contributing to pharmacovigilance and risk management system guidance [4]. The FDA has issued numerous specific guidance documents for cellular and gene therapy products, covering aspects from long-term follow-up to manufacturing considerations [75]. Notably, a significant regulatory gap exists in GTMP-specific guidance on immunogenicity and immunomodulation, highlighting an area requiring further regulatory development and harmonization [76] [77].

Recent Regulatory Developments

Regulatory requirements for ATMP pharmacovigilance continue to evolve rapidly. Key recent developments include:

• EMA's GMP Guideline Revisions: In May 2025, EMA proposed revisions to Part IV of the EU Guidelines on Good Manufacturing Practice specific to ATMPs, aiming to align with revised Annex 1, integrate ICH Q9 and Q10 concepts, and adapt to technological advancements in ATMP manufacturing [7].
• FDA's AI Guidance: In January 2025, the FDA released draft guidance on "Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products," providing a risk-based credibility assessment framework for AI applications in pharmacovigilance [78].
• EMA's ATMP Risk Management Guideline: The 2018 draft revised guideline on safety and efficacy follow-up and risk management emphasizes early risk detection during development and provides a framework for effective risk mitigation [74].

Table 1: Key Regulatory Guidelines for ATMP Pharmacovigilance

Regulatory Body	Guideline Focus	Key Elements	Status/Timeline
EMA	Safety and efficacy follow-up and risk management of ATMPs	Early risk detection, post-authorization safety studies, risk mitigation frameworks	Draft revised February 2018
FDA	Long Term Follow-up After Administration of Human Gene Therapy Products	Monitoring for delayed adverse events, long-term patient monitoring strategies	Final Guidance January 2020
EMA	GMP specific to ATMPs	Quality risk management, cleanroom standards, emerging technologies	Concept paper released May 2025, consultation until July 2025
FDA	Use of AI in regulatory decision-making	Risk-based credibility assessment, validation requirements for AI systems	Draft Guidance January 2025

Essential Components of ATMP Pharmacovigilance Systems

ATMP-Specific Safety Considerations

ATMPs present unique safety challenges that must be addressed in pharmacovigilance plans. Immunogenicity represents a particularly significant concern for gene therapy medicinal products (GTMPs), where immune responses against the vector or transgene product can impact both safety and efficacy [76] [77]. Other critical safety considerations include vector integration-related genotoxicity, off-target effects in genome-editing products, uncontrolled cell proliferation, and delayed adverse events that may manifest months or years after administration.

The persistence of biological activity distinguishes ATMPs from conventional pharmaceuticals and necessitates extended monitoring periods. For genetically modified cells, this includes monitoring for potential transformative events and phenotypic changes. The EMA's guideline emphasizes the need for tailored risk management strategies that address these product-specific characteristics throughout the entire product lifecycle [74].

Risk Management System Components

A robust risk management system for ATMPs should include both non-clinical and clinical elements tailored to the specific product characteristics. The following core components are essential:

• Pharmacovigilance System Master File (PSMF): Comprehensive documentation describing the pharmacovigilance system and its compliance with regulatory requirements [78].
• Safety Specification: Detailed characterization of the ATMP's safety profile based on all available data, identifying important potential risks, missing information, and populations potentially at risk.
• Pharmacovigilance Plan: Structured strategy comprising routine pharmacovigilance activities and additional post-authorization safety studies tailored to address identified and potential risks.
• Risk Minimization Measures: Implementation of tools beyond routine labeling to minimize identified risks, which may include educational materials, controlled access programs, and pregnancy surveillance systems.
• Benefit-Risk Balance Assessment: Ongoing evaluation of the therapy's benefits against its risks throughout the product lifecycle.

Table 2: Core Components of ATMP Risk Management Plans

Component	ATMP-Specific Considerations	Implementation Tools
Safety Specification	Unique mechanisms of action, long-term persistence, delayed effects	Nonclinical models, biomarkers, surrogate endpoints
Pharmacovigilance Plan	Extended follow-up requirements, specialized detection methods	Registries, long-term follow-up studies, targeted active surveillance
Risk Minimization	Specialized handling requirements, administration by qualified personnel	Healthcare provider training, patient counseling, medication guides
Benefit-Risk Assessment	Evolving benefit-risk profile over time, novel endpoints	Structured frameworks, patient-reported outcomes, real-world evidence

Implementation Strategies and Methodologies

Pharmacovigilance Process Workflow

The pharmacovigilance process for ATMPs requires specialized workflows that address their unique characteristics while maintaining compliance with regulatory requirements. The following diagram illustrates the core PV workflow for ATMPs:

PV Process Flow for ATMPs

This workflow highlights the continuous cycle of safety data management for ATMPs, emphasizing the need for specialized signal detection methods and extended evaluation periods that account for the potential delayed effects unique to these therapies.

Artificial Intelligence in ATMP Pharmacovigilance

The integration of Artificial Intelligence (AI) technologies is transforming pharmacovigilance for ATMPs, offering enhanced capabilities for processing complex safety data. Regulatory bodies including EMA and FDA have begun providing structured guidance for AI implementation in pharmacovigilance systems [78]. Key applications include:

• Automated Case Processing: Natural Language Processing (NLP) applications enable automated extraction of relevant medical information from unstructured text, standardization of medical terminology, and intelligent routing of cases based on content analysis [78].
• Advanced Signal Detection: AI-powered pattern recognition can identify subtle safety signals in large datasets, detect rare adverse events that might be missed by conventional methods, and analyze temporal patterns specific to ATMPs [78].
• Predictive Analytics: Machine learning models can provide early warnings for emerging safety concerns and predict adverse event occurrence in specific patient populations.

The implementation of AI systems requires careful attention to validation requirements, transparency, and maintenance of human oversight. The FDA's 2025 draft guidance emphasizes a risk-based credibility assessment framework that considers the context of use for specific AI applications [78].

AI Implementation Framework

Long-Term Follow-Up Strategies

Long-term follow-up (LTFU) is particularly critical for ATMPs due to their potential for persistent biological effects and delayed adverse events. The FDA's January 2020 guidance on "Long Term Follow-up After Administration of Human Gene Therapy Products" emphasizes the need for extended monitoring periods, in some cases spanning 5-15 years or longer depending on the product characteristics [75].

Effective LTFU strategies for ATMPs typically include:

• Patient Registries: Systematic collection of clinical and safety data from all treated patients, often with extended observation periods.
• Standardized Assessment Protocols: Comprehensive testing schedules including imaging, laboratory assessments, and functional evaluations at predetermined intervals.
• Retention Strategies: Implementation of patient engagement methods to maintain high follow-up rates over extended periods, which may include digital health technologies, patient support programs, and reminder systems.
• Data Integration: Combining data from multiple sources including electronic health records, claims data, and patient-reported outcomes to create comprehensive safety profiles.

Essential Research Reagents and Tools

Implementing robust pharmacovigilance and risk management plans for ATMPs requires specialized research reagents and technological tools. The following table outlines essential solutions for monitoring ATMP safety:

Table 3: Essential Research Reagent Solutions for ATMP Pharmacovigilance

Reagent/Tool Category	Specific Examples	Application in ATMP Pharmacovigilance
Immunogenicity Assays	Anti-drug antibody (ADA) assays, Neutralizing antibody (NAb) assays, T-cell activation assays	Detection of immune responses against gene therapy vectors or transgene products [76] [77]
Vector Shedding Assays	qPCR for viral vector detection, Plaque assays for replication-competent virus	Monitoring potential transmission to contacts and environmental safety [75]
Genotoxicity Testing	Integration site analysis (LAM-PCR, LDS-PCR), Off-target editing assessment (GUIDE-seq)	Evaluating potential for insertional mutagenesis and unintended genomic modifications
Cell Tracking Reagents	Genetic barcodes, Flow cytometry panels, PCR-based detection methods	Monitoring persistence, distribution, and potential transformation of cellular therapies
Biomarker Assays	Cytokine panels, Inflammatory markers, Tissue-specific damage markers	Early detection of adverse events and monitoring of biological responses
Bioinformatics Tools	Sequence analysis software, Immunophenotyping algorithms, AI-based signal detection	Analysis of complex datasets for safety signal identification [78]

Emerging Challenges and Future Directions

Addressing Current Regulatory Gaps

Despite recent advancements, significant regulatory gaps remain in ATMP pharmacovigilance. The current absence of GTMP-specific guidance on immunogenicity and immunomodulation represents a particular challenge for developers [76] [77]. Future regulatory development should address:

• Standardized immunogenicity assessment methodologies across product types
• Harmonized requirements for long-term follow-up across regulatory jurisdictions
• Advanced safety biomarker qualification and validation
• Integrated risk-benefit assessment frameworks specific to ATMPs

The ongoing work by the International Council for Harmonisation (ICH) and the Council for International Organizations of Medical Sciences (CIOMS) aims to address some of these gaps, with CIOMS Working Group XIV's report on artificial intelligence in pharmacovigilance currently under public consultation through June 2025 [78].

Technological Innovations and Trends

The future of ATMP pharmacovigilance will be shaped by several technological innovations and trends:

• Advanced AI Applications: Integration of large language models for enhanced case processing, development of AI systems for real-world evidence generation, and implementation of federated learning approaches for privacy-preserving AI [78].
• Digital Health Technologies: Use of wearable sensors, mobile health applications, and telemedicine platforms for continuous safety monitoring and real-world data collection.
• Advanced Analytics: Implementation of predictive toxicology models, systems pharmacology approaches, and multi-omics integration for proactive risk identification.
• Regulatory Innovation: Development of AI-specific regulatory pathways, implementation of continuous monitoring and adaptive approval processes, and enhanced collaboration between industry and regulators on AI development [78].

Implementing robust pharmacovigilance and risk management plans for ATMPs requires a specialized approach that addresses their unique scientific characteristics, regulatory requirements, and technical challenges. The rapidly evolving regulatory landscape necessitates proactive engagement with health authorities and careful attention to emerging guidelines from EMA, FDA, and other international bodies.

Successful pharmacovigilance strategies for ATMPs must incorporate long-term follow-up protocols, advanced signal detection methodologies, tailored risk minimization measures, and emerging technologies including artificial intelligence. As recognized in regulatory literature, there remains a clear need for continued development of GTMP-specific guidance, particularly in areas such as immunogenicity assessment [76] [77].

By implementing comprehensive, scientifically rigorous pharmacovigilance and risk management plans that address both current requirements and emerging challenges, developers can ensure the safe and effective use of these transformative therapies while maintaining compliance with evolving regulatory expectations across international jurisdictions.

EU vs. US Regulatory Frameworks: A Side-by-Side Analysis for Global Strategy

Advanced therapies represent a paradigm shift in medical treatment, moving from managing symptoms to addressing underlying disease mechanisms through innovative biological interventions. These complex products, encompassing cell, gene, and tissue-based therapies, fall under distinct regulatory frameworks in different jurisdictions. The European Union (EU) and the United States (US) have established sophisticated but differing regulatory pathways for these innovative therapies [79]. Understanding the precise terminology and classification systems is fundamental for researchers and drug development professionals navigating the global regulatory landscape, as misclassification at early development stages can significantly impact subsequent clinical trials and marketing authorization strategies [79]. This guide provides a technical comparison of how these powerful therapeutic modalities are defined and categorized by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), framed within the context of regulatory requirements for advanced therapy medicinal products (ATMP) research.

Regulatory Definitions and Classification Criteria

European Union Framework for Advanced Therapy Medicinal Products (ATMPs)

In the EU, Advanced Therapy Medicinal Products (ATMPs) are regulated under a centralized procedure as biological medicinal products. The legal basis is defined in Regulation (EC) No 1394/2007, which amends Directive 2001/83/EC and Regulation (EC) No 726/2004 [79]. ATMPs are categorized into four distinct classes based on their core technological characteristics and mechanisms of action [79] [4]:

• Gene Therapy Medicinal Products (GTMPs): These products contain genes that lead to a therapeutic, prophylactic, or diagnostic effect. They function by inserting 'recombinant' genes into the body, typically to treat genetic disorders, cancer, or long-term diseases. A recombinant gene is a stretch of DNA created in the laboratory, bringing together DNA from different sources [4].
• Somatic Cell Therapy Medicinal Products (SCTMPs): These contain cells or tissues that have been substantially manipulated to change their biological characteristics, or cells or tissues not intended to be used for the same essential functions in the body. They are used to cure, diagnose, or prevent diseases [4].
• Tissue-Engineered Products (TEPs): These contain cells or tissues that have been modified substantially to be used for repairing, regenerating, or replacing human tissue. The critical distinction from some cell therapies often lies in the product's intended function to regenerate or replace tissue structures [4].
• Combined ATMPs (cATMPs): This category includes any of the above three ATMP types combined with one or more medical devices as an integral part of the product. An example is cells embedded in a biodegradable matrix or scaffold [79] [4].

A cornerstone of the EU classification is the concept of "substantial manipulation." Cells or tissues that are not substantially manipulated and are intended for the same essential function fall under different legal frameworks (e.g., transplants) and are not classified as ATMPs [79]. The Committee for Advanced Therapies (CAT) is the specific EMA committee responsible for classifying products as ATMPs and assessing their quality, safety, and efficacy [4].

United States Framework for Cell and Gene Therapy Products

In the US, advanced therapies are regulated primarily as biological products under the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act [79]. The FDA's Center for Biologics Evaluation and Research (CBER) oversees these products, which are broadly categorized into two main groups [79] [75]:

• Gene Therapy Products: The FDA's definition of what constitutes a gene therapy product is largely equivalent to the EU's criteria. These products involve the introduction of genetic material to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use [79] [75].
• Cellular Therapy Products: This is a broad category that encompasses many of the products that the EU might classify as SCTMPs or TEPs. The US framework does not have a distinct, formal regulatory category for "tissue-engineered products" in the same way the EU does [79].

A critical differentiator in the US system is the category of "Human Cells, Tissues, and Cellular and Tissue-Based Products" (HCT/Ps). HCT/Ps are regulated solely under Section 361 of the Public Health Service Act and are not considered biological products (and thus not "advanced therapies") if they meet specific criteria: they are minimally manipulated, intended for homologous use only, and not combined with another drug or device (with some exceptions) [79]. The 21st Century Cures Act also established the Regenerative Medicine Advanced Therapy (RMAT) designation, an expedited program for promising regenerative medicine therapies, which includes many cell and gene therapy products [79] [75].

Comparative Analysis: EU vs. US Classification

Table 1: Comparative Terminology and Classification of Advanced Therapies in the EU and US

Aspect	European Union (EMA)	United States (FDA)
Umbrella Term	Advanced Therapy Medicinal Products (ATMPs)	Cellular and Gene Therapy Products (CGTs)
Main Categories	1. Gene Therapy Medicinal Products (GTMP)2. Somatic Cell Therapy Medicinal Products (SCTMP)3. Tissue-Engineered Products (TEP)4. Combined ATMPs (cATMP)	1. Gene Therapy2. Cellular Therapy
Key Legislation	Regulation (EC) No 1394/2007; Directive 2009/120/EC	Public Health Service Act; 21st Century Cures Act
Primary Regulatory Body	EMA's Committee for Advanced Therapies (CAT)	FDA's Center for Biologics Evaluation and Research (CBER)
Non-ATMP/Non-Biological Product Category	Cells/tissues for transplantation (not substantially manipulated, same function)	Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) under Section 361
Expedited Pathway	Conditional Marketing Authorization, PRIME	RMAT (Regenerative Medicine Advanced Therapy) Designation

The following diagram illustrates the logical decision pathways for classifying a product as an advanced therapy in the EU and US, highlighting the key differences in structure and criteria.

Experimental Protocols and Research Methodologies

The development of ATMPs requires specialized experimental protocols that address their unique biological nature, manufacturing complexity, and regulatory requirements. The following section outlines core methodologies relevant to ATMP research and development.

Protocol 1: Potency Assay Development for ATMPs

Objective: To establish a robust, quantitative potency assay that demonstrates the biological activity of an ATMP, as required by regulatory authorities for lot release and stability testing [75].

Methodology:

• Identify Mechanism of Action (MOA): Begin by definitively establishing the product's MOA. This is the foundation for all subsequent assay development.
• Assay Format Selection: Choose an assay format that quantitatively measures a specific biological response linked to the MOA. Options include:
  • Cell-based assays: Co-culture systems with reporter cells measuring cytokine release (e.g., for CAR-T products) or cytolytic activity.
  • Biochemical assays: ELISA for specific factor secretion, flow cytometry for surface marker expression.
  • 'Omics-based assays: RNA sequencing or proteomic profiling to establish a product-specific potency signature.
• Assay Qualification and Validation:
  • Specificity: Demonstrate that the assay measures the intended activity and is not influenced by non-relevant factors.
  • Accuracy/Precision: Determine intra-assay, inter-assay, and inter-operator variability. Aim for a precision profile with %CV < 20-25%.
  • Linearity and Range: Establish the assay's dynamic range where the response is linear and proportional to the product concentration or cell number.
  • Robustness: Test the assay's resilience to small, deliberate variations in protocol parameters (e.g., incubation time, temperature, reagent lots).

Regulatory Consideration: The FDA's "Potency Tests for Cellular and Gene Therapy Products" guidance emphasizes the need for a potency assay linked to the product's MOA, and the EMA has similar expectations [75]. The assay must be validated for its intended purpose before Biologics License Application (BLA) or Marketing Authorization Application (MAA) submission.

Protocol 2: Validation of a Manufacturing Process Change Using Comparability

Objective: To assess whether a change in the manufacturing process (e.g., scale-up, raw material substitution) adversely affects the critical quality attributes (CQAs) of the ATMP and to demonstrate product comparability [9].

Methodology:

• Pre-Change Analysis: Fully characterize at least three lots of the product manufactured with the pre-change process. This establishes the baseline for all CQAs.
• Define a Comparability Protocol: This is a prospective, approved plan that defines the CQAs to be tested, the analytical methods, and the acceptance criteria for concluding comparability.
• Post-Change Manufacturing and Testing: Manufacture a sufficient number of post-change lots (typically 3-5) and test them against the pre-change baseline using the defined battery of analytical methods.
• Multi-Attribute Analytical Testing:
  • Identity: Flow cytometry (phenotype), PCR (genotype), unique product identifiers.
  • Purity/Impurities: Viability, residual reagents, endotoxin, replication-competent virus testing for gene therapies.
  • Potency: The biological activity assay developed per Protocol 1.
  • Quantity: Cell count, vector titer, viable cell number.
• Statistical Analysis: Use appropriate statistical tests (e.g., equivalence testing, analysis of variance) to formally compare pre- and post-change data against the pre-defined acceptance criteria.

Regulatory Consideration: Both the FDA and EMA require a rigorous, risk-based approach to comparability. The EMA's 2025 guideline on clinical-stage ATMPs notes that "immature quality development may compromise use of clinical trial data to support a marketing authorization," underscoring the need for a well-controlled process [9]. The FDA's "Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products" draft guidance provides a detailed framework for this exercise [75].

The Scientist's Toolkit: Essential Reagents and Materials

The research and development of ATMPs rely on a suite of specialized reagents and materials to ensure product safety, identity, purity, and potency. The selection of these components is critical and must be documented thoroughly for regulatory filings.

Table 2: Key Research Reagent Solutions for ATMP Development

Reagent/Material Category	Specific Examples	Function in ATMP R&D	Key Regulatory Considerations
Cell Culture Media & Supplements	Serum-free media, Xeno-free cytokines (e.g., IL-2, SCF), Growth factors, Antibiotics	Provides the nutritive environment for ex vivo cell expansion and differentiation. Defines the cellular phenotype and function.	Documentation of origin, qualification testing, and avoidance of animal-derived components to minimize pathogen risk is critical [75] [7].
Gene Delivery Vectors	Lentiviral vectors, Adeno-associated viruses (AAV), Retroviral vectors, Plasmid DNA, CRISPR-Cas9 components	Facilitates the introduction, removal, or modification of genetic material in target cells for gene therapies and genetically-modified cell therapies.	Comprehensive testing for sterility, mycoplasma, endotoxin, adventitious agents, and replication-competent viruses (RCV) is required [75].
Cell Separation & Activation Reagents	Immunomagnetic beads (e.g., for CD4+ T-cell selection), Recombinant antibodies, Antigenic peptides, Cytokine cocktails	Enables the isolation and specific activation of target cell populations from a heterogenous starting material (e.g., apheresis product).	The degree of manipulation is a key classification factor. Reagents must be GMP-grade for clinical use [79] [7].
Analytical Assay Reagents	Flow cytometry antibodies, ELISA kits, PCR primers/probes, Cytotoxicity detection reagents, NGS libraries	Used for product characterization, including identity, purity, potency, and safety (e.g., tumorigenicity, off-target effects).	Assays must be validated per ICH guidelines. Critical reagents require strict lot-to-lot consistency testing and clear traceability [75] [9].
Scaffolds & Matrices (for TEPs/cATMPs)	Biodegradable polymers (e.g., PLA, PLGA), Collagen gels, Fibrin scaffolds, Hydrogels	Provides a three-dimensional structure for tissue-engineered products, supporting cell attachment, proliferation, and differentiation.	Classified as a medical device component. Biocompatibility and biodegradation profile must be thoroughly evaluated [79] [4].

Recent Regulatory Developments and Future Directions

The regulatory landscape for advanced therapies is dynamic, with both the EMA and FDA actively adapting their frameworks to keep pace with scientific innovation while ensuring patient safety.

• EMA's Evolving Guidelines: In July 2025, the EMA's new Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials came into effect [9]. This multidisciplinary document consolidates information from over 40 separate guidelines and is intended as a primary reference for clinical trial applications involving ATMPs. Furthermore, in May 2025, the EMA proposed revisions to the GMP guideline specific to ATMPs (Part IV) to align with the revised Annex 1 on sterile products, incorporate ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) principles, and provide guidance on new technologies like automated and closed systems [7].

• FDA's 2025 Draft Guidance Trio: In September 2025, the FDA released three new draft guidance documents aimed at refining the development pathway for cell and gene therapies [80]. These address:

  • Expedited Programs for Regenerative Medicine Therapies: Clarifies the use of RMAT, Fast Track, and Breakthrough Therapy designations.
  • Postapproval Data Capture: Provides recommendations on using real-world evidence to monitor long-term safety and efficacy.
  • Innovative Clinical Trial Designs: Encourages the use of adaptive, Bayesian, and externally controlled trials for small patient populations, which is common in rare diseases [80].

• Global Regulatory Convergence: Both agencies are increasingly participating in initiatives aimed at global regulatory convergence. The FDA's Gene Therapies Global Pilot Program (CoGenT), modeled after Project Orbis in oncology, explores concurrent, collaborative reviews with international partners like the EMA to reduce duplication and accelerate global patient access [80]. There is also a growing emphasis on the use of Artificial Intelligence (AI) in regulatory decision-making, with the FDA releasing draft guidance on the topic in January 2025 [80]. Despite these convergence efforts, differences remain in areas such as donor eligibility testing and phase-appropriate GMP expectations, which developers must still navigate [9].

The development of Advanced Therapy Medicinal Products (ATMPs) represents one of the most innovative yet complex frontiers in modern medicine. These therapies, which include gene therapies, somatic-cell therapies, tissue-engineered products, and combined ATMPs, offer unprecedented potential for treating previously incurable conditions [4]. However, their biological complexity and manufacturing processes present unique regulatory challenges. The global regulatory landscape for these products is characterized by both significant convergence in scientific principles and notable divergence in technical implementation between major jurisdictions [9]. For researchers and drug development professionals navigating this environment, understanding the nuances between the European Union (EU) and United States (US) regulatory frameworks is not merely an academic exercise but a practical necessity for efficient global development strategy.

The core challenge lies in balancing region-specific compliance with the efficiencies offered by harmonized approaches. As noted by regulatory experts, "Where there is divergence and incompatibility, efficient development and timely accessibility of innovative products for patients can be jeopardized" [9]. This technical guide examines the current state of Good Manufacturing Practice (GMP) expectations and donor eligibility requirements through the lens of regulatory convergence, providing a structured comparison to inform ATMP research and development planning. The analysis is particularly timely given several significant regulatory updates in 2025 that refine both European and American approaches to ATMP oversight [7] [81] [9].

Regulatory Frameworks and Classification Systems

Foundational Regulatory Structures

The regulatory frameworks governing ATMPs in the EU and US share common goals of ensuring product safety, quality, and efficacy while accommodating the distinctive nature of these innovative therapies. However, their structural approaches reflect different historical and legal traditions that influence implementation strategies for developers.

In the European Union, ATMPs are firmly established within the medicinal product framework under Directive 2001/83/EC and Regulation 726/2004/EC, with specific provisions detailed in the ATMP Regulation (EC) No 1394/2007 [63]. The regulation established the Committee for Advanced Therapies (CAT) as a multidisciplinary committee responsible for assessing ATMP quality, safety, and efficacy [4] [63]. The EU maintains four distinct ATMP categories: gene therapy medicinal products (GTMPs), somatic-cell therapy medicinal products (SCTMPs), tissue-engineered products (TEPs), and combined ATMPs [4] [17]. This classification system provides precise definitions that determine the applicable regulatory pathway, with all ATMPs requiring centralized authorization through the European Medicines Agency (EMA) to ensure consistent standards across member states [4].

In the United States, ATMPs are regulated as biological products under the Public Health Service Act, falling primarily into two sub-categories: cellular and gene therapy products (CGTs) [17]. The US framework distinguishes these products from "human cells, tissues, and cellular and tissue-based products (HCT/Ps)," which are subject to a different regulatory standard under 21 CFR Part 1271 [17]. A significant development in the US landscape is the Regenerative Medicine Advanced Therapy (RMAT) designation established under the 21st Century Cures Act, which provides expedited development and review pathways for products addressing serious conditions [17]. This designation exemplifies the adaptive regulatory approach to advancing innovative therapies while maintaining rigorous standards.

ATMP Classification Pathways

The following diagram illustrates the decision pathways for classifying advanced therapies in the EU and US regulatory systems:

This classification divergence means that a product might be regulated as an ATMP in the EU while falling under the HCT/P framework in the US, or vice versa, depending on the nature of cellular manipulation and intended use [17]. For developers, this necessitates early strategic planning and potentially different clinical development pathways for different regions.

Good Manufacturing Practice (GMP) Expectations

Current GMP Landscape and Recent Updates

Good Manufacturing Practice requirements form the cornerstone of ATMP quality assurance, ensuring that these complex biological products are manufactured consistently to appropriate quality standards. Both regions acknowledge the need for phase-appropriate GMP implementation, though their emphasis and verification mechanisms differ significantly.

In the European Union, the EMA has proposed significant revisions to Part IV of the EU GMP guidelines specific to ATMPs in 2025 [7]. These revisions aim to align ATMP-specific GMP requirements with the updated Annex 1 governing the manufacture of sterile medicinal products, which became effective in August 2023 [7]. Key focus areas include the development and implementation of a comprehensive Contamination Control Strategy (CCS), integration of ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) principles, and adaptation to technological advancements such as automated systems, closed single-use systems, and rapid microbiological testing methods [7]. The revised guidelines also promise 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 to accommodate the manual manipulations common in individualized ATMP batches [7].

The United States approach to GMP for ATMPs employs a graduated, risk-based implementation rather than mandatory verification at early stages [9]. The FDA's current thinking emphasizes phase-appropriate GMP compliance, with full verification typically occurring during pre-license inspection when a Biologics License Application (BLA) is submitted [9]. This approach acknowledges the evolving nature of manufacturing processes during development while maintaining focus on patient safety through adequate controls.

Comparative Analysis of GMP Expectations

Table: Comparison of GMP Expectations for ATMPs in EU and US

Aspect	European Union Approach	United States Approach
Legal Basis	Detailed GMP guidelines specific to ATMPs (Part IV) with recent 2025 revisions proposed [7]	Current Good Manufacturing Practice (cGMP) regulations with phase-appropriate implementation [9]
Compliance Verification	Mandatory through self-inspections and documented quality systems [9]	Attestation in early phases with verification during pre-license inspection [9]
Quality Systems	Integration of ICH Q9 and ICH Q10 requirements [7]	Quality systems approach with risk management principles [9]
Manufacturing Technologies	Specific guidance on qualifying and controlling new technologies (closed systems, automation) [7]	Process validation requirements with flexibility for emerging technologies [9]
Environmental Controls	Clear expectations for cleanroom classifications and barrier systems [7]	Risk-based environmental monitoring programs [9]
Documentation	Alignment with Common Technical Document (CTD) format, though using "Active substance" vs "Drug substance" terminology [9]	CTD format with "Drug substance" and "Drug product" terminology [9]

The International Society for Stem Cell Research (ISSCR) has responded positively to the proposed EMA revisions, supporting updates that "address inconsistencies, clarify ambiguities, and include guidance on the use of new manufacturing technologies" [82]. However, they recommend incorporating these updates into the main body of EudraLex Volume 4 rather than maintaining them as a separate document, suggesting ongoing evolution in the regulatory approach [82].

Donor Eligibility Requirements

Donor Screening and Testing Frameworks

Donor eligibility determination represents a critical component of ATMP safety, particularly for products incorporating human cells, tissues, or cellular components. The approaches between regions show significant divergence in specificity, legal basis, and implementation requirements, creating substantial challenges for global development programs.

In the United States, the FDA maintains a highly prescriptive framework for donor eligibility under 21 CFR Part 1271, Subpart C [81] [83] [84]. In January 2025, the FDA announced the availability of a new draft guidance document, "Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)" [81] [84]. This comprehensive guidance outlines specific requirements for donor screening and testing to minimize the risk of communicable disease transmission. The FDA mandates testing for specific pathogens including HIV-1 and 2, HBV, HCV, Treponema pallidum (syphilis), with additional requirements for viable leukocyte-rich products (HTLV-1/2, CMV) and reproductive HCT/Ps (Chlamydia trachomatis, Neisseria gonorrhea) [83]. The approach includes specific recommendations regarding testing methodologies, laboratory qualifications, and restrictions on pooling human cells or tissues from multiple donors [9] [83].

In contrast, the European Union provides more general guidance on donor eligibility while emphasizing compliance with relevant EU and member state-specific legal requirements [9]. The EMA's guideline on clinical-stage ATMPs references the importance of guarding against communicable disease transmission but defers to specific technical directives such as the European Tissues and Cells Directive (2004/23/EC) and its implementing directives for detailed requirements [9] [63]. This creates a more fragmented landscape where individual member state requirements may introduce additional considerations beyond the central EMA guidance.

Side-by-Side Comparison of Donor Eligibility Provisions

Table: Comparison of Donor Eligibility Requirements for ATMPs

Requirement	European Union Approach	United States Approach
Legal Basis	EU Tissues and Cells Directives (2004/23/EC) with member state implementations [9] [63]	21 CFR Part 1271, Subpart C with detailed FDA guidance documents [81] [83]
Testing Specificity	General requirements with reference to relevant communicable diseases [9]	Highly specific testing panel requirements (HIV, HBV, HCV, Treponema pallidum, etc.) [83]
Pathogen Coverage	Risk-based approach considering emerging pathogens [9]	Specific listed relevant communicable disease agents and diseases (RCDADs) [83] [84]
Testing Methodologies	Less prescriptive on specific methodologies	Specific test requirements and FDA-maintained list of approved donor screening tests [83]
Donor Screening	Required but with variability across member states	Standardized donor history questionnaires recommended [83]
Pooling Restrictions	General risk consideration for communicable disease transmission [9]	Specific restrictions on pooling of cells from different donors [9]
Exceptions	Not explicitly detailed in guidelines	Explicit exceptions for urgent medical need, first/second-degree blood relatives, and directed reproductive use [83]

A significant challenge for global development emerges from "nonconforming differences related to determining allogeneic donor eligibility" that "can and have resulted in timeline delays and increased cost to cell therapy product developers" [9]. This occurs when cellular starting materials obtained from donors screened and tested in compliance with one jurisdiction's requirements must be used in development under another regulatory authority with different requirements [9].

Implementation Strategies and Compliance Protocols

Practical Implementation Framework

Navigating the divergent GMP and donor eligibility requirements between regions demands systematic approaches that anticipate regulatory challenges while maximizing efficiency. The following workflow illustrates a recommended strategy for managing these parallel requirements throughout the product development lifecycle:

Essential Research Reagent Solutions for Compliance

Implementing effective compliance strategies requires specific reagents, systems, and documentation approaches. The following table outlines key solutions for addressing dual regulatory requirements:

Table: Research Reagent Solutions for ATMP Regulatory Compliance

Solution Category	Specific Examples	Regulatory Function
Donor Screening Tools	Standardized Donor History Questionnaires; FDA-listed communicable disease tests; Pathogen NAT assays [83]	Streamlines donor eligibility determination while meeting both EU and US requirements
Quality Management Systems	Electronic Quality Management Systems (eQMS) with ICH Q9/Q10 integration; Phase-appropriate GMP documentation systems [7] [9]	Supports graduated GMP implementation while maintaining data integrity across regions
Manufacturing Controls	Closed single-use systems with validation data; Automated manufacturing platforms; Rapid microbiological methods [7]	Addresses EU expectations for technology control while supporting US phase-appropriate validation
Analytical Development	Standardized potency assays; Process impurity profiling methods; Comparability protocols [9]	Facilitates manufacturing changes while maintaining product consistency for both regions
Documentation Templates	CTD-formatted documentation with region-specific modules; Comparative analysis tables for quality attributes [9]	Efficiently organizes submissions for both EMA and FDA review processes

Strategic Regulatory Engagement

For organizations navigating the complex transatlantic regulatory landscape, proactive regulatory engagement provides critical opportunities for alignment. The EMA emphasizes that "ATMP developers [should] seek early guidance at either the national member state or European level to inform development" [9]. Similarly, the FDA offers various pre-submission mechanisms for developmental feedback. The risk-based approach explicitly recommended in the EMA's clinical-stage ATMP guideline provides a common philosophical foundation for both regions, though implementation differs [9]. By emphasizing risk-informed development strategies in early regulatory interactions, sponsors can establish a framework that satisfies both regulatory systems while maintaining development efficiency.

The regulatory landscape for ATMPs demonstrates both significant convergence in fundamental quality principles and notable divergence in technical implementation between the EU and US. The GMP requirements show increasing alignment, particularly through the integration of ICH guidelines and quality risk management approaches, though differences remain in compliance verification timing and specific technical expectations [7] [9]. In contrast, donor eligibility requirements maintain substantial divergence, with the US maintaining a more prescriptive, specific approach while the EU employs a more general framework deferential to member state implementations [81] [9] [83].

For researchers and drug development professionals, success in this environment requires both deep understanding of the specific technical requirements and strategic approaches that maximize harmonization while addressing unavoidable regional differences. The recent 2025 updates to both EU GMP guidelines and FDA donor eligibility recommendations underscore the dynamic nature of this field and the importance of maintaining current regulatory intelligence [7] [81]. By implementing structured compliance strategies, engaging early with regulatory authorities, and developing manufacturing approaches that accommodate both frameworks, developers can navigate this complex landscape while advancing innovative therapies to patients needing these transformative treatments.

The development of robust potency assays for Advanced Therapy Medicinal Products (ATMPs) represents one of the most significant challenges in modern biopharmaceutical development. Potency assays are critical quality attributes that must demonstrate a direct correlation with the biological activity underpinning the product's intended therapeutic effect [85]. For ATMPs—which include gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines—the complex and often multifaceted mechanisms of action (MoA) create unique hurdles for developing analytical methods that meet regulatory standards [4]. These products exhibit considerable variability in starting materials and involve complex biological mechanisms that do not easily lend themselves to traditional pharmaceutical testing paradigms [85].

The regulatory landscape for ATMP potency assays is evolving rapidly, with agencies including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) providing increasingly specific guidance on expectations for assay validation and suitability [85] [86]. This technical guide examines current and emerging approaches for developing orthogonal and novel methodologies that can satisfy both scientific and regulatory requirements, with a particular focus on the integration of advanced technologies such as artificial intelligence and machine learning in assay design and selection.

Regulatory Framework and Challenges

The Evolving Regulatory Landscape

The regulatory framework governing ATMP potency assays continues to mature as scientific understanding advances. Globally, regulators require that potency assays demonstrate a direct link to the biological activity responsible for therapeutic efficacy [85]. The EMA's Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs in the European Union, providing recommendations on the quality, safety, and efficacy of these complex products [4]. Similarly, the FDA has issued updated guidance on potency assurance for Cellular and Gene Therapy Products, emphasizing the need for robust quantitative methods [85].

The ICH Q2(R2) guideline on validation of analytical procedures provides fundamental principles for assay validation, defining key parameters including accuracy, precision, specificity, linearity, and range [86]. These parameters form the foundation for demonstrating assay suitability, though ATMPs often require additional considerations beyond traditional pharmaceuticals. Regulatory submissions must provide comprehensive data packages demonstrating that potency assays are fit-for-purpose throughout the product lifecycle—from early clinical development through commercial marketing authorization [87].

ATMP-Specific Challenges in Potency Assay Development

The development of potency assays for ATMPs faces several distinct challenges compared to conventional pharmaceuticals, as summarized in the table below.

Table 1: Key Challenges in ATMP Potency Assay Development

Challenge Category	Specific Issues	Potential Impact
Product Complexity	Multifaceted mechanisms of action; Living cells as products; Heterogeneous cell populations	Difficulty identifying a single potency marker; Need for multiple assays to capture different aspects of biological activity
Manufacturing Variability	Variable starting materials; Process-related impurities; Donor-to-donor variability	Assay must accommodate legitimate product variability while detecting unacceptable deviations
Analytical Technical Constraints	Limited sample availability (especially autologous); Lack of appropriate reference standards; Short product shelf-lives	Necessitates miniaturized and rapid testing methods; Requires careful assay qualification
Regulatory Science Gaps	Evolving regulatory expectations; Limited published standards for novel modalities; Uncertain correlation between in vitro and clinical outcomes	Need for early and continuous regulatory engagement; Requirement for scientific justification of approach

These challenges necessitate innovative approaches to potency assay development, including the implementation of orthogonal method combinations and the adoption of novel technologies that can better capture biological complexity [85].

Orthogonal and Novel Methodological Approaches

Orthogonal Assay Strategies

Orthogonal testing strategies employ multiple independent methods to measure the same quality attribute, providing greater confidence in results than any single method could offer. For ATMP potency assessment, orthogonal approaches are particularly valuable given the complex MoAs of these products. A comprehensive orthogonal strategy typically includes a combination of cell-based assays, biochemical assays, and molecular methods, each targeting different aspects of the product's biological activity [88].

Cell-based assays represent the cornerstone of potency assessment for many ATMPs, as they capture the complexity of the entire biological system and provide functional characterization of the product's activity [88]. These assays measure relevant cellular responses such as cytotoxicity (for effector cell therapies), differentiation capacity (for stem cell products), or transduction efficiency (for gene therapies). When developing orthogonal approaches, cell-based assays are typically complemented by biochemical methods that quantify specific analytes such as cytokine secretion, surface marker expression, or metabolic activity. Molecular methods including quantitative PCR (qPCR), droplet digital PCR (ddPCR), and next-generation sequencing provide additional layers of characterization, particularly for gene-modified products where vector copy number, transgene expression, or gene editing efficiency are critical quality attributes [85].

Emerging Technologies and Novel Methodologies

The field of ATMP potency assessment is being transformed by several emerging technologies that offer enhanced sensitivity, reproducibility, and biological relevance.

Table 2: Emerging Technologies for ATMP Potency Assessment

Technology	Application in Potency Assessment	Regulatory Considerations
AI/ML-Enabled Assay Development	Reverse-engineering in-silico MoA into mechanistically relevant assays; Predictive modeling of assay performance; Continuous assay optimization	Demonstrable biological relevance; Validation according to ICH Q2(R2); Transparency in algorithms and training data
Reporter Gene Assays	Quantitative measurement of specific pathway activation; High-throughput screening format; Reduced variability compared to primary cell-based assays	Establishment of relevance to clinical mechanism; Comprehensive validation including specificity assessment
Digital PCR	Absolute quantification of vector copy number; Detection of rare events (e.g., off-target editing); Enhanced precision over qPCR	Standardization of sample preparation; Demonstration of linearity and precision across expected range
Multi-omics Approaches	Comprehensive characterization using transcriptomics, proteomics, metabolomics; Identification of novel potency markers; Systems biology understanding of MoA	Data integrity and analytical validation; Statistical rigor in marker identification; Demonstration of relevance to biological activity

Artificial intelligence and machine learning are playing an increasingly important role in potency assay development, particularly for ATMPs originating from AI-driven discovery platforms [88]. These approaches face the unique challenge of reverse-engineering the in-silico mechanism of action into a set of in-vitro and ex-vivo assays that regulators will accept as "mechanistically relevant" and "quantitative" [88]. Hybrid strategies combining established assay formats with AI-driven assay selection engines that continuously update the experimental plan as new data are generated show particular promise for addressing this challenge [88].

Experimental Protocols and Methodologies

Cell-Based Potency Assay Protocol

Cell-based assays remain essential for ATMP potency assessment as they most closely capture the biological activity relevant to the therapeutic mechanism. The following protocol outlines a generalized approach for developing and executing cell-based potency assays.

Protocol: Cell-Based Cytotoxicity Assay for Effector Cell Therapies

Purpose: To quantify the target cell killing activity of immune effector cell products (e.g., CAR-T, CAR-NK cells) as a measure of potency.

Materials and Reagents:

• Test Articles: Cryopreserved effector cell product (properly thawed and rested)
• Target Cells: Appropriate antigen-positive and antigen-negative cell lines
• Culture Medium: Complete medium supplemented with appropriate cytokines/growth factors
• Detection Reagent: Lactate dehydrogenase (LDH) release detection kit or fluorescent viability dye
• Equipment: CO₂ incubator, plate reader (absorbance or fluorescence), sterile tissue culture supplies

Procedure:

• Target Cell Preparation:
  • Harvest exponentially growing target cells and resuspend in complete medium
  • Seed antigen-positive and antigen-negative control cells in 96-well plates at 5,000-10,000 cells/well
  • Include wells for background control (medium only), target cell spontaneous release, and maximum release

• Effector Cell Preparation:

  • Thaw cryopreserved product rapidly at 37°C and wash to remove cryoprotectant
  • Rest cells for 2-4 hours in complete medium at 37°C, 5% CO₂
  • Count and assess viability (should be ≥70% for assay validity)
  • Prepare serial dilutions to establish effector-to-target (E:T) ratios (typically 10:1 to 1:1)

• Co-culture Setup:

  • Add effector cells to target cells at designated E:T ratios
  • Include target cells alone as spontaneous release control
  • Include target cells with lysis solution as maximum release control
  • Centrifuge plates briefly (200 × g, 2 minutes) to initiate cell contact
  • Incubate for 4-24 hours (duration determined during assay development) at 37°C, 5% CO₂

• Cytotoxicity Measurement:

  • For LDH release: Transfer supernatant to new plate, add reaction mixture, incubate 20-30 minutes, measure absorbance at 490-500 nm
  • For viability dyes: Add dye according to manufacturer's instructions, incubate, measure fluorescence

• Data Analysis:

  • Calculate specific cytotoxicity using the formula: (Experimental - Spontaneous) / (Maximum - Spontaneous) × 100
  • Generate dose-response curves and determine EC₅₀ or other potency values
  • Compare to reference standard to assign potency units

Validation Parameters: Establish specificity, accuracy, precision, linearity, and range according to ICH Q2(R2) guidelines [86]. Demonstrate assay robustness to minor variations in E:T ratio, incubation time, and cell preparation methods.

Molecular Potency Assay Using Digital PCR

Digital PCR provides absolute quantification of nucleic acids without requiring standard curves, making it particularly valuable for assessing gene therapy products and genetically modified cell therapies.

Protocol: Vector Copy Number Determination Using Droplet Digital PCR

Purpose: To quantify the number of vector genomes per cell as a critical quality attribute for genetically modified ATMPs.

Materials and Reagents:

• Sample Material: Genomic DNA from transduced cells (100-200 ng/µL in TE buffer)
• Assay Components: ddPCR supermix, restriction enzyme (if needed), vector-specific primers and probe, reference gene primers and probe
• Consumables: DG8 cartridges, gaskets, droplet generation oil, 96-well PCR plates
• Equipment: Droplet generator, thermal cycler, droplet reader

Procedure:

• Assay Design:
  • Design primers and probe to target unique sequence in vector (e.g., transgene, promoter)
  • Select reference gene (e.g., RNase P, albumin) for normalization to diploid genome equivalent
  • Validate specificity using appropriate positive and negative controls

• Reaction Setup:

  • Prepare 20 µL reactions containing 1× ddPCR supermix, 900 nM primers, 250 nM probe, and 50-100 ng genomic DNA
  • Include no-template controls, positive controls (cells with known VCN), and reference gene assay
  • Add restriction enzyme if needed to reduce viscosity and improve partitioning efficiency

• Droplet Generation:

  • Transfer 20 µL reaction mixture to DG8 cartridge wells
  • Add 70 µL droplet generation oil to appropriate wells
  • Place gasket and process in droplet generator
  • Carefully transfer generated droplets (40 µL) to 96-well PCR plate

• PCR Amplification:

  • Seal plate with foil heat seal
  • Run amplification with optimized cycling conditions:
    • 95°C for 10 minutes (enzyme activation)
    • 40 cycles of: 94°C for 30 seconds, 58-60°C for 60 seconds
    • 98°C for 10 minutes (enzyme deactivation)
    • 4°C hold

• Droplet Reading and Analysis:

  • Place plate in droplet reader for simultaneous fluorescence measurement of all wells
  • Set appropriate thresholds to distinguish positive and negative droplets
  • Analyze data using companion software to calculate copies/µL for both target and reference
  • Calculate vector copy number as: (Target copies/µL) / (Reference copies/µL) × 2

Validation Parameters: Establish specificity, limit of blank, limit of detection, precision (repeatability and intermediate precision), and accuracy using spike-recovery studies [85] [86].

Regulatory Validation and Lifecycle Management

Analytical Method Validation Framework

The validation of analytical methods, including potency assays, must follow established regulatory guidelines while addressing ATMP-specific considerations. The ICH Q2(R2) guideline provides the foundational framework for validation, outlining key parameters that must be demonstrated for analytical procedures [86]. The table below summarizes the validation parameters and their application to ATMP potency assays.

Table 3: Analytical Validation Parameters for ATMP Potency Assays (Based on ICH Q2[R2])

Validation Parameter	Definition	Application to ATMP Potency Assays	Typical Acceptance Criteria
Accuracy	Closeness of agreement between accepted reference value and measured value	For cell-based assays: Recovery of spiked reference material; Comparison to well-characterized biological standard	Recovery within 70-130% for biological assays; Justified based on product variability
Precision	Degree of agreement among individual test results	Assessed at multiple levels: repeatability (same analyst/day), intermediate precision (different analysts/days), reproducibility (between labs)	RSD ≤20-30% for biological assays; Based on product and assay variability
Specificity	Ability to measure analyte unequivocally in presence of interfering components	Demonstration that matrix components, process impurities, or related substances do not interfere	No significant interference observed; Maintains accuracy and precision in presence of potential interferents
Linearity	Ability to obtain results proportional to analyte concentration	Tested across theoretical range of activity; May not be linear across entire range for biological systems	R² ≥0.95 across validated range; Visual inspection of linearity plot
Range	Interval between upper and lower levels of analyte that demonstrate suitable precision, accuracy, and linearity	Should encompass expected potency range from lowest to highest expected values	Typically 50-150% of target potency; Justified based on product knowledge
Robustness	Capacity to remain unaffected by small, deliberate variations in method parameters	Evaluation of impact of factors such as cell passage number, reagent lots, incubation times	Method performs acceptably across expected operational variations

The validation approach should be science-based and risk-informed, with the extent of validation justified based on the assay's purpose and stage of product development [86]. Early-phase clinical trials may require less comprehensive validation than assays intended for marketing authorization applications, with the understanding that validation should be updated as development progresses.

Assay Lifecycle Management

Potency assay development and validation should be viewed as an iterative process that evolves throughout the product lifecycle. During early development, the focus should be on identifying assays that are biologically relevant to the mechanism of action, with preliminary qualification to demonstrate fitness for purpose [87]. As development progresses toward later-phase clinical trials, assays should be further optimized and validated to meet full ICH Q2(R2) requirements [86].

Lifecycle management includes ongoing monitoring of assay performance through system suitability tests and statistical quality control measures. Any changes to the assay procedure—whether due to reagent obsolescence, process improvements, or scaling needs—should be managed through a formal change control process with appropriate assessment of the impact on method validity. Comparability studies should be conducted to demonstrate that method changes do not affect the ability to accurately measure product potency [87].

Implementation Strategies and Future Directions

Practical Implementation Framework

Successful implementation of orthogonal and novel potency methodologies requires a systematic approach that integrates scientific, technical, and regulatory considerations. The following strategies can facilitate effective implementation:

• Early Regulatory Engagement: Proactively seek regulatory feedback on potency assay strategies through scientific advice procedures [4]. Early alignment on the suitability of novel approaches can prevent costly delays during marketing authorization applications.

• Risk-Based Approach: Implement a risk-based strategy that focuses resources on the most critical aspects of potency assessment. Prioritize assays that measure attributes most closely linked to clinical outcomes and implement appropriate controls for higher-risk aspects of the methodology.

• Comprehensive Training: Ensure technical staff receive thorough training on both the technical execution of novel methodologies and the underlying principles of assay validation. The EMA and EATRIS offer training modules specifically designed for ATMP developers [4].

• Technology Transfer Planning: Develop detailed technology transfer protocols when moving assays between sites or to contract testing organizations. Include comparative testing and statistical analysis to demonstrate equivalency.

Essential Research Reagent Solutions

The successful development and implementation of ATMP potency assays requires carefully selected research reagents and materials. The table below outlines key reagent categories and their functions in potency assessment.

Table 4: Essential Research Reagents for ATMP Potency Assay Development

Reagent Category	Specific Examples	Function in Potency Assessment	Quality Considerations
Reference Standards	WHO International Standards; In-house primary reference; Commercial reference materials	Calibration of assays; System suitability testing; Potency unit assignment	Well-characterized; Documented stability; Appropriate storage conditions
Cell-Based Assay Reagents	Reporter cell lines; Target cells; Primary cells; Culture media; Cytokines/growth factors	Provide biological context for functional assays; Measure relevant pharmacological activity	Authentication; Purity assessment; Freedom from contaminants; Consistent performance
Molecular Assay Components	Primers and probes; Enzymes (polymerases, restriction enzymes); dNTPs; Standardized buffers	Enable quantification of genetic elements; Assessment of product identity and purity	Quality certification; Lot-to-lot consistency; Minimal non-specific activity
Detection Reagents	Fluorescent dyes; Antibodies; Enzyme substrates; Luminescent detection systems	Signal generation for quantitative measurement; Specific detection of analytes of interest	Validation for intended use; Minimal background; Appropriate sensitivity
Separation Materials	Chromatography columns; Electrophoresis gels; Filtration devices; Magnetic beads	Isolation or separation of analytes from interfering substances; Sample preparation	Reproducible performance; Minimal non-specific binding; Compatibility with samples

Future Directions and Emerging Trends

The field of ATMP potency assay development continues to evolve rapidly, with several emerging trends likely to shape future regulatory acceptance:

• Increased Use of AI/ML in Assay Development: Artificial intelligence and machine learning are being applied to optimize assay conditions, select the most predictive biomarkers of potency, and even design novel assay formats [88]. As these technologies mature, regulatory frameworks will need to adapt to ensure appropriate validation of AI-derived methods.

• Advanced Multi-analyte Approaches: Technologies such as multiplexed immunoassays, mass cytometry, and single-cell RNA sequencing enable simultaneous measurement of multiple potency markers, providing a more comprehensive assessment of product quality [88].

• Process Analytical Technologies (PAT): The implementation of real-time potency monitoring during manufacturing represents a paradigm shift from end-product testing to continuous quality assurance. While technically challenging for complex ATMPs, PAT approaches could significantly enhance product consistency.

• Harmonization of Global Standards: International harmonization of potency assay expectations continues to progress, with collaborative efforts between EMA, FDA, and other regulatory agencies helping to establish more consistent requirements [85].

Regulatory acceptance of orthogonal and novel methodologies will continue to depend on demonstrated scientific rigor, comprehensive validation, and clear linkage to biological activity and clinical outcomes. By adopting a systematic, science-based approach to potency assay development and validation, ATMP developers can navigate the complex regulatory landscape while ensuring the quality, safety, and efficacy of these innovative therapies.

The authorization of an Advanced Therapy Medicinal Product (ATMP) by a regulatory body represents a significant scientific achievement, yet it marks only the initial step toward patient access. The period following regulatory approval unveils a complex landscape of economic evaluations, reimbursement negotiations, and health system readiness assessments that ultimately determine real-world availability. For researchers and drug development professionals, understanding these post-authorization realities is critical, as scientific innovation alone cannot ensure that transformative therapies reach patients. The European Union's centralized authorization system has granted marketing approval for numerous ATMPs, but their subsequent market availability reveals stark disparities across Member States, creating a paradoxical situation where authorized medicines remain inaccessible to most eligible patients [89] [29]. This whitepaper examines the structural, economic, and evidentiary factors shaping ATMP commercialization within the framework of regulatory science, providing a technical analysis of the barriers and potential solutions for achieving equitable patient access.

The ATMP Access Landscape: Quantitative Analysis

Disparities in Market Availability

Recent research evaluating the market availability of 18 EU-authorized ATMPs across 23 Member States demonstrates significant inequities in patient access. The data reveal that a patient's geographical location substantially influences their ability to receive advanced therapies, with Germany (89%), France (61%), and Italy (61%) demonstrating the highest availability ratios, while Estonia and Latvia reported no ATMP launches on their markets [89]. This analysis, with data verified by National Competent Authorities (NCAs) for 74% of the surveyed EU MS, highlights that pricing and reimbursement processes represent just one dimension of the access challenge.

Table 1: ATMP Market Availability Across Selected EU Member States

Member State	ATMP Availability Ratio	Notable Characteristics
Germany	89%	Leading market; early adoption
France	61%	Strong reimbursement framework
Italy	61%	Dedicated innovation fund
Estonia	0%	No ATMPs launched
Latvia	0%	No ATMPs launched
Average of analysed EU MS	26%	Significant access inequality

Product-Specific Availability Patterns

Beyond country-level disparities, availability varies considerably across individual ATMPs. Certain products, particularly CAR T-cell therapies for hematologic malignancies, have achieved broader market penetration, while other innovative treatments remain limited to few markets. The correlation between ATMP characteristics and availability reveals that only time since marketing authorization showed significance for CAR T-cell therapies, while target patient population size and cost demonstrated no consistent statistical relationship with availability across product categories [89].

Table 2: ATMP Products with Highest Market Penetration in EU

ATMP Product	Number of EU MS (% of analysed MS)	Therapeutic Area	Year of MA
Zolgensma	19 (83%)	Spinal muscular atrophy	2020
Kymriah	18 (78%)	Hematologic malignancies	2018
Tecartus	14 (61%)	Hematologic malignancies	2020
Yescarta	14 (61%)	Hematologic malignancies	2018
Luxturna	10 (43%)	Ocular genetic disorder	2018
Alofisel	9 (39%)	Crohn's disease	2018

Methodological Challenges in Evidence Generation

Clinical Trial Design Limitations

The evidence base supporting ATMP approvals typically differs substantially from traditional pharmaceuticals, creating challenges for health technology assessment (HTA) bodies and payers. A methodological analysis of clinical trials supporting ATMP authorizations reveals distinctive characteristics that contribute to post-authorization evidence gaps:

• Median pivotal-trial enrollment: 75 patients [90]
• Single-arm trials: 56% of registrational studies [90]
• Open-label designs: 91% of pivotal studies [90]
• Limited follow-up periods: Often insufficient for assessing long-term durability and safety [90]

These methodological characteristics reflect the challenges of studying therapies for rare diseases and life-threatening conditions but create significant uncertainties regarding comparative effectiveness, long-term clinical outcomes, and real-world performance.

Post-Authorization Evidence Generation Frameworks

To address pre-authorization evidence limitations, regulatory and HTA bodies increasingly emphasize post-authorization evidence generation as a condition for market access. The following workflow illustrates the continuous evidence generation pathway from clinical development through post-authorization phases:

Diagram 1: ATMP Evidence Generation Pathway

This evolving framework requires researchers to design evidence generation strategies that extend well beyond initial approval, incorporating real-world data collection, registry development, and long-term follow-up studies to address evidence gaps identified during regulatory and HTA review [90].

Regulatory and HTA Evolution

EU Regulatory Framework for ATMPs

The regulatory foundation for ATMPs establishes specific requirements that distinguish them from conventional pharmaceuticals:

• Centralized Authorization Procedure: Mandatory EU-wide marketing authorization through EMA [4] [29]
• Committee for Advanced Therapies (CAT): Specialized committee within EMA responsible for ATMP evaluation [4] [29]
• Combined ATMP Classification: Specific regulations for products incorporating medical devices as integral components [4] [91]
• Hospital Exemption: Provision for non-routine use of unlicensed ATMPs in hospital settings under specific conditions [91]

The regulatory framework continues to evolve, with the Substances of Human Origin (SoHO) Regulation (EU 2024/1938) scheduled to apply from 2027, replacing previous directives and establishing updated standards for quality and safety of human-derived materials used in ATMPs [29].

EU HTA Regulation and Joint Clinical Assessment

A significant development in the European ATMP landscape is the implementation of the EU HTA Regulation (EU 2021/2282), with joint clinical assessments (JCAs) for ATMPs becoming mandatory from January 2025 [92] [29]. This regulation introduces:

• Harmonized Evidence Requirements: Standardized methodologies for clinical and economic evidence generation
• Joint Scientific Consultations: Opportunity for parallel regulatory and HTA advice during development
• Coordinated Assessment Process: Reduced duplication across member states while preserving national decision-making autonomy

The JCA process creates both opportunities and challenges for ATMP developers, requiring strategic evidence planning that addresses both regulatory and HTA needs from early development stages [92].

Pricing, Reimbursement, and Market Access Barriers

Structural Challenges in ATMP Financing

The distinctive characteristics of ATMPs create fundamental tensions with conventional pharmaceutical reimbursement systems:

• High Upfront Costs vs. Long-term Benefits: Traditional cost-effectiveness models struggle with the temporal mismatch between immediate budget impact and benefits that may accrue over decades [90]
• Durability Uncertainty: Limited long-term data at launch creates challenges in demonstrating sustained treatment effects [90] [92]
• Budget Impact Concentration: Particularly for ultra-rare diseases, one-time therapies clear pent-up demand rapidly, concentrating expenditure into initial budget cycles [90]
• Absence of Comparators: For conditions with no existing treatment, the lack of cost offsets further complicates economic evaluation [90]

These structural mismatches have led to the withdrawal of commercially non-viable ATMPs despite regulatory approval, exemplified by Bluebird bio's retraction of Zynteglo and Skysona following stalled reimbursement negotiations [90].

Innovative Payment Models

To address these challenges, payers and manufacturers are piloting a spectrum of innovative payment arrangements that better align with ATMP characteristics:

Table 3: Innovative Payment Models for ATMPs

Payment Model	Mechanism	Implementation Requirements
Coverage with Evidence Development (CED)	Temporary reimbursement conditional on post-launch data collection for reassessment	National registry infrastructure; predefined endpoints and reassessment criteria
Outcomes-Based Agreements	Payment linked to individual patient results (response, survival milestones)	Clinical data collection systems; clear outcome definitions; audit processes
Spread Payments/Annuities	Upfront cost divided into instalments over multiple years	Multi-year budget flexibility; accounting treatment as operational expenditure
Subscription Models	Fixed annual fee for unlimited patient access	Transparent patient definition; volume monitoring mechanisms
Expenditure Caps	Total spending cap with rebates above threshold	Real-time sales tracking; reconciliation processes

These innovative approaches aim to balance patient access with financial sustainability while generating additional evidence to reduce clinical and economic uncertainties [90] [92].

System Readiness and Implementation Challenges

Healthcare System Infrastructure Barriers

Beyond economic considerations, ATMP accessibility depends on specialized healthcare delivery capabilities that remain unevenly distributed:

• Specialized Treatment Centers: Limited availability of facilities with expertise in patient selection, cell handling, and administration [90]
• Geographic Disparities: Concentration of qualified centers creates travel burdens and access inequalities for patients in underserved regions [89] [90]
• Supply Chain Complexity: Requirements for cryopreservation, cold chain logistics, and tightly coordinated manufacturing timelines create operational challenges [93]
• Clinical Workforce Expertise: Shortage of healthcare professionals trained in ATMP administration and toxicity management [90]

Current estimates indicate the industry is manufacturing tens of thousands of ATMP doses annually but reaching only approximately 20% of the eligible patient population across the U.S. and Europe, highlighting the significant infrastructure limitations [93].

Research Reagents and Technical Requirements

The development and manufacturing of ATMPs require specialized reagents and materials that differ substantially from traditional pharmaceuticals. The following table details key research solutions essential for ATMP development and their specific functions:

Table 4: Essential Research Reagent Solutions for ATMP Development

Research Reagent/Material	Function in ATMP Development	Technical Specifications
Cell Separation Media	Isolation of specific cell populations from heterogeneous mixtures	Density gradient formulations; GMP-grade compatibility
Cryopreservation Solutions	Maintenance of cell viability during frozen storage	DMSO-containing or DMSO-free formulations; controlled-rate freezing compatibility
Gene Editing Reagents	Genetic modification of cells for therapeutic effect	CRISPR-Cas9 systems; viral and non-viral delivery vehicles
Cell Culture Media	Ex vivo expansion and maintenance of therapeutic cells	Serum-free formulations; cytokine/growth factor supplements
Viral Vector Systems	Delivery of genetic material to target cells	Lentiviral, retroviral, AAV platforms; GMP manufacturing capability
Biomaterial Scaffolds	Structural support for tissue-engineered products	Biodegradable polymers; 3D architecture customization

These specialized reagents require stringent quality control and documentation to meet regulatory standards for ATMP manufacturing [4] [91].

Strategic Framework for Optimizing ATMP Access

Integrated Evidence Planning

Successful ATMP commercialization requires coordinated evidence generation strategies that address both regulatory and HTA requirements throughout the product lifecycle. The following framework illustrates the multi-stakeholder coordination necessary for optimizing ATMP access:

Diagram 2: Multi-Stakeholder Evidence Generation Coordination

This integrated approach requires early and continuous engagement with all stakeholders, including regulators, HTA bodies, payers, clinicians, and patients, to align evidence requirements and establish feasible pathways for addressing evidentiary gaps [92] [29].

Market Access Implementation Strategy

Achieving optimal patient access requires a systematic approach to market preparation and launch execution. A 5-step playbook for ATMP market access success includes:

• Early Integrated Evidence & Value Story Alignment: Develop and evidence a compelling value narrative tailored to HTA and payer needs, addressing uncertainties through robust study design and real-world evidence planning [92].
• Strategic Launch Sequencing: Model reference pricing impacts and sequence market entries to preserve price integrity, prioritizing high-value markets to establish favorable benchmark prices [92].
• Innovative Contracting Solutions: Design outcomes-based agreements, annuity models, or coverage with evidence development schemes to address payer concerns about cost, uncertainty, and budget impact [90] [92].
• Tailored Stakeholder Engagement: Adapt value communications to address specific national HTA requirements and clinical practice contexts, incorporating perspectives from patients and clinicians to strengthen value propositions [92].
• Post-Launch Value Optimization: Implement comprehensive real-world data collection strategies to demonstrate long-term outcomes, comparative effectiveness, and system impacts, reinforcing value claims during subsequent price negotiations [92].

This strategic framework emphasizes that ATMP commercialization success depends on addressing evidence, economic, and system readiness challenges through coordinated planning across development, regulatory, and commercial functions.

The post-authorization journey for ATMPs reveals critical interdependencies between regulatory science, health technology assessment, and healthcare system capabilities. While regulatory approval provides market entry permission, real-world patient access depends on addressing complex challenges related to evidence generation, economic sustainability, and delivery system readiness. The increasing implementation of joint clinical assessments in the EU, alongside evolving payment models and infrastructure development, represents promising pathways toward more equitable access. For researchers and drug development professionals, successfully navigating these post-authorization realities requires integrated planning that begins early in product development and extends throughout the product lifecycle. By adopting strategic approaches to evidence generation, stakeholder engagement, and market preparation, the ATMP field can better fulfill its potential to deliver transformative treatments to patients in need across diverse healthcare systems.

Conclusion

The regulatory pathway for ATMPs is complex and rapidly evolving, underscored by a fundamental tension between groundbreaking innovation and the need for robust, scalable infrastructure. Success hinges on a deep understanding of both regional specifics—such as the EU's new 2025 clinical trial guideline and upcoming SoHO Regulation—and global trends toward regulatory convergence in CMC requirements. Developers must adopt a proactive, strategic approach, engaging with regulators early and often, building quality and scalability into processes from the outset, and preparing for significant post-authorization challenges in market access. The future of ATMPs will be shaped by advancements in AI, organoid technology, and more flexible regulatory and payment models, all aimed at fulfilling the promise of delivering these life-changing therapies to patients worldwide.

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• 93. ATMP Development in 2025: Promise, Pressure, and the ... [https://www.cryoport.com/bio-blog-atmp-development-in-2025-promise-pressure-and-the-push-to-scale/]