EudraGMDP Database: The Essential Guide to ATMP Manufacturing Licenses and Compliance

Abstract

This guide provides researchers, scientists, and drug development professionals with a comprehensive understanding of the EudraGMDP database and its critical role in the regulatory landscape for Advanced Therapy Medicinal Products (ATMPs). It covers foundational knowledge on navigating the public database for GMP certificates and manufacturing authorizations, outlines the procedural steps for obtaining and maintaining ATMP manufacturing licenses, addresses common compliance challenges and optimization strategies, and explains how to use the database for due diligence and regulatory intelligence to ensure robust quality assurance and supply chain security.

Understanding EudraGMDP: The EU's Central Hub for ATMP Manufacturing Oversight

What is the EudraGMDP Database? Core Purpose and Key Stakeholders

The EudraGMDP (European Union Drug Regulating Authorities Good Manufacturing and Distribution Practice) database is a central repository operated by the European Medicines Agency (EMA) for regulatory information on manufacturing, import, and wholesale distribution authorisations, as well as GMP and GDP certificates within the European Economic Area (EEA) [1] [2]. It serves as a critical tool for ensuring transparency and coordination in the oversight of medicinal product quality.

Core Purpose and Strategic Objectives

The establishment of the EudraGMDP database serves several fundamental purposes within the EU regulatory framework [1]:

• Information Sharing: Facilitates improved sharing of GMP and GDP information between regulators and the public, including the pharmaceutical industry
• Inspection Coordination: Aids the coordination of inspections of manufacturers in third countries among national competent authorities
• Process Efficiency: Eliminates the need for industry to submit paper documents to support marketing-authorisation and variation applications
• Supply Chain Protection: Helps protect the medicine distribution chain and active-substance supply chain by facilitating the verification of legitimate actors
• Global Cooperation: Facilitates the sharing of information on the outcomes of inspections conducted by EEA authorities with regulatory authorities worldwide

Database Content and Document Types

The EudraGMDP database contains specific types of regulatory documents and information, detailed in the table below.

Table: Key Document Types in the EudraGMDP Database

Document Category	Specific Types	Relevance to ATMPs
Authorisations	Manufacturing and Import Authorisations [1]	Required for all ATMP manufacturers in the EU [3]
Certificates	Good Manufacturing Practice (GMP) Certificates [1] [2]	Confirms compliance with ATMP-specific GMP guidelines [3]
Registrations	Active Substance Manufacturers, Importers, or Distributors [1]	Essential for traceability of ATMP components
Compliance Statements	Non-Compliance Reports [2]	Identifies manufacturers failing to meet standards

For Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products, the EudraGMDP database plays a particularly crucial role [3] [4]. ATMP manufacturers must hold a manufacturing authorisation issued by the national competent authority of the Member State where they operate, and information on these authorisations is accessible via EudraGMDP [3].

Key Stakeholders and Their Interactions

The EudraGMDP database serves multiple stakeholders with distinct roles and requirements. The diagram below illustrates how these key groups interact with the database and each other.

Stakeholder Interactions with EudraGMDP

Regulatory Authorities

• EEA Member States: National competent authorities have full read and write access to EudraGMDP and are responsible for entering data as it becomes available [1]
• International Partners: Several international regulatory partners have unrestricted read access, with some like Japan's MHLW and PMDA also having write access [1]
• EMA Role: The EMA maintains and operates the database, providing coordination and harmonization [3]

Industry Stakeholders

• Marketing Authorisation Holders: Rely on the database to verify the compliance status of their manufacturing sites [5]
• Manufacturers: Must ensure their organization details are correctly recorded in EMA's Organisation Management Service (OMS) before applying for authorisations [1]
• ATMP Developers: Particularly benefit from the database's ability to provide transparency in the complex ATMP manufacturing landscape [3] [4]

Integration with Other EU Regulatory Systems

The EudraGMDP database does not operate in isolation but is part of an integrated EU regulatory framework for medicines. Since January 2022, manufacturers, importers, and distributors must ensure their organization details are correctly recorded in EMA's Organisation Management Service (OMS) before applying to national competent authorities for authorisations or certificates [1]. This integration ensures more reliable data in EudraGMDP via the consistent use of organization master data, reduces the need for data entry and cleansing, and enhances the interoperability of IT systems [1] [6].

Table: Key Regulatory Resources for ATMP Research and Development

Resource Name	Type	Primary Function in ATMP Development
EudraGMDP Database	Regulatory Database	Verification of manufacturing authorisations and GMP compliance of suppliers and contractors [1] [3]
Organisation Management Service (OMS)	Master Data Repository	Source of validated organization master data used as a reference in EU regulatory activities [6]
EMA's Committee for Advanced Therapies (CAT)	Scientific Committee	Provides ATMP classification and evaluation of ATMP Marketing Authorisation Applications [4]
Good Manufacturing Practice (GMP) Guidelines	Regulatory Guidance	Detailed quality standards for manufacturing processes, with specific guidelines for ATMPs [3]
European Pharmacopoeia	Quality Standard	Sets mandatory quality standards for all medicines marketed in Europe, including ATMPs [3]

Methodological Approach for Utilizing EudraGMDP in ATMP Research

For researchers and drug development professionals working with ATMPs, a systematic approach to using the EudraGMDP database involves:

• Manufacturing Authorisation Verification: Confirm that any potential manufacturing partners hold valid authorisations in the EudraGMDP database, as this is a mandatory requirement for ATMP manufacturers in the EU [3]

• GMP Compliance Assessment: Check for GMP certificates and compliance statements for all sites involved in the manufacturing process, particularly important given the complex nature of ATMP manufacturing [3] [2]

• Supply Chain Due Diligence: Verify the registration of active substance manufacturers, importers, or distributors to ensure supply chain integrity [1]

• Organisation Data Management: Ensure all organization details are correctly mastered in the OMS, as this is a prerequisite for applications recorded in EudraGMDP [1] [6]

The EudraGMDP database continues to evolve, with its history showing progressive expansion from its initial launch in 2007 to the inclusion of GDP-related information and registration of active substance manufacturers in 2013 [1]. For ATMP researchers and developers, it remains an indispensable tool for navigating the complex regulatory landscape of advanced therapy medicinal products in the European Union.

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), understanding the regulatory landscape is as crucial as mastering the scientific challenges. The EudraGMDP database (European Union Drug Good Manufacturing and Distribution Practice) serves as a critical repository for regulatory compliance information across the European Economic Area (EEA) [1]. This database provides a window into the manufacturing compliance status of facilities producing ATMPs—complex medicines based on genes, cells, or tissues that represent the cutting edge of therapeutic innovation [7].

The concept of a European inspections database was established to provide EEA National Competent Authorities and the European Medicines Agency with a comprehensive overview of the status of pharmaceutical manufacturers [8]. For ATMP researchers, this system offers invaluable insights into manufacturing compliance, but with important limitations between what is publicly accessible and what remains within the regulatory domain. The database aims to improve information sharing between regulators and the public, aid coordination of inspections, and help protect the medicine distribution chain by facilitating verification of legitimate actors [1].

Understanding EudraGMDP Access Levels

Public Access Capabilities and Limitations

The publicly accessible version of EudraGMDP provides several key data categories relevant to ATMP research:

• GMP Certificates: Confirm manufacturing compliance for specific sites [8]
• Manufacturing and Import Authorisations (MIA): Show authorized manufacturing activities [8]
• Non-Compliance Statements: Identify facilities with compliance issues [8]
• GDP Certificates: Verify good distribution practice compliance [9]
• Active Substance Registrations: Document registered API manufacturers [8]

However, the public interface has significant limitations. The EMA explicitly states that it "accepts no responsibility or liability whatsoever arising out of or in connection with the information on this database" and notes that any questions about content should be directed to the relevant National Competent Authorities [10]. This disclaimer highlights the potential reliability gaps that researchers must consider.

Additionally, certain modules remain entirely hidden from public view, including the planning module for National Competent Authorities to share inspection plans for manufacturers in third countries [9]. For ATMP researchers, this means limited ability to anticipate future regulatory actions or understand the complete compliance landscape.

Regulatory Access Privileges

Regulatory authorities within the EEA benefit from significantly enhanced access to EudraGMDP compared to public users:

• Full read and write access to the complete database [1]
• GMP inspection planning modules for manufacturers in third countries [1]
• Detailed inspection reports and comprehensive compliance histories [11]
• Unredacted assessment documentation not available publicly [11]

International regulatory partners with mutual recognition agreements also enjoy privileged access. For instance, the Japanese Ministry of Health, Labour and Welfare and Pharmaceuticals and Medical Devices Agency gained write access to the database as early as October 2013 [1]. This tiered access structure creates a significant information asymmetry between regulatory bodies and public researchers.

Table: EudraGMDP Access Level Comparison

Information Type	Public Access	Regulatory Access	ATMP Research Relevance
GMP Certificates	Limited view	Complete	Confirms manufacturing compliance
Non-compliance Statements	Available	Detailed with history	Identifies compliance risks
Inspection Reports	Not available	Complete	Reveals specific manufacturing issues
Inspection Planning	Not available	Full visibility	Anticipates future regulatory actions
Third-Country Manufacturer Data	Limited	Comprehensive	Global supply chain verification

Quantitative Analysis of Information Availability

Document Accessibility in Reliance Procedures

Recent survey data from regulatory reliance procedures reveals which EudraGMDP-related documents are most frequently utilized in global regulatory submissions. This data provides insight into which documents researchers might find most valuable when verifying manufacturing compliance for ATMPs.

Table: Regulatory Document Utilization in Reliance Pathways

Document Type	Utilization Frequency	Primary Use Case in ATMP Research
CPP/eCPP (Certificate of Pharmaceutical Product)	92%	Verification of product approval status
GMP Certificate	86%	Confirmation of manufacturing compliance
Approval Letter	86%	Understanding approved indications and limitations
Initial Marketing Authorization CTD Dossier	83%	Comprehensive product understanding
EMA Final CHMP Assessment Report	45%	Insight into regulatory decision-making

Data gathered from across EU pharmaceutical trade associations indicates that the European Medicines Agency is one of the most frequently selected reference regulatory authorities for reliance procedures due to its transparency and easy access to assessment information [11]. However, researchers should note that significant hurdles persist, including additional administrative requirements (66% of respondents) and demands for unredacted assessment reports (54%) [11].

EudraGMDP Data Verification Protocol for ATMP Researchers

Experimental Methodology for Manufacturing Site Verification

For ATMP researchers selecting manufacturing partners or verifying supply chain compliance, the following structured protocol leverages EudraGMDP data effectively:

Phase 1: Preliminary Database Screening

• Access the EudraGMDP public portal via the official EMA website
• Search by manufacturer name and location to identify relevant GMP certificates
• Verify certificate validity noting that all certificates are extended until end of 2024 unless a clarifying remark indicates a shorter validity [12]
• Cross-reference with organizational data in EMA's Organisation Management Service (OMS), which became the master data source for organization-related details from January 2022 [1]

Phase 2: Comprehensive Compliance Assessment

• Analyze clarifying remarks on GMP certificates for scope limitations
• Check for non-compliance statements which may indicate recent compliance issues
• Verify geographical scope noting that for the UK, EU Law applies only to Northern Ireland from 1.1.2021, with documents issued by UK authorities no longer updated except for Northern Ireland sites [10]
• Document the inspection history through certificate issuance patterns

Phase 3: Regulatory Intelligence Integration

• Compile manufacturing authorization details specific to ATMP capabilities
• Identify any regulatory restrictions through certificate annotations
• Document supply chain linkages through active substance registrations
• Generate compliance verification report for internal documentation

ATMP Manufacturing Verification Workflow

Table: Essential Research Reagents for EudraGMDP Analysis

Research Tool	Function	Access Method
EudraGMDP Public Database	Primary source for GMP certificates and compliance data	Public access via EMA website
EMA Organisation Management Service (OMS)	Verification of organization master data	Company registration required
GMP Certificate Validator	Verification of certificate authenticity and current status	EudraGMDP built-in functionality
Active Substance Registration Database	Supply chain mapping for critical starting materials	Public module within EudraGMDP
EMA Q&A Guidance Documents	Interpretation of complex regulatory requirements	EMA website publication
Reliance Survey Data	Understanding of global regulatory acceptance patterns	Industry association reports

Regulatory Framework and Compliance Pathways for ATMPs

Legal Foundations and Data Governance

The EudraGMDP database operates within a specific legal framework established by Directive 2004/27/EC amending Directive 2001/83/EC on human medicinal products [8]. For ATMPs specifically, the European Commission has published detailed guidelines on GMP specific to these products in accordance with Article 5 of Regulation (EC) No 1394/2007 on ATMPs [7]. These guidelines provide the GMP requirements that should be applied in the manufacturing of ATMPs that have been granted a marketing authorization and/or used in clinical trial settings.

The data governance of EudraGMDP is characterized by distributed responsibility. While the EMA maintains and operates the database, the content is provided by the National Competent Authorities of the EEA [10]. This distributed model means that data quality and timeliness can vary between jurisdictions, creating challenges for researchers seeking comprehensive ATMP manufacturing intelligence.

Advanced Access Protocols for Research Applications

For research applications requiring deeper regulatory insight, several advanced approaches can supplement the limited public access to EudraGMDP:

Clinical Trial Manufacturing Verification When researching ATMPs in development, verification of clinical trial manufacturing compliance requires understanding that "each supply chain site must have a GMP certificate to manufacture investigational medicinal products" [13]. The EudraGMDP database authenticates these certificates, which are mutually recognized across the EEA.

Supply Chain Mapping Documenting the complete ATMP supply chain requires accessing multiple data points within EudraGMDP, including active substance manufacturer registrations and import authorizations [8]. The database facilitates "verification of legitimate actors" in the supply chain, which is particularly crucial for ATMPs given their complex manufacturing processes [1].

Regulatory Intelligence Forecasting While public access doesn't include inspection planning modules, researchers can develop forecasting models based on certificate expiration dates and historical re-inspection patterns. This approach allows anticipation of potential regulatory actions that might impact ATMP manufacturing continuity.

The EudraGMDP database represents a significant resource for ATMP researchers, but its value is constrained by the fundamental asymmetry between public and regulatory access. Understanding these limitations is essential for designing robust research protocols in advanced therapy development. By systematically applying the verification methodologies outlined in this guide and leveraging the available public data while recognizing its constraints, researchers can make more informed decisions about manufacturing partnerships and regulatory strategy.

The evolving nature of EudraGMDP—including the ongoing transition to OMS as the master data source and the expansion of electronic certification—suggests that accessibility may improve over time [1]. However, the inherent tension between regulatory transparency and protection of commercially sensitive information will likely maintain some level of access asymmetry. For the ATMP research community, developing sophisticated approaches to maximize the utility of publicly accessible data while understanding its limitations remains an essential competency in the rapidly advancing field of advanced therapies.

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), the EudraGMDP database serves as a critical regulatory tool for verifying compliance across the manufacturing supply chain. Maintained by the European Medicines Agency (EMA), this database provides transparency into the regulatory status of manufacturers and distributors involved in ATMP production [8] [1]. ATMPs—encompassing gene therapies, somatic-cell therapies, and tissue-engineered products—represent a rapidly advancing field with complex manufacturing requirements [14]. The EudraGMDP database contains three essential data modules relevant to ATMP development: Manufacturing and Import Authorisations (MIA), Good Manufacturing Practice (GMP) Certificates, and Active Product Ingredient Registrations (API REG) [15]. Understanding how to access and interpret these data modules is crucial for ensuring regulatory compliance throughout the ATMP development lifecycle.

Core Data Modules in EudraGMDP

The EudraGMDP database integrates several key data modules that provide a comprehensive view of the regulatory compliance status for ATMP manufacturing. The following table summarizes these core modules:

Data Module	Scope and Purpose	Relevance to ATMPs
Manufacturing/Import Authorisation (MIA)	Authorisation required for any legal entity manufacturing medicinal products in the EU or importing from third countries [3].	Mandatory for all ATMP manufacturers [3]. The MIA is issued by the National Competent Authority of the Member State where the activities occur [8].
GMP Certificates	Certificates issued after successful inspections confirm compliance with Good Manufacturing Practice standards [8].	Critical for ATMPs due to complex manufacturing processes using biological materials [3]. Confirms adherence to GMP guidelines specific to ATMPs [3].
API Registrations	Registration of manufacturers, importers, and distributors of active substances used as raw materials in medicines [15].	Essential for tracing the origin and quality of biological active substances used in ATMPs [15].

The Manufacturing and Import Authorisation (MIA) serves as the foundational legal requirement for any entity involved in ATMP manufacturing within the EU [3]. This authorization verifies that the manufacturer has adequate facilities, equipment, and quality control systems, and employs a Qualified Person (QP) responsible for batch certification [3]. For ATMPs, which often use substances of human origin and have complex, personalized manufacturing processes, the MIA provides assurance that the manufacturer operates under standardized quality systems [3].

GMP Certificates within EudraGMDP provide evidence that a manufacturing site has undergone inspection and complies with the principles of Good Manufacturing Practice [8]. For ATMPs, the European Commission has issued detailed GMP guidelines specific to these products, addressing challenges such as maintaining sterility throughout manufacturing, controlling variability in biological materials, and validating process consistency despite small batch sizes [3]. These certificates are particularly important for ATMPs due to their complex manufacturing processes and the use of live biological materials with short shelf lives [3].

The Active Product Ingredient Registration (API REG) module tracks manufacturers, importers, and distributors of active substances used in medicinal products [15]. For ATMPs, this is crucial for tracing the origin and quality of biological active substances, ensuring they meet required standards before incorporation into the final product [15].

Regulatory Workflow for ATMP Compliance Verification

The process of verifying ATMP manufacturing compliance involves multiple steps and interactions between different regulatory bodies and the EudraGMDP database. The following diagram illustrates the key relationships and workflows:

This workflow demonstrates how ATMP developers interact with regulatory bodies and the EudraGMDP database throughout the product development lifecycle. The National Competent Authorities (NCAs) of EU Member States are responsible for issuing Manufacturing and Import Authorisations, conducting GMP inspections, and recording API registrations [8] [3]. The EMA maintains and operates the EudraGMDP database, while also providing scientific advice and ATMP classification services [14] [1]. Researchers and developers access the publicly available EudraGMDP database to verify the compliance status of manufacturing partners and suppliers [8].

Methodologies for Regulatory Data Verification

EudraGMDP Database Query Protocol

Verifying the compliance status of ATMP manufacturers and suppliers requires systematic querying of the EudraGMDP database. The following methodology outlines the standard operating procedure for regulatory due diligence:

• Access Point: Navigate to the publicly accessible EudraGMDP database through the EMA website. No login is required for public access, making this a readily available resource for researchers [15].

• Organisation Identification: Before querying the database, ensure you have the correct legal entity name and location details for the manufacturer, importer, or distributor. Since January 2022, organisation-related details in EudraGMDP are drawn from EMA's Organisation Management Service (OMS), ensuring consistency across systems [1].

• Module-Specific Search Strategies:

  • For MIA verification: Search by the manufacturer's name and country to confirm they hold a valid Manufacturing and Import Authorisation for the specific activities being performed [8].
  • For GMP compliance checking: Search the GMP certificate module using the manufacturer's details to verify the existence and validity of GMP certificates issued after successful inspections [8] [1].
  • For API traceability: Query the API registration module to confirm that active substance manufacturers, importers, or distributors have registered their activities with the relevant National Competent Authority [15].

• Data Interpretation: Note that EudraGMDP content is provided by National Competent Authorities, and the EMA accepts no responsibility for the accuracy of this third-party content [8]. Always verify critical compliance information directly with the relevant NCA when making significant decisions.

Manufacturing Authorisation Application Process

For researchers transitioning into ATMP development, understanding the Manufacturing Authorisation application process is essential:

• Pre-application Preparation: Engage with the National Competent Authority early for scientific advice and guidance. Prepare documentation demonstrating compliance with EU GMP standards, particularly the specific guidelines for ATMPs [3].

• Technical Documentation: Submit comprehensive technical documentation covering pharmaceutical quality, manufacturing process details, quality control procedures, and stability data. For ATMPs, this should specifically address challenges such as the use of substances of human origin, limited shelf life, and complex logistics [3].

• Facility Readiness: Ensure manufacturing facilities, equipment, and quality systems are GMP-compliant before inspection. Implement a pharmaceutical quality system that addresses ATMP-specific challenges like maintaining sterility throughout manufacturing and controlling variability of biological materials [3].

• Qualified Person: Designate a Qualified Person (QP) responsible for certifying that each batch of ATMP has been manufactured and tested in accordance with requirements [3].

Resource	Function & Application	Access Point
EudraGMDP Database	Primary source for verifying manufacturing authorisations, GMP compliance, and API registrations for ATMP supply chain partners [8] [1].	EMA Website
EMA ATMP Classification	Scientific recommendation on whether a product meets the definition of an ATMP; crucial for determining applicable regulatory requirements [14] [16].	EMA CAT Procedure
GMP Guidelines for ATMPs	Specific EU guidelines on Good Manufacturing Practice for ATMPs, addressing their unique characteristics and manufacturing challenges [3].	European Commission
Organisation Management Service (OMS)	Master database for organisation-related details; must be correctly recorded before applying for manufacturing authorisations [1].	EMA OMS
National Competent Authorities (NCAs)	Issue manufacturing authorisations, conduct GMP inspections, and provide regulatory guidance at the member state level [3].	National Agencies

This toolkit provides researchers with essential resources for navigating the complex regulatory landscape for ATMPs. The EudraGMDP database serves as the central verification tool, while the EMA's ATMP classification procedure helps determine the appropriate regulatory pathway [14]. The specific GMP guidelines for ATMPs address unique manufacturing challenges such as the use of substances of human origin, limited shelf life, and complex logistics [3]. Proper registration in the Organisation Management Service (OMS) is a prerequisite for manufacturing authorisation applications since 2022 [1]. Finally, National Competent Authorities provide member state-specific regulatory oversight and support throughout the ATMP development process [3].

For researchers and drug development professionals working with Advanced Therapy Medicinal Products, the EudraGMDP database provides an essential window into the regulatory compliance of manufacturing operations. The three core data modules—Manufacturing and Import Authorisations, GMP Certificates, and API Registrations—offer a comprehensive framework for verifying that ATMP manufacturers and their supply chains operate in compliance with EU regulatory requirements. As the ATMP field continues to evolve, with increasing numbers of therapies reaching clinical development and marketing authorisation stages [16], understanding how to effectively utilize these regulatory tools becomes increasingly important. By systematically applying the verification methodologies and resources outlined in this guide, researchers can better navigate the complex regulatory landscape for these innovative therapies, ultimately contributing to the development of safe and effective ATMPs for patients.

The EudraGMDP database is the European Union's central repository for information on manufacturing and import authorisations, as well as Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) certificates for both human and veterinary medicinal products [1]. Established and maintained by the European Medicines Agency (EMA), this database serves a critical function in the regulatory ecosystem by enhancing transparency and information sharing among regulators, the pharmaceutical industry, and the public [8]. For researchers and developers working with Advanced Therapy Medicinal Products (ATMPs)—a category encompassing gene therapies, somatic-cell therapies, and tissue-engineered medicines—understanding the legal framework governing EudraGMDP is essential for ensuring regulatory compliance throughout the product development lifecycle [14].

The legal foundation for EudraGMDP was established to facilitate several key objectives: improving information sharing between regulators and the public, aiding coordination of inspections for manufacturers in third countries, eliminating the need for industry to submit paper documents to support marketing-authorisation applications, and protecting the medicine distribution chain by verifying legitimate actors [1]. For ATMPs specifically, which are often characterized by complex manufacturing processes and the use of substances of human origin, compliance with the legal requirements documented in EudraGMDP is particularly crucial due to the sophisticated nature of these therapies and their potential risks if improperly manufactured or distributed [14] [7].

Core Legal Framework and Governing Documents

Primary Legislation

The EudraGMDP database operates under a structured hierarchy of legal instruments, with Directives and Regulations establishing its fundamental existence and operational requirements. The following table summarizes the core legal documents that form the primary basis for the database:

Table 1: Primary Legal Acts Governing the EudraGMDP Database

Legal Act	Type	Key Provision	Relevance to EudraGMDP
Directive 2001/83/EC (as amended)	Directive	Article 111(6) [8] [17]	Mandates the establishment of a Union database containing manufacturing/import authorizations and GMP/GDP certificates.
Regulation (EU) 2019/6	Regulation	Article 91(3) [10]	Governs veterinary medicinal products and requires GMP certificates to be entered into EudraGMDP.
Directive 2001/82/EC	Directive	Article 80(6) [17]	Provides the veterinary medicinal products equivalent to Directive 2001/83/EC.
Regulation (EC) No 1394/2007	Regulation	Specific to ATMPs [14]	Provides the legal framework for ATMPs, which are centrally authorized and recorded in EudraGMDP.

Directives require transposition into national law by Member States, while Regulations are directly applicable across the EU. This combination ensures both the existence of the database at the Union level and its operational integration into national regulatory systems [8]. The legal framework has evolved, with the concept of a European inspections database first introduced by amending Directives 2004/27/EC and 2004/28/EC [8]. The system was first launched in April 2007, with subsequent expansions adding GMP non-compliance information (2009), inspection planning for third-country manufacturers (2012), and GDP information with active substance manufacturer registrations (2013) [1].

Specific Provisions for Advanced Therapy Medicinal Products

ATMPs are subject to the same fundamental GMP and GDP requirements as other medicinal products but are governed by additional specific regulations due to their unique characteristics. Regulation (EC) No 1394/2007 is the central legal framework for ATMPs, establishing specific requirements for their authorization and supervision [14]. According to this regulation, all ATMPs must be authorized centrally via the EMA, benefiting from a single evaluation and authorization procedure [14]. This centralized authorization makes the EudraGMDP database particularly crucial for ATMPs, as it provides the unified platform for tracking their manufacturing and distribution compliance across the entire European Economic Area.

The European Commission has published specific GMP guidelines for ATMPs under Article 5 of Regulation (EC) No 1394/2007, adapting standard GMP requirements to the particular characteristics of these complex products [7]. Furthermore, utilizing substances of human origin (such as blood, tissues, and cells) in ATMP manufacture requires compliance with additional legislative frameworks, including Directive 2002/98/EC and Directive 2004/23/EC, along with their associated implementing directives concerning procurement, donation, and testing [18]. These specific legal provisions for ATMPs are fully integrated into the EudraGMDP system, ensuring that the unique manufacturing and distribution challenges of advanced therapies are properly monitored and regulated.

Operational Mechanics and Legal Integration

Certificate and Authorization Management

The EudraGMDP database functions through a sophisticated legal framework that mandates what information must be recorded, who is responsible for submitting it, and under which specific legal provisions. The following table details the key document types managed within EudraGMDP and their governing legal bases:

Table 2: Legal Basis for Key Document Types in EudraGMDP

Document Type	Governing Legal Provision	Responsible Entity	Legal Requirement
GMP Certificate	Directive 2001/83/EC, Article 47; Regulation (EU) 2019/6, Article 93(2) [10]	National Competent Authority	To be entered into EudraGMDP per Article 111(6) of Directive 2001/83/EC and Article 91(3) of Regulation (EU) 2019/6 [10].
GDP Certificate	Directive 2001/83/EC, Article 111(6) [19]	National Competent Authority	Shall be entered into EudraGMDP in accordance with Article 111(6) of Directive 2001/83/EC as amended [19].
Manufacturing/Import Authorisation (MIA)	Directive 2001/83/EC [8]	National Competent Authority	Issued by the Member State where the manufacturer or importer operates [8].
Wholesale Distribution Authorisation	Directive 2001/83/EC [8]	National Competent Authority	Issued by the Member State where the wholesale distributor operates [8].
Active Substance Manufacturer/Importer/Distributor Registration	Directive 2001/83/EC [8]	Manufacturer/Importer/Distributor	Required to register activities with the National Competent Authority [8].

The legal framework establishes clear responsibilities for data submission. National Competent Authorities (NCAs) of EEA Member States possess full read and write access to EudraGMDP and are responsible for entering the data as it becomes available [1]. Several international regulatory partners also have unrestricted read access, with some mutual recognition agreement partners like Japan's MHLW and PMDA having write access to replace paper certificate exchanges [1]. This international dimension highlights how the legal framework facilitates global regulatory cooperation while maintaining the integrity of the EU pharmaceutical supply chain.

Recent Regulatory Evolution and Organizational Requirements

The legal framework governing EudraGMDP has continued to evolve, with significant updates in recent years enhancing data reliability and system interoperability. A crucial development came into effect on 28 January 2022, requiring manufacturers, importers, and distributors to ensure their organization-related details are correctly recorded in EMA's Organisation Management Service (OMS) before applying to national competent authorities for new or updated manufacturing authorizations, GMP compliance certificates, wholesale distribution authorizations, or registrations as active substance manufacturers, importers, or distributors [1]. This change supports the entry into force of the Veterinary Medicinal Products Regulation (Regulations (EU) 2019/6 and 2021/16, Article 9(h)), aiming to ensure more reliable data in EudraGMDP through the consistent use of organization master data, reduce the need for data entry and cleansing, and enhance the interoperability of IT systems [1].

This evolution in the legal technical requirements demonstrates a shift toward more integrated and standardized regulatory data management. Until further notice, these OMS requirements do not apply to GDP compliance certificates for companies distributing human and veterinary medicines, whose organization-related details can continue to be registered directly in EudraGMDP [1]. For ATMP developers, this streamlined approach to organization data management reduces administrative burden while increasing data consistency across the regulatory landscape—a particularly valuable benefit for organizations navigating the complex framework governing advanced therapies for the first time.

Practical Implementation for ATMP Researchers

Regulatory Pathway Visualization

The relationship between the legal framework, regulatory bodies, and ATMP developers in the context of EudraGMDP involves multiple interconnected components. The following diagram illustrates this regulatory ecosystem and information flow:

This diagram illustrates how the legal instruments mandate the database establishment, how regulatory bodies interact with the system, and what responsibilities ATMP developers have within this framework. The dashed line indicates the more recent OMS registration requirement that enhances data reliability [1].

Essential Research Toolkit for Regulatory Compliance

For researchers and drug development professionals working with ATMPs, navigating the EudraGMDP legal framework requires familiarity with key resources and processes. The following table serves as a strategic toolkit for ensuring compliance with the legal requirements documented in the database:

Table 3: Essential Regulatory Toolkit for ATMP Researchers

Resource/Process	Function in Legal Compliance	Relevance to ATMP Development
EudraGMDP Public Database	Verification of manufacturing authorizations and GMP/GDP compliance of suppliers and contractors [1] [8].	Essential for due diligence on contract manufacturing organizations (CMOs) for ATMP production.
EMA's Organisation Management Service (OMS)	Master data source for organization details required for regulatory submissions since January 2022 [1].	Critical first step for ATMP developers before applying for manufacturing authorizations.
GMP/GDP Q&A Documents	Regulatory interpretation of EU GMP/GDP guidelines, maintained by the GMP/GDP Inspectors Working Group [5].	Provides clarity on complex GMP applications for novel ATMP manufacturing processes.
ATMP Classification Procedure	Formal process to determine whether a product qualifies as an ATMP [14].	Fundamental first regulatory step with significant implications for development pathway.
Committee for Advanced Therapies (CAT)	Scientific assessment body for ATMPs within EMA [14].	Provides recommendations on ATMP classification and evaluation during marketing authorization.
Specific GMP Guidelines for ATMPs	Adapted GMP requirements addressing specific characteristics of ATMPs [18] [7].	Tailored quality standards for complex ATMP manufacturing scenarios.

This toolkit provides ATMP researchers with essential resources for navigating the legal landscape. Particularly critical for ATMP developers is the ATMP classification procedure, which determines the regulatory pathway, and engagement with the Committee for Advanced Therapies (CAT), which provides the specialized expertise needed to evaluate these innovative products [14]. Furthermore, developers should note that ATMPs are eligible for significant fee reductions—65% for scientific advice (90% for SMEs) and 90% for the certification procedure—which can substantially reduce the financial burden of regulatory compliance [18].

The EudraGMDP database operates within a robust and evolving legal framework established by key Directives and Regulations that mandate its existence, structure, and content. For developers and researchers of Advanced Therapy Medicinal Products, understanding this legal basis is not merely an administrative exercise but a fundamental component of successful product development and regulatory strategy. The framework continues to adapt to technical advancements, as evidenced by the implementation of the Organisation Management Service requirement, demonstrating the European medicines regulatory network's commitment to enhancing data reliability and system interoperability. As the ATMP field continues to advance at a rapid pace, this solid legal foundation for manufacturing and distribution compliance provides both the necessary oversight for patient safety and the predictable structure needed to foster innovation in this cutting-edge therapeutic domain.

Advanced Therapy Medicinal Products (ATMPs)—encompassing gene therapies, somatic-cell therapies, and tissue-engineered products—represent a frontier in medical treatment, characterized by complex manufacturing processes and rigorous regulatory oversight [14]. Within the European Union, the regulatory framework for these innovative medicines is anchored by a collaborative governance model shared between the European Medicines Agency (EMA) and the National Competent Authorities (NCAs) of member states. This partnership is critical for ensuring that ATMPs meet the stringent standards for quality, safety, and efficacy required for patient administration. A cornerstone of this collaborative regulatory effort is the EudraGMDP database, a centralized system that facilitates the management and transparency of manufacturing and distribution authorizations, as well as Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) certificates [1]. This technical guide delineates the distinct and interconnected roles of the EMA and NCAs in managing this vital database, providing researchers and drug development professionals with a clear understanding of the operational infrastructure supporting ATMP regulation in the EU.

The EudraGMDP Database: Scope and Technical Architecture

Core Purpose and Functionality

The EudraGMDP database serves as the official Community repository for information pertaining to manufacturing and import authorizations, wholesale distribution authorisations, and GMP/GDP compliance certificates [1]. Its primary functions are multifaceted, designed to serve both regulatory bodies and the public. Technically, the database aims to improve information sharing between regulators and the public, aid in the coordination of inspections of manufacturers in third countries among NCAs, and eliminate the need for the pharmaceutical industry to submit paper documents to support marketing-authorisation applications [1]. Furthermore, it plays a crucial role in protecting the integrity of the medicine distribution and active-substance supply chains by facilitating the verification of legitimate actors.

Data Structure and Integration

A significant evolution in the database's technical architecture has been its integration with the EMA’s Organisation Management Service (OMS). Since January 2022, all organizations regulated through EudraGMDP—including EU and non-EU manufacturers, importers, and distributors of human and veterinary medicinal products and active substances—must be correctly registered in the OMS [1] [20]. This integration mandates that NCAs select organization name and address details from the OMS dictionary rather than manually entering this data, thereby ensuring more reliable data, reducing data entry redundancy, and enhancing the interoperability of IT systems [20]. The public version of EudraGMDP provides access to non-confidential information, promoting transparency while safeguarding commercially sensitive data [1].

Table: Key Data Categories in the EudraGMDP Database

Data Category	Description	Key Stakeholders
Manufacturing & Import Authorisations	Licenses granted to sites for producing or importing medicines.	NCAs, Manufacturing Sites
GMP/GDP Certificates	Documents certifying compliance with Good Manufacturing/Distribution Practice standards.	Inspectors, Quality Assurance
Statements of Non-Compliance	Public declarations of sites failing to meet GMP/GDP standards.	Regulators, Public
Active Substance Registrations	Records for manufacturers, importers, & distributors of active substances.	Supply Chain Actors

Distinct Roles and Responsibilities

European Medicines Agency (EMA): Centralized Stewardship

The EMA holds the central stewardship role for the EudraGMDP system. The Agency is responsible for the overall development, maintenance, and technical operation of the database [1]. This includes implementing system upgrades and ensuring its stability and accessibility for users across the EEA and internationally. Furthermore, the EMA provides critical guidance and support to national authorities and industry users, such as organizing webinars on new procedures like the OMS integration [20]. The EMA also facilitates international regulatory collaboration; several international partners, including the Japanese MHLW and PMDA, have read access to the database, and some have write access to support mutual recognition agreements [1].

National Competent Authorities (NCAs): Operational Data Management

The NCAs of member states are vested with the primary operational responsibility for data entry and management within EudraGMDP. They possess full read and write access to the database, which they use to input and update information as it becomes available [1]. Their key responsibilities include uploading data related to manufacturing and import authorizations, GMP/GDP certificates, and statements of non-compliance issued within their jurisdiction. NCAs are also responsible for using the database's planning module—not visible to the public—to coordinate inspection plans for manufacturers in third countries, thereby avoiding duplicate inspections and optimizing regulatory resources [1]. The accuracy and timeliness of the data within EudraGMDP are fundamentally dependent on the diligent actions of the NCAs.

Regulatory Workflows and Interactions

The management of ATMPs within the EU regulatory framework involves precise workflows and interactions between the EMA, NCAs, and marketing authorization holders. The diagram below illustrates the core regulatory oversight process for ATMP manufacturing and licensing, highlighting the flow of information and responsibilities.

The Hospital Exemption Pathway

A critical and complex aspect of ATMP regulation is the Hospital Exemption (HE) pathway. This clause allows ATMPs prepared on a non-routine basis and used within a single member state under the exclusive responsibility of a medical practitioner to be exempt from the centralised marketing authorization procedure [21] [22]. For HE ATMPs, the role of the NCA is paramount. The NCA of the member state is responsible for authorizing the manufacture of the exempted product and ensuring that national traceability, pharmacovigilance, and quality standards are equivalent to those applicable to centrally authorized ATMPs [22]. However, the implementation of the HE pathway has led to significant heterogeneity across member states, with divergences in the interpretation of "non-routine basis," "custom-made product," and the specific quality standards required [21] [22]. This has created regulatory challenges and highlighted the need for greater harmonization. The European Commission's 2023 proposal to revise pharmaceutical legislation includes measures to improve data collection and reporting on ATMPs used under HE, which would involve NCAs annually transferring data to the EMA, which would then manage a central repository [22].

Practical Research Guide: Utilizing EudraGMDP for ATMP Development

For researchers and drug development professionals, the EudraGMDP database is an indispensable tool for due diligence and regulatory intelligence.

Methodologies for Database Interrogation

A systematic approach to searching the database is crucial for obtaining accurate and comprehensive information. The following protocol outlines the key steps:

• Organization Verification via OMS: Before initiating a search, verify the correct and official details of the manufacturing or distribution organization in the Organisation Management Service (OMS). Since January 2022, EudraGMDP relies on OMS master data, ensuring consistency [1] [20].
• Structured Search Strategy: Use the public EudraGMDP interface to search by organization name, location, or specific certificate number. Filters can be applied to narrow results by activity type (e.g., "Manufacture of ATMPs"), product type, and country.
• Data Point Extraction and Analysis: Extract key data points from the search results, including the organization's activities, the status and date of the most recent GMP inspection, and any statements of non-compliance. This data is critical for assessing the compliance history and regulatory standing of a potential manufacturing partner.

Table: Essential Research Reagents for EudraGMDP Analysis

Research Tool	Function in Regulatory Research	Access Point
OMS (Organisation Management Service)	Provides verified master data for organizations, ensuring accurate identification in EudraGMDP searches.	EMA OMS System
EudraGMDP Public Interface	Primary tool for retrieving GMP certificates, manufacturing authorizations, and compliance statements.	EMA EudraGMDP Website
EMA Medicines Catalogue	Reference list of centrally authorized ATMPs, providing context for Hospital Exemption analyses.	EMA Website
HMA-EMA RWD Catalogue	For post-authorization studies; assesses real-world data sources used in safety monitoring.	HMA/EMA Catalogues

Application in ATMP Development Lifecycle

The information derived from EudraGMDP is critical at multiple stages of the ATMP lifecycle. During vendor qualification for contract manufacturing, the database provides an official record of a site's GMP compliance status. For regulatory strategy development, understanding the landscape of HE approvals across different NCAs can inform decisions on whether to pursue a centralized marketing authorization or a national HE pathway [21]. Furthermore, the post-authorization safety monitoring of ATMPs increasingly incorporates real-world data (RWD). A 2025 study found that 41.5% of post-authorization measures for ATMPs involved RWD, with registries being a primary source [23]. While not directly part of EudraGMDP, this trend underscores the importance of robust data management systems throughout a product's lifecycle, a principle embodied by the EudraGMDP database for manufacturing and distribution oversight.

The effective regulation of Advanced Therapy Medicinal Products in the European Union hinges on a sophisticated and collaborative database management system shared by the EMA and National Competent Authorities. The EudraGMDP database embodies this partnership, with the EMA providing centralised system stewardship and international coordination, and the NCAs fulfilling the critical role of operational data entry and national-level oversight. For researchers and drug development professionals, a nuanced understanding of this structure, including the distinct roles and their interaction in pathways like the Hospital Exemption, is not merely academic. It is a practical necessity for navigating the regulatory landscape, ensuring compliance, and ultimately advancing safe and effective innovative therapies to patients. The ongoing integration with the OMS and proposed reforms for better data collection on exempted ATMPs signal a continuous evolution of this system toward greater reliability, transparency, and interoperability.

Navigating the Regulatory Pathway: From Application to ATMP Manufacturing Authorization

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), navigating the EudraGMDP database is essential for regulatory compliance. A critical prerequisite step is the registration in the Organisation Management Service (OMS), which provides the master data for organizations involved in the manufacture of human and veterinary medicines [1].

From 28 January 2022, manufacturers, importers, and distributors must ensure their organization-related details are correctly recorded in the EMA's OMS before applying to National Competent Authorities (NCAs) for any new or updated Manufacturing and Importation Authorisation (MIA), GMP compliance certificate, Wholesale Distribution Authorisation, or registration of an active substance manufacturer, importer, or distributor [1]. This mandate supports the Veterinary Medicinal Products Regulation and aims to ensure more reliable data in EudraGMDP via the consistent use of organization master data, reducing the need for data entry and cleansing while enhancing the interoperability of IT systems [1].

Table: Key Mandates for OMS Registration in EudraGMDP Processes

Affected Activity	OMS Requirement Effective From	Applicable To
Manufacturing & Importation Authorisation (MIA)	28 January 2022	All EU and non-EU manufacturers and importers
GMP Compliance Certificate	28 January 2022	All EU and non-EU manufacturers
Wholesale Distribution Authorisation	28 January 2022	All EU and non-EU distributors
Active Substance Manufacturer/Importer/Distributor Registration	28 January 2022	All EU and non-EU active substance entities

Experimental Protocol: OMS Registration and Data Verification Workflow

This methodology details the procedural steps for an organization to verify and, if necessary, correct its data in the OMS before proceeding with a regulatory submission to an NCA.

Phase 1: Preliminary OMS Data Assessment

• Objective: To determine the current OMS registration status and accuracy of the organization's master data.
• Procedure:
  • Access the EudraGMDP Database: Navigate to the public version of the EudraGMDP database to search for your organization.
  • Data Verification Check: Cross-reference the organization's legal name, address, and other identifying details as they appear in EudraGMDP against your official internal documents.
  • Gap Analysis: Document any discrepancies, inaccuracies, or missing data found during the verification process.

Phase 2: OMS Data Remediation

• Objective: To submit corrections to ensure the organization's master data in OMS is accurate and complete.
• Procedure:
  • Initiate Change Request: If discrepancies are identified in Phase 1, submit a formal change request directly through the OMS platform [1].
  • Provide Supporting Documentation: Include all necessary legal and corporate documents that validate the correct organization details as part of the change request submission.
  • Await Confirmation: Monitor the status of the change request until a confirmation of successful data update is received from the OMS system.

Phase 3: Regulatory Application Submission

• Objective: To successfully submit a regulatory application to an NCA using the validated OMS master data.
• Procedure:
  • Confirm OMS Readiness: Ensure the OMS change request is fully processed and the master data is correct before initiating the application with the NCA.
  • Liaise with National Competent Authority (NCA): Engage with the relevant NCA for the application process. Per the new mandate, NCAs will no longer manually enter organization-related details into EudraGMDP but will rely exclusively on the master data held in OMS [1].
  • Reference OMS Code: Utilize the unique organization identifier from OMS in all communications and documentation submitted to the NCA.

Diagram 1: OMS registration and data verification workflow.

The Scientist's Toolkit: Essential Research and Regulatory Reagents

For professionals navigating the EudraGMDP and OMS landscape, the following "research reagents" are essential informational and procedural components.

Table: Essential Toolkit for EudraGMDP and OMS Research

Tool / Resource	Function / Purpose	Source / Location
Organisation Management Service (OMS)	Central repository for organization master data; mandatory for accurate identification in regulatory submissions.	EMA Organisation Management Service
EudraGMDP Public Database	Community database for verifying manufacturing/import authorisations, GMP/GDP certificates, and active substance registrations.	EMA EudraGMDP database [1]
Compilation of Union Procedures	Contains the official Union formats for API Registration Certificates and Manufacturing/Importation Authorisations.	Compilation of Union Procedures (revision 19.1) [24] [25]
GMP/GDP Inspectors Working Group Q&A	Provides critical interpretation of EU GMP guidelines, including contractual requirements between MAHs and MIA holders.	EMA Guidance on GMP and GDP [5]
National Competent Authorities (NCA) List	Essential for addressing content questions and submitting manufacturing authorisation applications linked to OMS data.	Available via the EudraGMDP database [25] [3]

Regulatory Context for ATMP Manufacturing Licenses

The requirement for OMS registration is framed within the broader regulatory context for ATMPs. Any legal entity manufacturing medicinal products in the EU must hold a manufacturing authorisation issued by the NCA of the Member State where the activities are carried out [3]. This authorisation is a prerequisite for GMP compliance, which for ATMPs involves unique challenges such as the use of substances of human origin, complex manufacturing processes, and extreme logistical complexity due to short shelf-lives [3].

The Manufacturing and Importation Authorisation (MIA) document itself follows a Union format established in accordance with Article 47 of Directive 2001/83/EC and is published in the Compilation of Union Procedures [25]. These authorisations are entered into the EudraGMDP database, as referred to in Article 40(4) of the same directive [25]. For the Qualified Person (QP) responsible for batch certification, a direct written contract must be in place with the Marketing Authorisation Holder (MAH), and robust contractual arrangements must govern relationships with all contract manufacturers, ensuring clear definition of activities and responsibilities [5]. The OMS system ensures that all these entities are uniquely and consistently identified throughout this complex regulatory chain.

The Manufacturing and Import Authorisation (MIA) Application Process

The Manufacturing and Import Authorisation (MIA) is a mandatory regulatory requirement for any legal entity intending to manufacture medicinal products within the European Union (EU) or import them from third countries into the European Economic Area (EEA) [3] [26]. This authorization process ensures that all pharmaceutical activities, including those for Advanced Therapy Medicinal Products (ATMPs), comply with stringent EU quality standards, primarily Good Manufacturing Practice (GMP) principles [8] [3]. The MIA framework is established under Article 40 of Directive 2001/83/EC for human medicinal products and relevant articles of Regulation (EU) 2019/6 for veterinary products [25] [3].

The national competent authorities (NCAs) of individual EU Member States assess applications and issue MIAs, which are then recorded in the centralized EudraGMDP database maintained by the European Medicines Agency (EMA) [25] [8] [26]. For manufacturers of ATMPs, this process presents unique challenges due to product complexity, the use of substances of human origin, and often limited shelf life, requiring particularly close interaction with regulators throughout the application journey [3].

MIA Application Types and Classification

The MIA licensing framework distinguishes between different authorization types based on the intended product scope and manufacturing activities. The European legislation mandates separate applications for different product categories, each with distinct regulatory bases and oversight requirements [27].

Table: Types of Manufacturing and Import Authorisations

Authorisation Type	Legislative Scope	Permitted Activities
MIA for Human Medicines	Directive 2001/83/EC [27]	Manufacturing and importation of medicinal products for human use from countries outside the EEA [27]
MIA for Veterinary Medicines (V MIA)	Regulation (EU) 2019/6 [27]	Manufacturing, testing, and importation of medicinal products for veterinary use from third countries [27]
MIA for Investigational Medicinal Products (IMP MIA)	Clinical Trials Framework [27]	Manufacturing and importation of IMPs for human use in clinical trials from countries outside the EEA [27]

Pre-Submission Phase: Preparation and Regulatory Interaction

Strategic Planning and Readiness Assessment

Companies should initiate preparations significantly in advance of the formal application, ideally six months or more before the intended submission date [27]. This phase involves developing a comprehensive pharmaceutical quality system and completing high-level qualification activities for premises and equipment [27]. For ATMP manufacturers, this includes addressing unique challenges such as maintaining sterility throughout complex processes, managing variability in biological materials, and establishing rigorous monitoring systems for starting materials of human origin [3].

Pre-Submission Meeting with Competent Authorities

Applicants should formally request a pre-submission meeting with the relevant NCA approximately six months before planned application submission [27]. During this meeting, companies present their manufacturing activities and seek clarification on application requirements and inspection expectations [27]. Regulatory objectives for this interaction include providing companies with guidance to successfully navigate the legislative timeline and discussing key project milestones [27].

For complex manufacturing scenarios such as ATMPs with decentralized production sites, early regulatory dialogue is particularly crucial to address evolving regulatory considerations for multi-site manufacturing [3]. Companies establishing new facilities or significantly upgrading existing sites can also request facility design reviews with GMP inspectors to evaluate qualification and validation planning [27].

Application Submission and Assessment Workflow

Formal Application Process

Following successful pre-submission interactions, the NCA provides the formal MIA application form when the company confirms readiness for inspection within 4 to 6 weeks [27]. The complete application dossier must demonstrate comprehensive compliance with GMP requirements and include all necessary technical documentation supporting the manufacturing and quality control processes [3].

A critical prerequisite for application submission is verifying the organization's registration in the Organisation Management Service (OMS), as EudraGMDP integration with OMS now requires all manufacturing sites to be correctly registered before authorities can issue documents [15] [28]. The OMS change request process typically takes 5-10 working days, which applicants must factor into their submission timeline [28].

GMP Inspection and Site Evaluation

The cornerstone of the MIA assessment process is the on-site GMP inspection conducted by the NCA [8] [15]. Inspectors evaluate whether the manufacturing site complies with EU GMP standards, covering facilities, equipment, personnel, documentation, quality control, and the pharmaceutical quality system [8] [15]. For ATMPs, inspections particularly focus on control of aseptic processes, validation of complex manipulation steps, and control of starting materials of human or biological origin [3].

The Role of the Qualified Person

A fundamental requirement for MIA holders is the presence of a Qualified Person (QP), who bears legal responsibility for ensuring that each product batch has been manufactured and tested in compliance with the authorization and regulatory requirements [3] [26]. The QP must possess specific expertise and qualifications defined in EU directives and is responsible for batch certification and release before products can be placed on the market [3] [26].

Post-Authorization Requirements and Compliance

Authorization Issuance and EudraGMDP Registration

Upon successful application assessment and GMP inspection, the NCA issues the MIA, which is subsequently recorded in the EudraGMDP database [25] [26]. National authorities like the Danish Medicines Agency and the Irish Health Products Regulatory Authority (HPRA) automatically submit authorized MIAs to EudraGMDP, making them publicly accessible for verification [27] [26]. Electronic authorisations in EudraGMDP have the same legal validity as hard copies, and most authorities no longer routinely issue physical documents [27].

Ongoing Compliance and Surveillance

MIA holders must maintain continuous GMP compliance and are subject to regular re-inspection by NCAs [3] [15]. The authorization remains valid provided the holder continues to meet the approved conditions and complies with pharmacovigilance requirements where applicable [3]. For ATMP manufacturers, maintaining compliance is particularly challenging due to process complexity and the need for continuous quality monitoring of variable biological materials [3].

Table: Key Regulatory Interactions Throughout the MIA Lifecycle

Process Stage	Primary Regulatory Contact	Key Activities & Objectives
Pre-Submission	National Competent Authority (NCA) [27] [3]	Pre-submission meetings; Facility design review; Regulatory guidance [27] [3]
Application Assessment	NCA Inspection Team [8] [15]	Documentation review; On-site GMP inspection; Compliance verification [8] [15]
Post-Authorization	NCA & EMA [3]	Regular surveillance inspections; Variation assessments; Compliance monitoring [3]
European Coordination	EMA & GMP/GDP IWG [3]	Harmonized GMP interpretation; Guideline development; Inspection coordination [3]

ATMP-Specific Considerations in the MIA Process

Special Challenges in ATMP Manufacturing Authorization

ATMP manufacturers face unique regulatory challenges throughout the MIA process, including extreme logistical complexity in managing patient cell collection, transportation, and final product delivery [3]. Additional hurdles include demonstrating process consistency despite biological variability, validating manufacturing processes with limited batch sizes, and managing high production costs associated with specialized facilities and personnel [3]. The limited shelf life of many ATMPs necessitates particularly robust logistical and quality control systems [3].

Regulatory Support for ATMP Developers

Recognizing these challenges, regulatory authorities provide specialized support mechanisms for ATMP developers. The EMA offers scientific advice and protocol assistance specifically tailored to ATMPs [3]. The Innovation Task Force (ITF) at EMA provides a multidisciplinary forum for early dialogue with developers of emerging therapies and technologies [29]. For smaller enterprises, the SME Office at EMA offers administrative assistance, fee reductions, and regulatory guidance [29].

Essential Documentation and Technical Reagents

The MIA application requires comprehensive technical documentation demonstrating GMP compliance and manufacturing capability. While the specific documentation requirements vary by product type and manufacturing activities, certain core elements are essential for all applications.

Table: Essential Research and Documentation Requirements for MIA Applications

Documentation Category	Purpose and Function	Regulatory Reference
Pharmaceutical Quality System Documentation	Demonstrates robust quality management covering all manufacturing and control activities [27] [3]	EU GMP Guidelines [3]
Site Master File	Provides comprehensive information about manufacturing premises, equipment, and operations [3]	EudraGMDP Requirements [8]
Quality Control Testing Methodologies	Validates analytical procedures for raw materials, intermediates, and finished products [3]	European Pharmacopoeia [3]
Process Validation Protocols	Demonstrates manufacturing process consistency, particularly challenging for variable ATMPs [3]	GMP Guidelines Specific to ATMPs [3]
Qualified Person Declaration	Confirms the appointment and qualifications of the responsible QP [3] [26]	Directive 2001/83/EC [3]
OMS Registration Proof	Verifies organization and site registration in the Organisation Management Service [28]	EudraGMDP Integration Requirements [28]

The MIA application process represents a critical regulatory pathway ensuring that medicinal products manufactured in or imported to the EEA meet stringent quality and safety standards. For ATMP developers, navigating this process requires careful planning, early regulatory engagement, and particular attention to product-specific challenges. The integration of authorized sites in the EudraGMDP database enhances transparency and provides a verification mechanism for regulatory compliance across the European pharmaceutical landscape. Through structured preparation and understanding of regulatory expectations, manufacturers can successfully obtain the necessary authorizations to bring innovative therapies to patients while maintaining the highest quality standards.

For any medicinal product intended for the European Union market, adherence to Good Manufacturing Practice (GMP) is a mandatory legal requirement, regardless of where in the world the manufacturer is located [30]. GMP is defined in EU law as “the part of the quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use” [7]. Its fundamental purpose is to ensure that medicines are of consistent high quality, are appropriate for their intended use, and meet the requirements of the marketing authorisation or clinical trial authorisation [30]. For Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products, demonstrating GMP compliance is particularly critical due to their inherent complexity, the use of substances of human origin, and often limited shelf life [18] [3]. The EudraGMDP database serves as the central repository for compliance information, playing a pivotal role in the regulatory ecosystem for ATMP manufacturing licenses [1].

The Legal Framework and GMP Guidelines for ATMPs

Core Legislation and Principles

The EU GMP framework is established through a series of key legal instruments. Directive 2001/83/EC, along with Directive (EU) 2017/1572, lays down the principles and guidelines of GMP for human medicines [30] [31]. The ATMP Regulation (EC) No. 1394/2007 provides the specific legal basis for regulating advanced therapies and mandates the development of detailed GMP guidelines tailored to their unique characteristics [7] [4]. Furthermore, any manufacturer or importer within the European Economic Area (EEA) must hold a manufacturing authorisation issued by the national competent authority of the Member State where the activities are performed [30] [3]. This authorisation is contingent upon full compliance with EU GMP standards.

ATMP-Specific GMP Guidelines

Recognizing the distinct challenges in ATMP manufacturing, the European Commission has published detailed GMP guidelines specific to ATMPs (Part IV of Eudralex Volume 4) [18] [31]. These guidelines adapt the fundamental GMP requirements to the specific characteristics of ATMPs, addressing novel and complex manufacturing scenarios and fostering a risk-based approach to manufacture and testing [18]. The guidelines cover the entire manufacturing process, emphasizing the importance of a robust Pharmaceutical Quality System and the application of Quality Risk Management (QRM) principles. Key areas of focus include the use of human tissues and cells, aseptic processing, control of starting materials, and the management of short shelf-lives and complex supply chains [18] [3]. A significant update is on the horizon, as the EMA has released a concept paper proposing revisions to Part IV to align with the updated Annex 1 on sterile products, integrate ICH Q9 and Q10 concepts, and provide clarifications on new technologies and cleanroom expectations [32]. The consultation for these revisions was open until 8th July 2025 [32].

Table 1: Key EU Legal Acts Governing GMP for ATMPs

Legal Act	Scope and Relevance
Directive 2001/83/EC	Establishes the core Community code relating to medicinal products for human use, including GMP principles [30] [31].
Commission Directive (EU) 2017/1572	Supplements Directive 2001/83/EC, specifically detailing GMP principles and guidelines for human medicines [31].
Regulation (EC) No 1394/2007	The "ATMP Regulation"; defines ATMPs and establishes the specific regulatory framework for them, including a mandate for ATMP-specific GMP guidelines [7] [4].
Commission GMP Guideline for ATMPs (Part IV)	Provides detailed, adapted GMP requirements for the manufacture of Advanced Therapy Medicinal Products [18].

GMP Inspections: Process and Methodologies

Inspection Responsibilities and Planning

In the EU, the responsibility for GMP inspections is shared between national and European authorities. National Competent Authorities (NCAs) are primarily responsible for inspecting manufacturing sites located within their own territories [30]. For manufacturing sites outside the EU, the responsibility falls to the NCA of the Member State where the EU importer is located, unless a Mutual Recognition Agreement (MRA) is in place with the country concerned [30]. The EMA plays a crucial coordinating role, particularly for medicines authorised through the centralised procedure, and facilitates cooperation between Member States for supervising sites outside the EU [30]. EU authorities plan inspections using a risk-based approach, and inspections may also be triggered by suspicions of non-compliance [30].

Inspection Procedures and Focus Areas for ATMPs

A GMP inspection is a comprehensive, on-site audit of a manufacturing facility and its quality system. The methodology involves a detailed review of documentation, interviews with personnel, and direct observation of processes and facilities. For ATMPs, inspectors pay particular attention to several critical areas.

• Control of Starting Materials: Given the use of human tissues and cells, there must be rigorous procedures for donor selection, procurement, testing, and traceability, ensuring compliance with relevant blood and tissue legislation [18] [3].
• Aseptic Processing and Sterility Assurance: Most ATMPs are sterile products that cannot be terminally sterilized. Inspections focus heavily on environmental monitoring, personnel training, validation of aseptic processes, and the use of technologies like isolators or biosafety cabinets [32].
• Quality Control and Testing: Inspectors verify that validated methods are in place to control the quality of the product at various stages. For ATMPs with small batch sizes and autologous products, this presents unique challenges for testing and validation of consistency [3].
• Data Integrity and Documentation: A thorough review of all batch documentation, standard operating procedures (SOPs), and the Pharmaceutical Quality System is conducted to ensure data is complete, accurate, and reliable.
• Supply Chain and Logistics: The inspection covers the control over the complex chain from donor/patient to facility and back to the patient, including transportation and conditions monitoring, which is critical for products with short stability periods [3].

The following diagram illustrates the logical workflow of the GMP inspection process for an ATMP manufacturing site.

Diagram 1: GMP Inspection Workflow for ATMP Sites

GMP Certificates and Compliance Statements

Issuance and Validity

Following a successful GMP inspection, the competent authority issues a GMP Certificate of Compliance [30] [7]. This certificate is entered into the EudraGMDP database and serves as formal evidence of GMP compliance at the time of the inspection [30] [1]. It is important to note that the validity of a GMP certificate is not perpetual. A significant regulatory change occurred following the COVID-19 pandemic. The temporary extension of GMP certificate validity, which was in place until the end of 2024, no longer applies from 2025 onward [30]. NCAs have resumed regular on-site inspections and will now decide on a case-by-case basis whether any additional extension to a GMP certificate is needed [30].

Non-Compliance and Regulatory Consequences

If an inspection reveals serious GMP deficiencies, the competent authority will issue a statement of non-compliance [7]. This is also recorded in the EudraGMDP database. Non-compliance can have severe regulatory consequences, including the suspension or revocation of the manufacturing authorisation, and can trigger urgent safety restrictions such as the prohibition of supply or withdrawal of batches from the market [7]. The discovery of non-conformities may also lead to an injunction, requiring the manufacturer to rectify the situation within a specified timeframe [7].

Table 2: GMP Certificate and Inspection Data in EudraGMDP

Document Type	Purpose and Significance	Publicly Accessible in EudraGMDP?
GMP Certificate	Formal evidence of GMP compliance following a successful inspection. Issued by an NCA.	Yes [1] [10]
Non-Compliance Statement	Official record of serious GMP failures identified during an inspection.	Yes [1] [7]
Manufacturing/Import Authorisation	License granted to a manufacturer/importer within the EEA to perform GMP activities.	Yes [1]
Inspection Planning (for third countries)	Used by NCAs to coordinate inspections of manufacturers outside the EU.	No [1]

The Central Role of the EudraGMDP Database

Function and Public Access

The EudraGMDP database is the official EU repository for GMP (and GDP) compliance information [1]. It is maintained and operated by the EMA, with the content provided directly by the NCAs of the EEA [1] [10]. The database aims to improve information sharing between regulators and the public, aid in the coordination of inspections (especially for manufacturers in third countries), and eliminate the need for industry to submit paper certificates to support marketing authorisation applications [1]. A publicly accessible version of the database allows manufacturers, marketing authorisation holders, and other stakeholders to verify the GMP compliance status of manufacturing sites worldwide [1] [7].

Practical Application in ATMP Development and Licensing

For researchers and professionals developing ATMPs, the EudraGMDP database is an indispensable tool. When compiling a Marketing Authorisation Application (MAA) or a Clinical Trial Application (CTA), the applicant must demonstrate that all manufacturing sites involved in the product's production are GMP compliant [30] [3]. Regulators assessing the application will use EudraGMDP to verify the GMP status of each site listed in the application dossier. Furthermore, the database is critical for supply chain management. An ATMP manufacturer is responsible for ensuring that its suppliers, including active substance manufacturers, are GMP compliant [30]. EudraGMDP facilitates this verification, helping to protect the integrity of the supply chain.

The following diagram outlines the logical relationships and information flow between the key entities in the GMP compliance ecosystem for ATMPs.

Diagram 2: GMP Compliance Information Flow

Essential Tools for GMP Compliance Research

For scientists and drug development professionals navigating the ATMP regulatory landscape, a set of key "research reagents" – in this case, official regulatory documents and digital tools – is essential for successful GMP compliance research and demonstration.

Table 3: Essential Research Tools for ATMP GMP Compliance

Tool / Resource	Function and Utility	Access Point
EudraGMDP Public Database	Primary source for verifying GMP certificates, manufacturing authorisations, and non-compliance statements for any site in the supply chain.	EMA EudraGMDP Website [10]
EU GMP Guidelines (Part IV for ATMPs)	The definitive technical document outlining the specific GMP requirements for Advanced Therapy Medicinal Products.	EudraLex - Volume 4 [31]
GMP/GDP Q&A Document	Provides official interpretations of the EU GMP guidelines, clarifying complex practical issues as they arise.	EMA GMP/GDP Q&A Page [5]
Compilation of Union Procedures	Contains the standardized formats for GMP certificates and detailed inspection procedures, ensuring harmonization across the EEA.	EMA Website [30] [10]
Organisation Management Service (OMS)	Database used to ensure consistent and accurate identification of organisations in EudraGMDP, required for applications from 2022.	EMA OMS [1]

For ATMPs, demonstrating GMP compliance through successful inspections and valid certificates is a non-negotiable pillar of the regulatory pathway to market. The process is underpinned by a robust and dynamic legal framework, which includes tailored guidelines for the unique challenges of advanced therapies. The EudraGMDP database stands as the cornerstone of this system, providing transparency, enabling regulatory coordination, and serving as a critical verification tool for industry professionals. As the ATMP field continues to evolve rapidly, with new technologies and manufacturing paradigms emerging, the regulatory framework is also adapting, as evidenced by the proposed revisions to the ATMP GMP guidelines [32]. For researchers and developers, a deep understanding of the interplay between inspections, certificates, and the EudraGMDP database is not merely a regulatory hurdle, but a fundamental component of ensuring that these innovative therapies are manufactured to the highest standards of quality and safety for patients.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking category of medications that utilize genes, cells, or tissues to treat or replace damaged organs and tissues, offering potential solutions for complex diseases through gene therapy, somatic cell therapy, tissue engineering, and combined therapies [33]. In the European Union, ATMPs are regulated under Regulation (EC) No. 1394/2007, which ensures these innovative products undergo appropriate regulatory evaluation according to the established framework for human medicinal products prior to clinical and commercial use [4] [34]. The European Medicines Agency (EMA) plays a central role in the scientific assessment of ATMPs, with the Committee for Advanced Therapies (CAT) performing primary evaluation of ATMP Marketing Authorisation Applications [4].

A key aspect of ATMP regulation involves the EudraGMDP database, which contains manufacturing and import authorizations, Good Manufacturing Practice (GMP) certificates, and non-compliance statements issued after inspections [35] [3]. This database, maintained and operated by the EMA with content provided by national competent authorities, serves as a crucial transparency and compliance tool for manufacturers, regulators, and stakeholders involved in ATMP development and manufacturing [35] [36]. For ATMPs specifically, manufacturing must comply with GMP principles outlined in Part IV of EudraLex Volume 4, which provides detailed guidelines for ATMPs in recognition of their unique characteristics and manufacturing challenges [34].

ATMP Manufacturing Challenges and the EudraGMDP Framework

Core Manufacturing Complexities

ATMP manufacturing presents distinctive challenges that differentiate it from conventional pharmaceutical production. These challenges stem primarily from the biological nature of the raw materials, complex manufacturing processes, and stringent regulatory requirements. Surveys of commercial ATMP developers in Europe reveal that manufacturing constitutes 15% of reported challenges, ranking among the top three barriers alongside country-specific requirements (16%) and clinical trial design (8%) [37]. The most significant challenges include:

• High Production & Development Costs: ATMP manufacturing requires specialized premises, equipment, and skilled personnel, coupled with rigorous monitoring and quality control systems. This creates particularly substantial barriers for smaller companies and academic institutions, which often lack the qualified personnel, infrastructure, and capital necessary for late-phase studies [3].

• Extreme Logistical Complexity: The collection of patients' cells, transportation to manufacturing facilities, and supply of finished ATMPs to healthcare providers creates supply chain challenges rarely encountered with traditional pharmaceuticals [3].

• Maintaining Sterility: Unlike traditional pharmaceuticals that can be terminally sterilized, ATMPs cannot undergo conventional sterilization methods (heat, radiation, or filtration) without compromising cell viability and product functionality [33].

• Product Variability: The use of biological materials and complex manipulation steps introduces a degree of variability in the finished product, particularly in autologous settings where each batch is patient-specific [3].

• Difficulty Validating Process Consistency: The autologous nature of many ATMPs and small batch sizes limit the number of analytical tests that can be performed, making it challenging to demonstrate comparability between production processes and batches [3].

Shelf-Life and Stability Challenges

The limited shelf-life of ATMPs presents another critical challenge for their development and commercialization. Unlike conventional pharmaceuticals, ATMPs often comprise living biological materials with limited viability outside specific conditions. The short shelf-life creates tremendous pressure on manufacturing, quality control, and distribution systems, particularly for products destined for patients in geographically dispersed locations [3].

Recent evidence suggests that proper cryopreservation techniques can significantly extend the functional shelf-life of cell-based ATMPs. Studies analyzing 19 different experimental ATMPs cryopreserved in liquid nitrogen vapors demonstrated stability for up to 13.5 years without diminished viability or efficacy when maintained below -150°C [38]. These findings indicate that stability studies for ATMPs may require approaches different from those used for traditional pharmaceuticals, potentially leading to significant cost savings in stability testing while maintaining safety standards.

Table 1: Key Challenges in ATMP Manufacturing and Potential Mitigation Strategies

Challenge Category	Specific Challenges	Potential Mitigation Strategies
Manufacturing Process	Sterility maintenance without terminal sterilization [33]	Closed automated systems; aseptic processing validation [33] [34]
	Product variability from biological materials [3]	Standardized characterization; quality control assays [33]
	Scalability of cell expansion [33]	Automated closed-system bioreactors [33] [39]
Supply Chain & Logistics	Short shelf-life [3]	Cryopreservation; decentralized manufacturing [38] [34]
	Extreme logistical complexity [3]	Distributed manufacturing models; optimized transport protocols [34]
Regulatory Compliance	Country-specific requirements [37]	Early regulatory dialogue; harmonized approaches [3]
	Demonstrating comparability [3]	Risk-based comparability assessments; extended analytical characterization [33]

Decentralized Manufacturing as a Strategic Solution

Centralized vs. Decentralized Manufacturing Models

To address the challenges of shelf-life and complex logistics, two primary manufacturing models have emerged for ATMPs: centralized and decentralized manufacturing. Centralized manufacturing represents the traditional approach, with a single facility responsible for production and supply to a large geographical region [34]. While this model offers economies of scale and centralized quality control, it presents significant challenges for autologous ATMPs, particularly regarding transportation times, cryopreservation requirements, and patient access limitations.

Decentralized manufacturing has emerged as an alternative model that establishes regional manufacturing centers ("hubs") close to treatment facilities, delivering products to their immediate environment [34]. This approach is particularly advantageous for autologous cell therapies with limited shelf-lives, as it minimizes transportation time and complexity while improving patient access to these innovative treatments.

Table 2: Comparison of Centralized vs. Decentralized ATMP Manufacturing Models

Aspect	Centralized Manufacturing	Decentralized Manufacturing
Facility Structure	Single production facility [34]	Multiple regional hubs [34]
Logistical Complexity	High (long-distance transport) [34]	Reduced (local transport) [34]
Shelf-Life Pressure	Significant [3]	Reduced [34]
Patient Access	Limited to those near facilities or with robust transport systems [34]	Improved access across broader geographic areas [34]
Quality Control	Centralized batch certification [3]	Distributed with central oversight [34]
Economic Considerations	High volume potential but significant infrastructure investment [3]	Reduced transport costs but multiple facility setup [34]
Regulatory Compliance	Single manufacturing authorization [3]	Multiple authorizations with harmonized standards [34]

Implementation Framework for Decentralized Manufacturing

Successful implementation of decentralized ATMP manufacturing requires careful attention to regulatory compliance, quality management, and operational coordination. According to EU guidelines, the following elements are essential for an effective decentralized manufacturing system:

• Central Facility Oversight: A central facility established in the EU must be identified to supervise decentralized sites. This central facility is responsible for ensuring personnel at all locations are adequately qualified and trained, and for conducting audits to confirm compliance with standardized procedures [34].

• Qualified Person (QP) Responsibility: The Qualified Person at the central facility maintains ultimate responsibility for certifying that each batch of ATMPs meets quality requirements and can be released. The QP may rely on data from decentralized locations, provided it has been generated by qualified personnel following established protocols [34].

• Technical Agreements: Formal contracts or technical agreements must be established between the central facility and decentralized locations, clearly defining the responsibilities of each party, including specific QP responsibilities [34].

• Automated and Closed Systems: To minimize variability between manufacturing sites, automated systems maintaining functional closure throughout the manufacturing process are preferred. Technologies such as sterile tube welders and aseptic access ports help maintain system integrity and reduce operator-induced variation [34].

Diagram 1: Decentralized ATMP Manufacturing Quality oversight model showing the relationship between the central facility, decentralized manufacturing sites, and the qualified person's role in batch release.

Technical Protocols and Research Reagent Solutions

Stability Testing Protocol for ATMPs

Stability studies are critical for establishing the shelf-life of ATMPs and ensuring their safety and efficacy upon administration. The following protocol outlines a comprehensive approach to stability testing for cell-based ATMPs, based on methodologies that have demonstrated long-term stability for up to 13.5 years [38]:

Objective: To determine the shelf-life of cryopreserved ATMPs and guarantee their efficacy and safety upon infusion by evaluating critical quality attributes over time.

Materials and Equipment:

• Cryopreservation solution (e.g., culture medium with 10% DMSO)
• Controlled-rate freezer
• Liquid nitrogen storage system (-150°C or lower)
• Sterility testing system (e.g., BacT/ALERT)
• Flow cytometer for immunophenotyping
• Potency assay materials (dependent on mechanism of action)

Procedure:

• Cryopreservation: Resuspend the final ATMP product in an appropriate cryopreservation solution, typically containing 10% DMSO as a cryoprotectant. Transfer to appropriate primary containers (cryobags or vials).
• Controlled Freezing: Utilize a controlled-rate freezer to gradually reduce temperature at approximately 1°C per minute to -40°C, then at 3-5°C per minute to -100°C or lower.
• Long-term Storage: Transfer cryopreserved products to liquid nitrogen vapor phase storage (-150°C or lower) for long-term preservation.
• Stability Timepoints: Remove representative samples at predetermined timepoints (e.g., initial, 3 months, 6 months, 1 year, then annually) for comprehensive testing.
• Quality Attribute Testing: At each timepoint, assess:
  • Cell Viability: Using trypan blue exclusion or flow cytometry with viability dyes.
  • Immunophenotype: Characterize surface marker expression via flow cytometry.
  • Potency: Perform mechanism-relevant functional assays (immunosuppression, cytotoxicity, cytokine release, proliferation/differentiation capacity).
  • Microbiological Attributes: Test for sterility, endotoxin levels, and mycoplasma contamination.
• Data Analysis: Compare results across timepoints to identify any significant changes in quality attributes. Establish acceptance criteria for each parameter based on clinical relevance.

Interpretation: Consistent maintenance of all critical quality attributes within established acceptance criteria indicates product stability at the storage conditions tested. Any significant decline in viability, potency, or changes in phenotype may indicate limited stability and require shelf-life adjustment.

Essential Research Reagent Solutions

Successful ATMP development and manufacturing requires specialized reagents and materials that meet rigorous quality standards. The following table outlines key research reagent solutions essential for addressing ATMP-specific challenges:

Table 3: Essential Research Reagent Solutions for ATMP Development and Manufacturing

Reagent Category	Specific Examples	Function in ATMP Development
Cryopreservation Media	DMSO-containing solutions; serum-free formulations	Maintain cell viability and functionality during frozen storage [38]
Cell Culture Supplements	GMP-grade cytokines, growth factors	Direct cell differentiation, expansion, and maintain phenotype [33]
Quality Control Assays	Sterility testing systems; endotoxin detection kits	Ensure product safety and freedom from contamination [33] [38]
Potency Assay Reagents	Target cells; detection antibodies; cytokine ELISA kits	Measure biological activity critical to therapeutic effect [38]
Gene Delivery Vectors	GMP-grade viral vectors (lentivirus, retrovirus)	Facilitate genetic modification in gene therapy products [37] [4]
Aptamers and Characterization Reagents	Flow cytometry antibodies; PCR primers and probes	Characterize product identity, purity, and impurities [38]

Diagram 2: ATMP stability study workflow showing the integration of quality control testing and long-term stability monitoring within the manufacturing process.

Regulatory Strategy and EudraGMDP Documentation

Navigating the EudraGMDP Database for ATMP Manufacturing

The EudraGMDP database serves as a critical tool for transparency and compliance in ATMP manufacturing. Understanding how to access and interpret information within this database is essential for all stakeholders involved in ATMP development and commercialization. The database contains several key modules relevant to ATMP manufacturers [35] [3]:

• Manufacturing Import Authorisation (MIA): Documents the authorization required for manufacturing (including importing) medicinal products within the European Community.
• GMP Certificates: Contains records of Good Manufacturing Practice certificates issued following satisfactory inspections, confirming compliance with EU GMP standards.
• GMP Non-Compliance Statements: Includes statements issued when inspections reveal GMP deficiencies, providing important transparency about manufacturing issues.
• Active Substance Manufacturer Registration: Records registration of manufacturers handling active substances used as raw materials in medicinal products.

For ATMP developers, regularly consulting the EudraGMDP database provides insights into regulatory expectations, helps in qualifying contract manufacturing organizations, and offers learning opportunities from regulatory decisions concerning similar products. The public accessibility of this database promotes transparency and facilitates informed decision-making throughout the ATMP development lifecycle [35] [36].

Regulatory Considerations for Decentralized Manufacturing

Implementing decentralized manufacturing models requires careful navigation of the EU regulatory framework. Current EU law stipulates that each production site must hold a manufacturing authorisation and comply with GMP specific to ATMPs [3]. This requirement creates particular complexity for decentralized models involving multiple manufacturing locations.

The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains potential provisions that may facilitate decentralized manufacturing. Specifically, Article 142 states that by derogation "the manufacturing authorisation shall not be required for [...] the decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site" [3]. While this potential regulatory evolution could significantly streamline decentralized manufacturing implementation, it remains uncertain whether this amendment will be adopted.

In the current regulatory environment, successful decentralized manufacturing implementation requires [34]:

• Comprehensive technical agreements defining responsibilities between central and decentralized sites
• Robust quality management systems ensuring consistency across manufacturing locations
• Extensive documentation demonstrating process validation and comparability between sites
• Clear communication and coordination with national competent authorities across jurisdictions

The successful development and commercialization of ATMPs requires innovative approaches to address their unique complexities, particularly regarding manufacturing models and shelf-life limitations. Decentralized manufacturing represents a promising strategy for overcoming these challenges, especially for autologous therapies with limited stability. When implemented with robust quality systems and regulatory compliance, this approach can significantly improve patient access while maintaining product quality and safety.

Future developments in ATMP manufacturing will likely focus on further advancing decentralized models, potentially supported by regulatory evolution specifically addressing multi-site manufacturing. Additionally, continued research into cryopreservation methodologies and stability testing protocols will help extend shelf-lives and reduce the logistical burdens associated with these innovative therapies. As the ATMP field continues to mature, the EudraGMDP database will remain an essential resource for ensuring transparency, compliance, and continuous improvement in manufacturing practices across the industry.

For researchers and developers navigating this complex landscape, early engagement with regulatory authorities through scientific advice procedures, thorough understanding of EudraGMDP documentation requirements, and strategic implementation of appropriate manufacturing models will be critical success factors in bringing these promising therapies to patients in need.

The development and manufacture of Advanced Therapy Medicinal Products (ATMPs) operate within a sophisticated European Union regulatory ecosystem designed to ensure patient safety and product quality. For researchers and drug development professionals, navigating this landscape requires strategic interaction with three key regulatory entities: National Competent Authorities (NCAs), the European Medicines Agency (EMA) through its scientific advice procedures, and the Good Manufacturing Practice/Good Distribution Practice Inspectors Working Group (GMP/GDP IWG). These interactions are crucial for successful market authorization, with the EudraGMDP database serving as the central repository for manufacturing and compliance information. Understanding the distinct roles and interrelationships of these bodies is fundamental to streamlining the development pathway for ATMPs, which face unique challenges such as complex manufacturing processes, use of substances of human origin, and limited shelf lives [7] [3].

The regulatory framework mandates that any legal entity manufacturing ATMPs within the EU must hold a manufacturing authorisation from the NCA of the member state where the activities occur [3]. Furthermore, compliance with Good Manufacturing Practice (GMP), a set of quality standards ensuring products are consistently produced and controlled according to quality standards, is mandatory [7]. The complexity of ATMPs has led to the publication of detailed GMP guidelines specific to ATMPs by the European Commission, providing a tailored framework for these innovative products [7] [3]. The entire process is supported by a system of scientific advice, harmonized interpretation, and public databases, which together facilitate a coordinated approach to ATMP regulation across the European Economic Area (EEA).

The Regulatory Pillars: Core Functions and Interactions

National Competent Authorities (NCAs)

NCAs are the primary regulatory bodies in each EU Member State responsible for the direct oversight of medicinal product manufacture [3]. Their functions are hands-on and foundational to the regulatory system.

• Granting Manufacturing Authorisations: A manufacturing authorisation, issued by the NCA of the member state where the activities are carried out, is a legal requirement for any company producing ATMPs [3]. The NCA reviews and assesses the application to ensure the applicant can comply with EU quality standards, including GMP and the European Pharmacopoeia [3].
• Conducting GMP Inspections: NCAs are responsible for conducting regular and repeated on-site inspections of manufacturing sites to verify that all processes, including quality control, meet mandatory EU GMP requirements [7] [3]. These inspections assess the quality standards of manufacturing and ensure operations align with the relevant marketing authorisation.
• Batch Release and Enforcement: For biological medicinal products like ATMPs, the NCA is responsible for the official batch release before a product can be marketed [7] [3]. They also have the authority to take urgent measures—such as prohibition of manufacture or product withdrawal—in response to serious GMP non-compliance [7].
• Providing Scientific Advice and Guidance: NCAs act as a key entry point for applicants, providing regulatory and scientific advice, as well as guidance, to support compliance with EU GMP [3]. This includes support for micro, small, and medium-sized enterprises (SMEs) and academic institutions navigating the regulatory landscape [3].

EMA Scientific Advice and Protocol Assistance

The EMA offers a critical service through its Scientific Advice Working Party (SAWP) and Emergency Task Force (ETF), providing developers with prospective guidance on their medicine development plans [40]. This interaction is separate from the marketing authorisation assessment and is designed to strengthen the evidence generated during development.

Scientific advice is particularly valuable when developing innovative medicines, deviating from existing guidelines, or when developers have limited regulatory experience [40]. For ATMP developers, this advice can cover quality, non-clinical, and clinical aspects, as well as overall development strategy. A special form of scientific advice, called protocol assistance, is available for developers of designated orphan medicines, which includes many ATMPs for rare diseases [40]. Furthermore, the EMA encourages parallel scientific advice with bodies like the U.S. FDA and the EU Coordination Group on Health Technology Assessment (HTACG), allowing for coordinated feedback that can streamline global development and market access [41].

Table: Types of EMA Scientific Advice and Their Application to ATMPs

Type of Advice	Providing Committee	Key Features	Relevance to ATMP Development
Standard Scientific Advice	Scientific Advice Working Party (SAWP)	Prospective guidance on quality, non-clinical, and clinical development plans [40].	Advising on complex manufacturing, testing, and clinical trial design for novel therapies.
Protocol Assistance	Scientific Advice Working Party (SAWP)	Special advice for orphan medicines, including demonstration of significant benefit [40].	Critical for ATMPs targeting rare diseases to confirm orphan drug criteria and development pathway.
ETF Scientific Advice	Emergency Task Force (ETF)	For medicines targeting public health emergencies (e.g., pandemics, antimicrobial resistance) [40].	Supports development of ATMPs for urgent public health threats, including advice on clinical trials.
Parallel Advice (with FDA/HTA)	SAWP in cooperation with other bodies	Coordinated feedback from multiple regulators and/or health technology assessment bodies [41].	Aligns regulatory and reimbursement requirements for complex, high-cost ATMPs early in development.
Advice on Medicine Repurposing	SAWP	Tailored support for not-for-profit organisations and academics [41].	Supports finding new uses for existing therapies, potentially including some ATMPs.

The procedure for seeking scientific advice is structured. After registering with the EMA, the developer submits a formal request via the IRIS platform, including a briefing document with specific questions and proposed development pathways [40]. The EMA validates the questions and appoints two SAWP coordinators who form assessment teams. These teams prepare reports, and the SAWP may consult other EMA committees, external experts, and patients before consolidating a final response, which is then adopted by the CHMP and sent to the developer [40]. It is crucial to note that while complying with scientific advice increases the chances of marketing authorisation, the advice is not legally binding and does not guarantee a positive assessment outcome [40].

The GMP/GDP Inspectors Working Group (GMDP IWG)

The GMP/GDP IWG is a central harmonisation body, chaired by the EMA and composed of senior GMP inspectors from the EEA member states, the European Commission, and observers from bodies like the EDQM and WHO [42]. Its primary role is to ensure a common understanding and uniform application of GMP and GDP standards across the EU.

• Harmonising GMP/GDP Guidance: The working group meets regularly to consider new and revised GMP and GDP-related guidance, which is normally developed by drafting groups [42]. This is vital for ATMPs, as it helps create a consistent regulatory environment for these complex products across all member states.
• Developing Union Procedures: The group is responsible for developing community-wide procedures for GMP inspections, known as the Compilation of Union Procedures [42]. This ensures that inspection methodologies and standards are aligned.
• Interacting with International Partners: The IWG liaises with mutual recognition agreement (MRA) partners, the Pharmaceutical Inspection Co-operation Scheme (PIC/S), WHO, and other international bodies to facilitate global regulatory cooperation [42].
• Coordinating with Assessors: Recognizing the complementary nature of inspection and assessment, the EMA arranges at least one annual joint meeting between the IWG and the CHMP's Quality Working Party. This interaction is key to ensuring that quality considerations are seamlessly integrated from development through to authorisation and inspection [42].

The Central Role of the EudraGMDP Database

The EudraGMDP database is the EU's community database on manufacturing and import authorisations, as well as GMP and GDP certificates [1]. It is operated by the EMA and is a critical tool for both regulators and industry, playing multiple key roles in the regulatory framework for ATMPs.

• Information Sharing and Transparency: The public version of the database provides access to non-confidential information, improving transparency and allowing industry stakeholders to verify the compliance status of manufacturers [1] [7].
• Inspection Coordination and Planning: The database aids in the coordination of inspections of manufacturers in third countries among EEA national competent authorities. A non-public planning module allows regulators to share inspection plans, ensuring efficient use of resources [1].
• Supporting Marketing Authorisation Applications: The database eliminates the need for companies to submit paper GMP certificates to support marketing-authorisation and variation applications, as regulators can verify compliance directly through EudraGMDP [1].
• Supply Chain Protection: By facilitating the verification of legitimate actors, the database helps protect the medicine and active substance supply chain [1]. For ATMPs, which often have complex and global supply chains for starting materials, this is particularly important.

A significant update is the requirement for organisations to have their details correctly recorded in EMA's Organisation Management Service (OMS) before applying for new or updated manufacturing authorisations in EudraGMDP. This ensures more reliable data, reduces manual entry, and enhances IT system interoperability [1].

Diagram: Regulatory Interaction Workflow for ATMP Manufacturers. This diagram shows the pathways for scientific advice, manufacturing authorisation, and inspection, and how outcomes are centralised in the EudraGMDP database.

A Strategic Guide for ATMP Developers

Experimental Protocols for Regulatory Interaction

Success in ATMP development hinges on treating regulatory interaction as a core experimental activity. The following methodologies provide a roadmap for engaging with regulators.

Protocol 1: Requesting and Utilizing EMA Scientific Advice This protocol outlines the steps for obtaining and implementing regulatory guidance during ATMP development [40].

• Pre-Submission (Planning & Registration): Determine the critical development questions most suitable for scientific advice (e.g., novel endpoints, complex manufacturing controls). If new to the process, consider requesting a preparatory meeting with the EMA. Ensure your organisation and product are registered with the EMA.
• Formal Request (Submission & Validation): Prepare a comprehensive Briefing Document within the IRIS platform. This document must clearly articulate the specific scientific questions and the developer's proposed development plan and justification for each question. The EMA will then validate the questions.
• Assessment (Coordinator Appointment & Reporting): The EMA's SAWP will appoint two coordinators with relevant expertise. Each coordinator forms an assessment team to prepare a report addressing the questions. During this phase, be prepared to provide additional documentation or clarifications if requested.
• Interaction & Consultation (SAWP Meeting & Expert Input): The SAWP may invite the developer to a meeting to discuss points of disagreement or complex issues. The SAWP also consults other EMA committees, external experts, and patients to widen the pool of expertise.
• Finalization (CHMP Adoption & Implementation): The SAWP consolidates its response, which is then discussed and formally adopted by the CHMP. The final advice letter is sent to the developer. The development team must then formally integrate the advice into the Target Product Profile and overall development strategy.

Protocol 2: Navigating GMP Compliance and NCA Inspection This protocol describes the process for achieving and maintaining GMP compliance for an ATMP, culminating in the NCA inspection [7] [3] [5].

• System Establishment (Pharmaceutical Quality System): Establish, implement, and maintain a robust Pharmaceutical Quality System (PQS) as required by GMP. This is the foundational system that ensures consistent product quality.
• Authorisation Application (Submission to NCA): Compile and submit a manufacturing authorisation application to the relevant NCA. This includes all technical and scientific data demonstrating compliance with GMP, including the specific GMP guidelines for ATMPs. Ensure organisation details are verified in the OMS.
• Pre-Inspection Readiness (Internal Audit & Documentation): Conduct thorough internal audits and gap analyses against EU GMP standards, specifically the ATMP-specific guidelines. Prepare all required documentation, including Standard Operating Procedures (SOPs), validation protocols, and quality control records, for inspector review.
• On-Site Inspection (NCA Led): Host the NCA inspection team for a comprehensive on-site assessment. The inspection will evaluate premises, equipment, personnel, procedures, and the overall PQS against the information in the manufacturing authorisation.
• Outcome and Follow-up (Certificate & CAPA): Following a positive inspection, the NCA will issue a GMP certificate, which is entered into the EudraGMDP database. For any deficiencies, implement a rigorous Corrective and Preventive Action (CAPA) plan and submit it to the NCA for approval.

The Scientist's Toolkit: Essential Regulatory Documents

Engaging effectively with regulators requires a specific set of "reagents" – in this case, key documents and database tools. The following table details these essential items.

Table: Essential Regulatory Documents and Tools for ATMP Developers

Tool/Document	Function/Purpose	Source/Agency
EU Guidelines on GMP specific to ATMPs	Provides the mandatory quality standards tailored to the unique challenges of manufacturing ATMPs, covering aspects from using substances of human origin to complex processes [7] [3].	European Commission
EudraGMDP Database	The central repository to verify manufacturing authorisations and GMP compliance status of sites, and to which your own organisation's authorisations and certificates will be uploaded [1] [7] [3].	European Medicines Agency (EMA)
Scientific Advice Briefing Document	The formal proposal submitted to EMA outlining the development plan and specific scientific questions for which guidance is sought; the core of the scientific advice procedure [40].	Applicant / Developer
Pharmaceutical Quality System (PQS)	The internal quality system required by GMP that ensures medicinal products are of the quality required for their intended use; it is the primary subject of GMP inspections [7].	Applicant / Manufacturer
GMP/GDP IWG Q&A Documents	Provides additional interpretation of EU GMP and GDP guidelines, offering practical clarity on complex topics and reflecting a harmonised EU position [5].	EMA (GMP/GDP IWG)

Quantitative Data and Compliance Timelines

Understanding the timelines and formal requirements for regulatory procedures is key to efficient project planning. The following table summarizes key quantitative aspects of the regulatory interactions discussed.

Table: Key Quantitative Data on Regulatory Procedures

Procedure / Aspect	Frequency / Timeline	Key Quantitative Requirement / Data Point
GMP/GDP IWG Meetings	Meets four times a year [42].	Composed of representatives from EEA Member States, European Commission, and observers from EDQM, WHO, etc. [42].
Product Quality Review (PQR)	Expected annually, but timeframes can be adjusted with justification based on manufacturing and campaign duration [5].	Must include review of stability results, returns, complaints, recalls, deviations, and regulatory background [5].
Supply Chain Verification	Periodic verification of the entire supply chain back to the active substance starting materials [5].	The frequency of this verification should be based on risk assessment [5].
EudraGMDP Data Entry	Data is entered by EEA Member States as it becomes available [1].	International partners with MRAs (e.g., Japan's MHLW/PMDA) have write access to the database [1].
Scientific Advice (Biosimilars)	Standard scientific advice timelines plus an extra month for SAWP review [41].	A pre-submission meeting is encouraged to review the suitability of the data package [41].

For researchers and developers of ATMPs, a proactive and strategic approach to interacting with the EU regulatory network is not optional—it is a critical component of success. The frameworks provided by the EMA's scientific advice, the harmonised guidance of the GMP/GDP IWG, and the oversight and authorisation by NCAs are designed to guide developers through the complexities of ATMP development. Mastery of these interactions, coupled with the diligent use of tools like the EudraGMDP database, enables the efficient generation of robust data needed for market authorisation. By integrating these regulatory strategies early and throughout the development lifecycle, scientists and drug development professionals can significantly de-risk their projects, accelerate timelines, and ultimately contribute to bringing transformative advanced therapies to patients in need.

Mitigating Risks and Ensuring Continuous Compliance in ATMP Manufacturing

The EudraGMDP database is the European Union's central repository for information on manufacturing and distribution authorisations, as well as Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) certificates [1]. For researchers, scientists, and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), this database serves as a critical tool for ensuring supply chain integrity and regulatory compliance. The system, maintained by the European Medicines Agency (EMA), provides transparency into the regulatory status of manufacturers and distributors, with national competent authorities across the European Economic Area (EEA) regularly contributing data [1] [43]. The public version of the database, available since 2011, offers access to non-confidential information, enabling pharmaceutical companies and researchers to verify the compliance status of partners throughout the supply chain [1].

For ATMP manufacturers specifically, the EudraGMDP database provides essential visibility into compliance documentation, which is particularly crucial given the complex manufacturing and distribution challenges associated with these therapies [3]. ATMPs face unique hurdles including extreme logistical complexity, maintaining sterility throughout processes, and managing the variability of biological materials [3]. Understanding how to properly interpret non-compliance reports within this database is therefore fundamental for research integrity and patient safety.

Recent Case Studies of GDP Non-Compliance and WDA Withdrawals

Analysis of Recent Enforcement Actions

Recent entries in the EudraGMDP database reveal patterns in regulatory enforcement that offer valuable insights for ATMP researchers and manufacturers. The following cases from 2024-2025 illustrate common deficiencies leading to Wholesale Distribution Authorisation (WDA) withdrawals:

Table: Recent GDP Non-Compliance Cases from EudraGMDP Database

Country	Inspection Date	Report Date	Report Number	Key Deficiencies	Regulatory Action
Germany [44]	15 April 2025	16 April 2025	NC/410.0410/2025	No designated Responsible Person; unsuitable premises and equipment	WDA suspended (with revocation after 2 months)
Austria [45] [46]	6 February 2025	19 May 2025	482952-102672721	Undisclosed specific details of GDP non-compliance	WDA withdrawn
Ireland [45] [46]	24 July 2024	4 June 2025	2024/35203/W13004/00001	Violations of Chapters 4, 5, 7, 9 of EU GDP guidelines; cold chain failures	WDA revoked; pharmacy-level recall

Interpretation of Deficiency Patterns

The cases above demonstrate critical failure points in distribution practices that are particularly relevant to ATMPs. The German case highlights the fundamental importance of personnel qualification and adequate infrastructure – both crucial for handling complex ATMPs with limited shelf lives [44] [3]. The Irish case emphasizes supply chain integrity challenges, specifically noting temperature control failures during transit that compromised product integrity [45]. For ATMP researchers, these cases underscore the vulnerability of biological products to distribution failures and the importance of maintaining complete control over the supply chain.

The Irish case specifically referenced non-compliance with Chapters 4, 5, 7, and 9 of the EU GDP guidelines [45]. These chapters cover critical areas that align closely with ATMP distribution challenges:

• Chapter 4: Documentation requirements
• Chapter 5: Operations principles
• Chapter 7: Complaints, returns, and recalls
• Chapter 9: Transportation management

The reference to "increased risk of falsified medicines reaching patients" in the Irish case demonstrates how distribution non-compliance can directly impact product authenticity and patient safety [45].

Analytical Framework for Evaluating Non-Compliance Reports

Systematic Assessment Methodology

Proper interpretation of non-compliance reports requires a structured analytical approach. Researchers should employ the following methodology when evaluating EudraGMDP entries for due diligence or risk assessment purposes:

Diagram 1: Methodology for analyzing GMP non-compliance reports. This workflow outlines the systematic process for evaluating regulatory deficiencies, from initial database access to final risk assessment.

Critical Assessment Parameters

When analyzing non-compliance reports, researchers should evaluate the following key parameters that directly impact ATMP manufacturing and distribution:

• Deficiency Criticality Level: Determine whether findings are critical, major, or minor based on their potential impact on product quality and patient safety. Critical deficiencies typically result in immediate WDA suspension or revocation.

• Root Cause Analysis: Identify underlying systemic issues rather than focusing solely on surface-level violations. The German case demonstrating lack of Responsible Person and inadequate facilities indicates fundamental quality system failures [44].

• Corrective and Preventive Actions (CAPA): Evaluate whether the non-compliance report includes requirements for corrective actions or demonstrates a pattern of repeated deficiencies.

• Supply Chain Implications: Assess how the non-compliance affects the broader supply chain, particularly crucial for ATMPs with complex cold chain requirements and limited shelf lives [3].

Technical Requirements for ATMP Manufacturing and Distribution Compliance

Essential Research Reagents and Compliance Tools

Table: Essential Research Toolkit for ATMP Compliance Management

Tool Category	Specific Solution	Application in Compliance Management
Regulatory Databases	EudraGMDP Public Access [1]	Verification of manufacturer/distributor compliance status
Quality Management	Organisation Management Service (OMS) [1]	Master data management for regulatory submissions
Temperature Monitoring	Mean Kinetic Temperature (MKT) Calculators [47]	Evaluation of storage/transport conditions against GDP requirements
Documentation Systems	Electronic Quality Management Systems (eQMS)	Management of GMP/GDP documentation requirements
Risk Assessment Tools	Failure Mode Effects Analysis (FMEA) Templates	Proactive risk assessment for ATMP supply chain vulnerabilities

Advanced Technical Protocols for Compliance Verification

For researchers validating ATMP manufacturing and distribution partners, the following technical protocols should be implemented:

Protocol 1: Comprehensive Supplier Qualification Methodology

• Objective: Systematically evaluate potential ATMP manufacturers and distributors for regulatory compliance
• Procedure:
  • Query EudraGMDP database for target organization using multiple identifiers (name, DUNS number, location)
  • Review five-year history of GMP/GDP certificates and non-compliance reports
  • Analyze specific deficiency patterns and regulatory actions
  • Verify Organisation Management Service (OMS) data consistency [1]
  • Conduct gap analysis against specific ATMP requirements [3]
• Quality Control: Cross-reference data with national competent authority databases and perform on-site audits for critical partners

Protocol 2: ATMP-Specific Distribution Risk Assessment

• Objective: Identify and mitigate distribution risks specific to advanced therapy medicinal products
• Procedure:
  • Map complete cold chain requirements based on product stability profiles
  • Evaluate temperature monitoring systems and data integrity
  • Assess Responsible Person qualifications and availability [47]
  • Review validation documentation for shipping containers and transport routes
  • Verify emergency procedures for temperature excursions
• Documentation: Maintain comprehensive risk assessment reports aligning with EU GDP Chapter 9 requirements [45]

Strategic Implications for ATMP Research and Development

Mitigating Compliance Risks in ATMP Manufacturing

The analysis of non-compliance reports reveals several strategic considerations for ATMP researchers and developers. The regulatory landscape for ATMPs is particularly complex due to the use of substances of human origin, cellular materials with limited shelf lives, and extreme logistical requirements [3]. Understanding common pitfalls in GMP/GDP compliance enables proactive quality system design that addresses these vulnerabilities before they result in regulatory actions.

The personnel qualifications requirement highlighted in multiple non-compliance cases is especially critical for ATMPs, where manufacturing processes often involve complex biological manipulations that require highly specialized expertise [44] [3]. Similarly, the facility and equipment deficiencies noted in the German case report take on added significance for ATMPs, where maintaining sterility throughout production is particularly challenging [44] [3].

Future Directions in ATMP Regulatory Compliance

Recent regulatory developments suggest increasing attention to ATMP manufacturing and distribution challenges. The proposed Directive reforming the Union code relating to medicinal products for human use contains provisions for decentralized manufacturing sites that could potentially operate near patients [3]. This evolution in regulatory thinking acknowledges the unique logistical challenges of ATMPs while maintaining quality standards.

For researchers, the continuing harmonization of GMP inspection procedures through the GMP/GDP Inspectors Working Group provides more predictable regulatory requirements across the EEA [5] [3]. The increasing use of the Organisation Management Service (OMS) for master data management further supports regulatory consistency by ensuring accurate organization information across the EudraGMDP database [1].

Interpreting GMP non-compliance reports and WDA withdrawals requires both technical understanding of regulatory requirements and strategic appreciation of their implications for ATMP development. The case studies analyzed demonstrate that regulatory actions typically result from systemic failures in quality management rather than isolated deficiencies. For ATMP researchers, proactive compliance management using the EudraGMDP database as a due diligence tool is essential for mitigating supply chain risks. The unique characteristics of advanced therapies – including their complex manufacturing processes, limited stability, and specialized distribution requirements – make thorough understanding of GMP/GDP compliance particularly critical for successful product development and patient access.

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), a robust Quality Management System (QMS) is not merely a regulatory requirement—it is the fundamental backbone that ensures product quality, patient safety, and regulatory compliance throughout the product lifecycle. The European Medicines Agency (EMA) emphasizes that the QMS must ensure medicinal products are "consistently produced and controlled according to the quality standards appropriate to their intended use" [5]. Within the specific context of ATMP manufacturing, which involves complex biological materials and processes, QMS gaps can lead to critical failures during regulatory inspections, with findings documented in the EudraGMDP database—the official European Union database containing manufacturing authorisations, GMP certificates, and non-compliance reports [8].

This technical guide examines the most prevalent and critical QMS gaps in ATMP development, focusing on procedural deficiencies, change control weaknesses, and risk management shortcomings. For ATMP manufacturers, understanding these gaps is essential for successful licensing applications and maintaining compliance visibility within the EudraGMDP system, which provides regulatory stakeholders with complete information on the status of pharmaceutical manufacturers [8].

QMS Procedural Gaps in ATMP Environments

Procedural gaps represent fundamental weaknesses in the documented quality system that can compromise the entire manufacturing process. For ATMPs, these gaps are particularly problematic due to the complex and often novel manufacturing paradigms involved.

Inadequate Pharmaceutical Quality System Procedures

The EU GMP Guide Chapter 1 requires an effective Pharmaceutical Quality System that includes annual product quality reviews, even when no manufacturing has occurred during the review period [5]. Common procedural gaps include:

• Missing or inadequate Standard Operating Procedures (SOPs) for critical processes, particularly in managing ATMP-specific challenges like short product shelf life and variable biological starting materials [48] [3].
• Failure to establish review timeframe criteria in SOPs for product quality reviews, with insufficient justification for adjusted timeframes based on manufacturing and campaign duration [5].
• Incomplete quality and regulatory reviews that omit essential elements such as stability results, returns, complaints, recalls, deviations, and regulatory background assessments [5].

Supply Chain Documentation Deficiencies

ATMPs face extreme logistical complexity due to the need to collect patient cells, transport them to manufacturing facilities, and supply the finished product to healthcare providers [3]. Procedural gaps in this area include:

• Failure to document the complete supply chain for active substances back to the manufacturer of the active substance starting materials, a requirement specifically highlighted in EU GMP guidance [5].
• Inadequate verification procedures for incoming consignments of active substances, failing to confirm they originate from approved suppliers and manufacturers [5].
• Missing periodic verification of the entire supply chain for individual batches based on risk assessment, essential for maintaining an auditable trail back to starting material manufacturers [5].

Table 1: Common Procedural Gaps and Their Regulatory Consequences

Procedural Gap Area	Specific Deficiency	Potential Regulatory Impact
Document Control	Lack of version control for manufacturing procedures	EudraGMDP non-compliance report [49]
Quality Reviews	Annual PQR not conducted or incomplete	Manufacturing authorization suspension [5]
Supply Chain Security	Inadequate supplier qualification files	Observations during routine inspections [48]
Batch Traceability	No clear connection between bulk and finished product batch numbers	Product recall complications [5]

Change Control System Deficiencies

Change control represents a particularly vulnerable area in ATMP QMS due to the complex, evolving manufacturing processes and the challenge of demonstrating comparability after process modifications.

Inadequate Change Control Processes

A formal, risk-based change control process is essential for evaluating, approving, and implementing modifications that could affect product quality or regulatory compliance [50]. Critical gaps include:

• Lack of formal assessment and approval for changes to processes, equipment, or materials, particularly during technology transfer between GMP facilities—a common challenge in ATMP development [51].
• Insufficient verification protocols to demonstrate that changes function as intended without unintended consequences, especially critical for ATMPs where process changes can significantly impact critical quality attributes [50] [52].
• Failure to update documentation and training simultaneously with change implementation, leading to personnel using outdated instructions and procedures [50].

Change Control Board and Governance Gaps

Effective change control requires clear governance structures, which are often underdeveloped in ATMP organizations, particularly in academic settings transitioning to GMP operations:

• Absence of a defined Change Control Board (CCB) with cross-functional representation to evaluate change requests, assess risks, and approve implementations [50].
• Inadequate risk assessment integration using structured tools like FMEA for processes or ISO 14971 for medical devices to rate severity, occurrence, and detection of potential failure modes [50].
• Poor regulatory intelligence for categorizing changes according to EMA Variations Regulation pathways (Type IA, IB, II), potentially leading to incorrect regulatory submissions [50].

Figure 1: Optimal Change Control Workflow for ATMP Manufacturing - This process ensures systematic evaluation, approval, and verification of changes, with particular importance for ATMPs where process modifications can significantly impact product quality attributes [50] [52].

Risk Management Implementation Failures

Risk management is especially critical for ATMPs due to their complex pharmacological characteristics, biological variability, and frequently limited product stability profiles.

Inadequate Proactive Risk Assessment

Many ATMP manufacturers implement reactive rather than proactive risk management, leading to several common gaps:

• Failure to identify and manage risks for processes where specific controls (like metal detection) might be avoided through proper risk analysis, as recommended in EU GMP Chapter 3 [5].
• Missing risk-based decision making when considering unusual approaches, such as creating "super batches" from multiple individual batches, without applying rigorous Quality Risk Management principles [5].
• Inadequate assessment criteria that fail to consider critical factors such as equipment usage time, pharmaceutical form, expiry dating, stability studies, reference sampling, and product criticality [5].

Supply Chain Risk Oversight

The globalized nature of pharmaceutical supply chains introduces significant risks, particularly for temperature-sensitive ATMPs with complex logistics requirements:

• Insufficient mapping, qualification and assurance of transportation routes during routine operations, without proper change management controls [48].
• Inadequate oversight of third-party logistics providers (3PLs) and storage facilities, despite outsourcing to multiple partners becoming increasingly common in ATMP distribution [48].
• Poor control of geo-political risks affecting global distribution, including customs procedures, tariffs, and quality oversight across international boundaries [48].

Table 2: Risk Management Gaps and Mitigation Strategies for ATMP Manufacturers

Risk Category	Common Gaps	Recommended Mitigation Strategy
Process Risks	Failure to validate consistency of ATMP production with small sample sizes [3]	Implement enhanced process analytical technologies and comparability protocols
Supply Chain Risks	Inadequate temperature control during transport of short shelf-life products [3]	Deploy real-time monitoring and blockchain-based traceability solutions [48]
Data Integrity Risks	Poorly controlled access permissions and insufficient monitoring/logging [49]	Implement robust user identification systems and audit trails
Personnel Risks	Sharing of Responsible Person credentials with unauthorized staff [49]	Establish strict access controls and regular accountability verification

EudraGMDP Database: A Tool for QMS Gap Analysis

The EudraGMDP database serves as a crucial resource for identifying systemic QMS issues across the industry. By analyzing non-compliance reports, manufacturers can anticipate inspector focus areas and proactively address vulnerabilities.

Learning from Non-Compliance Reports

Recent entries in EudraGMDP reveal patterns of QMS failures relevant to ATMP manufacturers:

• Data integrity issues with critical observations including unauthorized personnel accessing accounts and performing quality-related decisions, as documented in a January 2025 GDP Non-Compliance Report for a Hungarian wholesaler [49].
• Inadequate IT controls where systems failed to regulate access permissions, lacked sufficient monitoring, logging, and user identification, and exhibited poor remote access management [49].
• Authorization deficiencies leading to partial suspension of wholesale distribution licenses, permitting only critical medicines to be moved to saleable stock during suspension periods [49].

Contract Management and Oversight Gaps

EU GMP Chapter 7 requires specific contractual arrangements that are particularly challenging for ATMP manufacturers with complex supply chains:

• Missing direct written contracts between Marketing Authorization Holders (MAHs) and Manufacturing Importation Authorization (MIA) holders responsible for Qualified Person (QP) certification [5].
• Inadequate "chain of contract" setups without robust communication protocols between MAHs, MIA holders, and contract manufacturers [5].
• Failure to ensure MIA holder access to all contracts in multi-party arrangements, compromising oversight and traceability [5].

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

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

Reagent/Material	Function in ATMP Development	Critical Quality Considerations
Characterized Cell Lines	Serve as reference materials for process validation and analytical development	Genetic stability, identity, purity, and functional potency [52]
Reference Standards	Enable qualification of critical quality attributes (CQAs) during comparability studies	Well-defined specifications and established stability profiles [52]
Vector Standards	For gene therapy products, provide benchmarks for transduction efficiency and safety testing	Titre, infectivity ratio, absence of replication-competent viruses [52]
Process Analytical Technology Tools	Enable real-time monitoring of critical process parameters	Validation according to ICH guidelines, suitability for real-time deployment [51]

Experimental Protocols for Addressing Key QMS Gaps

Protocol for Change Control Implementation Validation

Objective: To verify that a proposed change to an ATMP manufacturing process does not adversely impact critical quality attributes that correlate with safety and efficacy.

Methodology:

• Pre-change Characterization: Conduct comprehensive testing on three consecutive pre-change batches to establish baseline CQA profiles [52].
• Risk Assessment: Perform structured FMEA evaluating severity, occurrence, and detection scores for potential impacts of the proposed change [50].
• Comparative Testing: Implement the change and manufacture three post-change batches using identical starting materials where possible.
• Analytical Comparability: Subject pre- and post-change batches to identical battery of analytical tests focusing on CQAs identified during product development.
• Stability Assessment: Initiate accelerated and real-time stability studies on post-change batches using the same protocol as for pre-change batches.

Acceptance Criteria: Post-change batches must meet all pre-defined specifications and demonstrate comparable performance in functional potency assays within pre-established equivalence margins [52].

Protocol for Supply Chain Risk Assessment

Objective: To identify and mitigate risks in the ATMP supply chain, particularly crucial for products with limited shelf life and complex logistics.

Methodology:

• Supply Chain Mapping: Document all entities involved in the manufacturing and distribution process, from starting material procurement to patient delivery [5] [3].
• Vulnerability Analysis: Evaluate each node in the supply chain for potential failure modes, including transportation delays, temperature excursions, and documentation errors.
• Supplier Qualification: Implement a risk-based auditing program focusing on critical suppliers, with particular attention to those handling unprocessed starting materials of human origin [48].
• Chain of Identity Verification: For autologous products, establish and validate systems ensuring correct patient attribution throughout the supply chain [3].

Output: A documented risk assessment informing supplier qualification levels, monitoring frequency, and contingency planning for supply chain disruptions.

Addressing QMS gaps in procedures, change control, and risk management is essential for successful ATMP development and regulatory approval. The unique challenges of ATMPs—including complex biological starting materials, limited product stability, and sophisticated manufacturing processes—demand particularly rigorous quality systems. By learning from non-compliance patterns documented in the EudraGMDP database, implementing robust change control processes validated through appropriate experimental protocols, and deploying comprehensive risk management strategies, ATMP developers can enhance their regulatory compliance posture while advancing innovative therapies to patients. The continuing evolution of regulatory guidance, including emerging technologies like blockchain for enhanced traceability, will further shape QMS expectations for these transformative medicinal products [48].

For researchers and developers in the advanced therapy medicinal product (ATMP) space, the integrity of the supply chain is not merely a logistical concern but a critical component of product efficacy and patient safety. Good Distribution Practice (GDP) forms the regulatory bedrock for ensuring that medicinal products, including highly sensitive ATMPs, are consistently stored, transported, and handled under suitable conditions as specified in their marketing authorizations [53]. The primary objective of GDP is to safeguard product identity, quality, purity, and efficacy throughout the complex journey from the manufacturer to the patient [47]. For ATMPs, which often include autologous and allogeneic cell and gene therapies, this challenge is magnified. These products are characterized by extremely short shelf lives, sometimes as brief as 12 to 48 hours for fresh cell products, and often require cryogenic storage in vapor phase nitrogen [54] [55]. A single breach in temperature control or a failure in chain of custody can render a life-saving therapy useless, resulting in irrevocable harm to the patient and the loss of immense research and development value. Therefore, a robust, well-understood, and meticulously controlled system for overseeing third-party logistics (3PL) and transportation partners is not just a regulatory formality—it is an indispensable element of successful ATMP development and commercialization.

This guide provides a technical overview of the regulatory framework, risk-based oversight methodologies, and practical implementation strategies for ensuring supply chain security, with a specific focus on the role of the EudraGMDP database in the context of ATMP manufacturing and distribution.

Regulatory Framework and the EudraGMDP Database

Core Principles of Good Distribution Practice (GDP)

The European Union's GDP guidelines establish a comprehensive framework for the entire pharmaceutical supply chain. Compliance ensures that medicines are always stored in the right conditions, contamination is avoided, and the right products reach the right addressee within a satisfactory time period [53]. Furthermore, distributors must implement a system for tracing faulty products and executing effective recalls [53]. These principles are universally applicable; however, their implementation for ATMPs demands exceptional rigor due to the unique and patient-critical nature of these products.

The EudraGMDP Database in Regulatory Oversight

The EudraGMDP database is a pivotal tool for regulatory compliance and supply chain verification. Maintained by the European Medicines Agency (EMA), this publicly accessible database contains information on wholesale distribution authorisations and GDP certificates issued following inspections by EU competent authorities [53] [1].

• Function and Purpose: EudraGMDP aims to improve information sharing, aid in the coordination of inspections, and help protect the medicine distribution chain by facilitating the verification of legitimate actors [1]. For an ATMP developer qualifying a 3PL, checking their GDP status in EudraGMDP is a fundamental first step.
• Data Content: The database includes wholesale distribution authorisations and details of registered importers and distributors of active substances in the European Economic Area (EEA) [53]. After an inspection, authorities issue a GDP certificate or a non-compliance statement, which is entered into EudraGMDP [53].
• Role in ATMP Supply Chains: The database allows manufacturers and marketing authorization holders to verify the GDP compliance of their wholesale distributors and logistics partners. It is a key resource for initial qualification and ongoing monitoring of third parties, providing transparency and supporting a risk-based oversight approach.

Table: Key Regulatory Components for Supply Chain Security

Component	Description	Relevance to ATMPs
GDP Guidelines	EU regulations for wholesale distribution of medicinal products [53].	Ensures integrity of ATMPs during storage and transport; critical for short-lived, temperature-sensitive products.
EudraGMDP Database	Public database of GDP certificates and non-compliance reports [1].	Enables verification of 3PL compliance status; essential for supplier qualification.
Responsible Person (RP)	A designated, permanently available person responsible for GDP compliance [48].	Ensures continuous oversight; critical for managing complex, patient-specific ATMP supply chains.
Wholesale Distribution Authorisation (WDA)	Mandatory license for entities distributing medicinal products [53].	3PLs storing products for more than 24-72 hours typically require a WDA [56].

Recent Regulatory Updates

The regulatory landscape is dynamic. A critical update for 2025 is the end of the blanket extension for GDP certificates that was in place during the COVID-19 pandemic. The EMA has confirmed that from 2025, this extension no longer applies, as national competent authorities have resumed regular on-site inspections [53] [47]. Companies must ensure their and their partners' certificates are current, as any lapse could disrupt the supply of essential ATMPs.

ATMP-Specific Supply Chain Challenges and Considerations

ATMPs introduce a paradigm shift in supply chain logistics, moving from a linear, bulk-supply model to a complex, often patient-specific, network.

• Patient-Centric and Circular Supply Chains: Autologous therapies, such as CAR-T cells, involve a circular supply chain. Cells are procured from a patient, shipped to a manufacturing facility, processed, and then shipped back to the same patient [57]. This requires a flawless chain of identity (COI) and chain of custody (COC) to prevent catastrophic mix-ups.
• Stringent and Variable Storage Conditions: Many ATMPs require deep-frozen or cryogenic conditions. Distribution in vapor phase nitrogen dry shippers is common but presents scalability challenges as product volumes grow into the thousands of doses annually [54]. Temperature monitoring throughout the journey is non-negotiable.
• Complex Regulatory Starting Points: The supply chain for an ATMP often begins at a clinical procurement site, which must comply with the EU Tissues & Cells Directives [54]. This requires robust third-party agreements that clearly define roles, responsibilities, and communication pathways for license status and adverse event reporting [54].
• Global Logistics and Importation: For therapies manufactured in a single central facility (e.g., in the US for EU patients), importation processes can cause significant delays. The requirement for Qualified Person (QP) certification of each patient-specific batch can add up to two days to the timeline, posing a direct risk to patients waiting for life-saving therapy [55].

The diagram below illustrates the complex, patient-specific journey of an autologous ATMP, highlighting critical control points and potential bottlenecks.

Diagram: The Patient-Specific ATMP Supply Chain. This diagram outlines the circular journey of an autologous ATMP, highlighting critical control points for identity, temperature, and quality release that require stringent oversight of third-party logistics partners.

Implementing Effective Oversight of Third-Party Logistics

Qualification and Audit Processes

A risk-based approach to qualifying and auditing 3PLs is a cornerstone of GDP compliance. The responsibility for ensuring that contracted service providers comply with GDP ultimately rests with the Wholesale Distribution Authorisation (WDA) holder or the marketing authorization holder [56].

• Audit Scope and Frequency: Companies must have an internal audit program that covers all outsourced activities [56]. The frequency and depth of audits should be commensurate with the risk posed by the service. A 3PL handling cryopreserved CAR-T products would warrant a more rigorous and frequent audit schedule than one handling stable, small-molecule products.
• Risk-Based Methodology: The current EU GDP requires manufacturers to audit and approve all their outsourced activities. The selection and approval of these facilities, which can number in the hundreds when including transportation hubs, should be supported by a formal risk assessment. Companies can utilize shared audits or 'paper audits' depending on the complexity of operations and the sensitivity of the products involved [56].
• Key Audit Focus Areas: An audit of a 3PL for ATMP logistics should focus on:
  • Temperature Mapping and Monitoring: Validation data for storage areas and transport vehicles.
  • Emergency Procedures: Plans for equipment failure, transport delays, and natural disasters.
  • Data Integrity: Systems for maintaining accurate, tamper-proof records of storage and shipping conditions.
  • Training: Evidence of initial and ongoing GDP training for all relevant staff [48].

The Role of the Responsible Person (RP)

The Responsible Person is a linchpin in the oversight of 3PLs. The RP must be permanently and continuously available, possess the requisite authority to carry out their duties and have a firm understanding of GDP principles [48]. Their specific responsibilities in managing 3PLs include:

• Oversight of Operations: The RP actively oversees all activities related to procurement, storage, and distribution, including those performed by partners [48].
• Management of Returns and Recalls: The RP ensures that robust procedures are in place and followed by 3PLs for handling returned products and executing recalls efficiently [48].
• Quality Agreements: The RP is instrumental in establishing and reviewing contracts that must "clearly define the duties of each party and shall contain a statement that the Contract Acceptor will comply with the GDP principles" [56]. A common citation from authorities is that contracts lack clear roles and responsibilities [48].

Technical and Quality Agreements

A comprehensive quality or technical agreement is the contractual embodiment of oversight. It transforms regulatory expectations into actionable, mutually understood responsibilities.

Table: Essential Components of a 3PL Quality Agreement

Agreement Section	Key Content for ATMP Logistics
Roles & Responsibilities	Unambiguous definition of tasks for the MAH, WDA holder, and 3PL. Specifies the designated RP and their responsibilities.
Scope of Services	Detailed description of the services provided (e.g., storage at -150°C, transport in dry shippers, packaging).
Quality & GDP Compliance	A binding statement that the 3PL will comply with EU GDP guidelines for all relevant activities.
Temperature Controls & Monitoring	Specification of required storage/transport conditions, data logging requirements, and procedures for handling temperature excursions.
Handling of Deviations	Process for the 3PL to immediately notify the MAH/WDA holder of any deviations (e.g., power outage, transport delay).
Complaints & Recalls	Defined process for the 3PL's role in supporting product recalls and handling complaints related to distribution.
Record Keeping & Access	Agreement on record retention periods and the right of the MAH and regulatory authorities to access records and audit the facility.
Subcontracting	Stipulation that the 3PL cannot subcontract services without the prior written approval of the MAH/WDA holder.

The Scientist's Toolkit: Essential Documentation and Compliance Tools

For researchers and drug development professionals, managing supply chain security involves a suite of essential documents and tools. These items form the backbone of a compliant and secure oversight system for third-party logistics.

Table: Essential Tools for Oversight of Third-Party Logistics

Tool or Document	Function in Supply Chain Oversight
EudraGMDP Database	The primary tool for verifying the GDP certification status of a potential or current wholesale distribution partner [1].
Quality Risk Management (QRM) System	A formal framework for identifying, assessing, and mitigating risks associated with the supply chain, used to prioritize audit activities and define control strategies [56].
Technical/Quality Agreement	The binding document that legally defines the roles, responsibilities, and quality expectations between the marketing authorization holder and the logistics provider [56].
Supplier Audit Report	The formal output of an on-site or remote audit, documenting compliance gaps and corrective and preventive actions (CAPA) required of the 3PL.
Standard Operating Procedures (SOPs)	Internal procedures governing the selection, qualification, and ongoing management of third-party logistics providers.
Performance Quality Indicators	Key metrics (e.g., on-time delivery, rate of temperature excursions) for the ongoing monitoring of 3PL performance.

The following workflow outlines the core process for qualifying and managing a third-party logistics provider, from initial risk assessment to continuous monitoring.

Diagram: 3PL Qualification and Management Workflow. This diagram summarizes the key stages in the lifecycle of managing a third-party logistics provider, emphasizing the critical role of the EudraGMDP check and continuous monitoring.

In the high-stakes field of ATMP development, securing the supply chain through rigorous oversight of third-party logistics is a scientific and regulatory imperative. The unique characteristics of ATMPs—their patient-specificity, extreme sensitivity, and logistical complexity—demand a proactive, risk-based approach that goes beyond mere compliance. The EudraGMDP database serves as a critical tool for initial verification, but it is only the beginning. A comprehensive strategy, built on a foundation of thorough auditing, unambiguous quality agreements, and empowered Responsible Persons, is essential. As the regulatory landscape evolves and ATMP pipelines expand, the developers who master the intricacies of supply chain security will be the ones who successfully translate revolutionary science into reliable, life-changing treatments for patients.

For researchers and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), maintaining product quality and regulatory compliance does not end with manufacturing. The complex, often fragile nature of these therapies makes Good Distribution Practice (GDP) compliance particularly challenging yet absolutely essential. GDP ensures that the quality, efficacy, and integrity of ATMPs are preserved throughout storage and transportation, safeguarding products from manufacturer to patient [47]. This technical guide examines two cornerstone elements of GDP compliance: comprehensive personnel training and the strategic role of the Responsible Person (RP). Framed within research utilizing the EudraGMDP database for ATMP manufacturing license verification, this whitepaper provides methodologies for ensuring regulatory adherence in the dynamic ATMP landscape [1] [10].

Good Distribution Practice (GDP) Fundamentals for ATMPs

Core Principles and Regulatory Scope

GDP represents a quality system for the distribution sector, ensuring that medicinal products are consistently stored, transported, and handled under appropriate conditions as required by the Marketing Authorisation (MA) or product specification. For ATMPs, which can include gene therapies, somatic-cell therapies, and tissue-engineered products, this is particularly critical due to their often limited shelf-life and sensitivity to environmental conditions [14] [47].

The European Medicines Agency (EMA) clarifies that GDP compliance is a legal obligation in many countries, subject to regular inspections by regulatory authorities. The responsibility extends beyond manufacturers to include wholesalers, logistics providers, and storage/transport service companies who must all implement and maintain GDP-compliant processes [47]. This comprehensive scope ensures product integrity throughout the entire supply chain.

Recent Regulatory Developments (2024-2025)

The regulatory landscape for GDP has undergone significant recent updates that researchers must note:

• Certificate Validity: Blanket extensions for GDP certificates issued during the pandemic are no longer granted in 2025. National authorities have resumed regular on-site inspections, though individual extensions may still be granted in exceptional cases [47].
• Remote RP Activities: The EMA has published new guidance acknowledging that remote activities of the Responsible Person may be permitted if accepted by the national competent authority where the authorized site is located. However, as a general rule, RP activities should be carried out within the EU/EEA (or Northern Ireland) [47].
• International Harmonization: The United States Pharmacopeia (USP) published a new chapter <1079.2> on Mean Kinetic Temperature (MKT) in December 2024, providing global guidance for evaluating storage and transportation conditions, with specific consideration for climatic zone IVb [47].

The Responsible Person (RP): Roles, Responsibilities, and Regulatory Requirements

Core Duties and Functions

The Responsible Person carries ultimate responsibility for ensuring GDP compliance within a wholesale distribution authorisation holder's operations. Key duties include:

• Overseeing Compliance: Ensuring that quality systems are established and maintained to guarantee GDP compliance throughout all distribution activities [47].
• Product Integrity Management: Implementing procedures to ensure that ATMPs are stored and transported under appropriate conditions, maintaining their quality and integrity [47].
• Supply Chain Security: Verifying that all partners in the supply chain, including subcontractors, maintain appropriate GDP compliance [47].
• Documentation Oversight: Ensuring proper record-keeping practices are maintained for all distribution activities, a critical requirement for ATMP traceability [5].

Qualification Requirements and Recent Updates

Regulatory authorities have specified clear qualification expectations for RPs:

Table: Responsible Person Qualification Requirements

Competency Area	Specific Requirements	Regulatory Source
Education & Experience	Appropriate qualifications and practical experience in pharmaceutical distribution	EMA GDP Guidelines [47]
Regulatory Knowledge	Comprehensive understanding of GDP regulations and relevant pharmaceutical legislation	EMA GDP Guidelines [47]
Language Proficiency	Good knowledge of the local language (as specifically mandated by Swissmedic with a 12-month compliance period)	Swissmedic Technical Interpretation I-SMI.TI.17e [47]
Geographic Presence	Activities generally must be carried out within the EU/EEA, with remote activities subject to national authority approval	EMA Q&A Document (April 2024) [47]

The language proficiency requirement highlighted by Swissmedic demonstrates how national authorities are specifying RP qualifications with increasing precision. Companies whose currently appointed RP does not meet updated language requirements have a defined compliance period (until August 2025 per Swissmedic) to either appoint a new RP with the required skills or ensure the current RP acquires them [47].

EudraGMDP Database: A Research Tool for Verification and Compliance

Database Functionality and Research Applications

The EudraGMDP database serves as a crucial verification tool for researchers and professionals investigating ATMP manufacturing and distribution licenses. Maintained and operated by the EMA, this database provides public access to non-confidential information on manufacturing and import authorisations, plus GDP certificates [1] [10].

For those researching ATMP supply chains, the database enables:

• Verification of Authorisations: Confirming that manufacturers and distributors hold appropriate valid authorisations [1] [3].
• Supply Chain Mapping: Identifying legitimate actors throughout the distribution chain to ensure GDP compliance at all stages [1].
• International Collaboration: Supporting coordination between regulators worldwide, with several international regulatory partners having access to the database [1].

Practical Research Application

When researching ATMP manufacturing licenses, the EudraGMDP database provides critical verification capabilities. The diagram below illustrates the research workflow for validating ATMP supply chain compliance:

Diagram Title: ATMP Supply Chain Verification Workflow

Since January 2022, manufacturers, importers, and distributors must ensure their organization details are correctly recorded in EMA's Organisation Management Service (OMS) before applying to national competent authorities for authorizations. This enhancement supports more reliable data in EudraGMDP through consistent use of organization master data [1].

Training Methodologies for GDP Awareness

Establishing Comprehensive Training Programs

Effective GDP training programs for personnel handling ATMPs should incorporate multiple instructional approaches:

• Structured Curriculum: Developing training modules covering GDP principles, temperature management, documentation practices, and contingency planning [47].
• Case-Based Learning: Implementing scenario-based training using real-world examples of distribution challenges specific to ATMPs [14].
• Practical Demonstrations: Conducting hands-on sessions for temperature monitoring equipment, packaging systems, and emergency procedures [47].

Specialized ATMP Training Components

Training must address the unique characteristics of ATMPs that differentiate them from conventional pharmaceuticals:

Table: Specialized ATMP Training Components

Training Component	Key Content Areas	Rationale
Temperature Management	Mean Kinetic Temperature (MKT) calculations, monitoring equipment use, excursion response protocols	ATMPs often have strict, narrow temperature parameters [47]
Chain of Identity	Procedures for maintaining patient-specific product identity, documentation requirements	Critical for autologous therapies where products are patient-specific [14] [3]
Time Sensitivity	Scheduling, emergency contingency planning, communication protocols	Many ATMPs have extremely limited shelf life [3]
Regulatory Navigation	EudraGMDP use, RP responsibilities, inspection readiness	Complex regulatory framework requires specialized knowledge [1] [3]

Experimental Protocol: Training Effectiveness Assessment

Objective: To evaluate the effectiveness of GDP training programs in improving personnel compliance and knowledge retention.

Methodology:

• Pre-assessment of GDP knowledge using standardized questionnaire
• Implementation of training intervention using multimodal approach
• Post-training assessment using same questionnaire immediately after training
• Follow-up assessment at 30, 90, and 180-day intervals
• Correlation of assessment results with observed compliance metrics

Materials:

• GDP Knowledge Assessment Tool (validated questionnaire)
• Training materials (modules, case studies, practical demonstrations)
• Assessment scoring system
• Statistical analysis software for results interpretation

Key Metrics:

• Knowledge retention rate over time
• Reduction in distribution deviations
• Improvement in documentation accuracy
• Increase in proactive compliance behaviors

This protocol enables organizations to quantitatively measure training effectiveness and identify areas requiring reinforcement, particularly important for ATMP handling where errors can have serious consequences [47].

Research Reagent Solutions: Essential Tools for ATMP Distribution Research

Table: Key Research Resources for ATMP Distribution Compliance

Resource/Platform	Function in Research	Application Context
EudraGMDP Database	Verification of manufacturing authorizations and GDP certificates	Primary source for validating legitimate supply chain actors [1] [10]
EMA GDP Guidelines	Reference for regulatory requirements and compliance standards	Foundation for developing training programs and quality systems [5] [47]
Organisation Management Service (OMS)	Source of verified organization master data	Ensuring accurate entity information in regulatory submissions [1]
USP Chapter <1079.2>	Guidance on Mean Kinetic Temperature calculations	Technical reference for temperature monitoring protocols [47]
IPEC GDP Guide for Pharmaceutical Excipients	Reference for excipient distribution standards	Supporting comprehensive supply chain quality management [47]

Implementation Framework: Integrating Personnel and Systems

Strategic RP Deployment

Organizations must strategically deploy RP resources to ensure continuous GDP compliance:

Diagram Title: RP Responsibility Distribution Framework

The framework acknowledges recent regulatory flexibility regarding remote RP activities while emphasizing that core responsibilities must remain within EU/EEA jurisdiction unless specifically approved by national authorities [47].

Compliance Monitoring and Continuous Improvement

Maintaining GDP compliance requires ongoing monitoring and improvement processes:

• Regular Internal Audits: Conducting systematic reviews of distribution processes against GDP requirements [47].
• Performance Metrics: Tracking key indicators such as temperature excursion rates, documentation errors, and training compliance [47].
• Management Review: Implementing structured review processes to assess GDP system effectiveness and identify improvement opportunities [5].
• Inspection Readiness: Maintaining continuous preparedness for regulatory inspections through mock audits and documentation reviews [1].

For researchers and drug development professionals working with ATMPs, ensuring GDP awareness and RP availability represents a fundamental component of regulatory compliance and product quality. The specialized nature of ATMPs demands particularly robust distribution controls, comprehensive personnel training, and strategic deployment of Qualified Responsible Persons. The EudraGMDP database serves as an essential research tool for verifying the compliance status of manufacturing and distribution partners. As regulatory frameworks continue to evolve, particularly with recent updates to GDP certificate validity and RP location requirements, maintaining current knowledge and adaptable quality systems becomes increasingly critical. By implementing the frameworks and methodologies outlined in this technical guide, organizations can strengthen their ATMP distribution capabilities, ensuring these innovative therapies reach patients with their quality, efficacy, and integrity fully intact.

The landscape for Advanced Therapy Medicinal Products (ATMPs) is evolving at an unprecedented pace, driven by both therapeutic innovation and regulatory modernization. Within the European Union, the EudraGMDP database serves as a critical transparency tool, providing public access to Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) compliance data for manufacturing authorizations and certifications [58] [59]. For researchers, scientists, and drug development professionals working with ATMPs, this database represents more than a regulatory checkpoint; it is a foundational element for building supply chain integrity. ATMPs, including cell and gene therapies, present unique "vein-to-vein" supply chain challenges due to their personalized nature, sensitivity to environmental conditions, and complex regulatory requirements [60] [61]. The integration of blockchain technology offers a transformative approach to meet these challenges, enabling enhanced traceability, security, and compliance. This guide explores the strategic preparation for evolving GDP requirements and blockchain adoption, framed within the essential context of EudraGMDP compliance for ATMP manufacturing and distribution.

Evolving Good Distribution Practice (GDP) Requirements for 2025

The regulatory framework for GDP is dynamic, with recent updates emphasizing stricter controls, digital transformation, and enhanced supply chain oversight. Compliance is no longer merely a regulatory obligation but a critical component of product quality and patient safety.

Key Regulatory Developments in the EU

Building on the article "GDP Update 2023/2024," several significant changes have emerged in 2024 and the first quarter of 2025 [47]:

• Certificate Validity: The blanket extensions for GDP certificates granted during the pandemic have officially concluded. As of a February 2025 update from the European Medicines Agency (EMA), extensions will no longer be granted automatically, though they may be considered on a case-by-case basis by national authorities [47].
• Remote Activities of the Responsible Person (RP): In April 2024, the EMA published a new Q&A document clarifying that remote activities for the Responsible Person could be permissible if accepted by the national competent authority. However, as a general rule, RP activities should be carried out within the EU/EEA [47].
• National Implementations: Authorities like Germany's ZLG have updated several procedural documents related to GDP for active substances, including clarifications for the registration of full-line wholesalers and increased use of the EudraGMDP database [47].

Table 1: Updated GDP Compliance Checklist for 2025 Key Areas

Compliance Area	Key Requirement	2025 Update / Emphasis
Warehouse Standards	Temperature mapping; Real-time monitoring for cold chain; Separate quarantine areas [62].	Annual temperature mapping (vs. biennial); Blockchain-based location tracking for high-risk products [62].
Documentation & Record-Keeping	Quality Management System (QMS) manual; Full audit trail of product movements [62].	Paper records no longer accepted for batch tracing; Must use cloud-based systems with 10-year retention [62].
Transportation & Logistics	GPS-tracked vehicles with temperature logging; Validated cold chain packaging [62].	"Last mile" delivery now under GDP scope; Required use of tamper-evident seals with serialization [62].
Staff Training	Qualified Person (QP) designated; Annual GDP training for all staff [62].	Data integrity training for IT/ERP system users; Fraud detection protocols for receiving staff [62].

The Critical Role of Data Integrity

Underpinning all GDP requirements is the fundamental principle of data integrity. The ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, and Available) provide a framework for ensuring data trustworthiness [60]. For ATMPs, where processes can be variable and patient-specific, controlling the data generated is paramount. Effective data integrity is achieved through a combination of controls [60]:

• Behavioral Controls: Fostering a culture of quality and integrity.
• Technical Controls: Implementing systems that enforce data integrity by design (e.g., access controls, audit trails).
• Procedural Controls: Establishing clear, documented procedures for data management.

Blockchain Technology as a Paradigm Shift for ATMP Traceability

Blockchain, a form of Decentralized Distributed Ledger Technology (DDLT), offers a secure, transparent, and immutable method for recording transactions across a network of participants [63]. Its core principles—consensus, provenance, immutability, and finality—directly address the most pressing challenges in the ATMP supply chain [61].

How Blockchain Addresses ATMP-Specific Challenges

The "vein-to-vein" supply chain for autologous and allogenic ATMPs is exceptionally complex, involving multiple stakeholders and stringent environmental requirements. Blockchain technology provides solutions for several key challenges [64] [61]:

• Ensuring Product Integrity: ATMPs are highly sensitive to their environment. When integrated with IoT sensors, a blockchain ledger can provide an immutable record of temperature, geolocation, and other critical parameters throughout the product's journey, from the patient to the manufacturing facility and back [61].
• Enhancing Coordination and Transparency: The decentralized nature of blockchain allows all permissioned stakeholders—hospitals, manufacturers, logistics providers, and even regulators—to monitor the status of the therapy in real-time based on a single source of truth. This solves coordination issues inherent in centralized or paper-based systems [64] [61].
• Securing Patient Data and Maintaining Chain of Identity: Blockchain can manage patient consent and link the product to the patient securely using encryption and selective data disclosure, which is critical for preventing mix-ups in autologous therapies [64].

The Regulatory and Efficiency Argument: Zero-Knowledge Proofs

A particularly powerful application of blockchain for GDP compliance is the use of zero-knowledge proofs (ZKPs). This cryptographic method allows a party to prove that a given statement is true without revealing the underlying data [64]. In practice, a manufacturer could demonstrate to a regulator that all GDP requirements for a shipment were met (e.g., temperature was maintained, all hand-offs were recorded) without exposing the entire, potentially commercially sensitive, dataset. This facilitates "compliance by exception," where regulators can focus their oversight on processes that have deviated from the standard, significantly reducing monitoring costs and increasing efficiency [64] [61].

A Protocol for Implementing a Blockchain-Enabled Traceability System

Integrating blockchain into an ATMP supply chain requires a structured, agile methodology. The following protocol, derived from proposed and ongoing research, provides a roadmap for implementation [64].

Phase 1: Stakeholder Analysis and System Definition

• Objective: Map all stakeholders and define user requirements.
• Methodology:
  • Identify Consortium Members: Assemble all parties involved in the vein-to-vein chain: the ATMP manufacturer, contract manufacturing organizations (CMOs), treatment centers, logistics providers, and potentially regulators [61].
  • Conduct Focus Groups: Hold meetings to understand pain points, data flows, and specific regulatory requirements at each stage. Identify where monitoring costs are highest and how a decentralized system could reduce them [64].
  • Define Data Standards: Agree on the data attributes to be recorded on the blockchain (e.g., time stamps, temperature readings, product status) and those to be stored off-chain for performance and privacy [64].

Phase 2: Platform Customization and Smart Contract Development

• Objective: Develop and customize the core blockchain platform and its business logic.
• Methodology:
  • Select Blockchain Architecture: Choose a permissioned (private) blockchain platform, such as Hyperledger Fabric, which is suited for business applications where participant identity is known and transaction privacy is important [65] [63].
  • Develop Smart Contracts: Code the business logic into smart contracts. These self-executing contracts will automate key processes. For example, a smart contract could:
    • Automatically flag a shipment if a temperature excursion is recorded by an IoT sensor.
    • Update the product status from "in transit" to "received" upon verification of a digital signature at the treatment center.
    • Trigger a payment upon confirmation of successful product administration [64].
  • Integrate with Legacy Systems: Develop application programming interfaces (APIs) to connect the blockchain platform with existing ERP, QMS, and EudraGMDP database systems for seamless data flow [64].

The following diagram illustrates the core workflow and stakeholder interactions in a blockchain-enabled ATMP supply chain.

Phase 3: Migration, Integration, and Evaluation

• Objective: Deploy the system and evaluate its performance against key metrics.
• Methodology:
  • Pilot Implementation: Launch the system for a single therapy or a limited number of treatment centers.
  • Data Collection and Evaluation: Monitor key performance indicators (KPIs) including:
    • Reduction in communication time between stakeholders.
    • Elimination of manual data entry errors and paperwork.
    • Number of prevented shipment failures or mix-ups.
    • Reduction in regulatory monitoring costs through the use of ZKPs [64].
  • Iterative Scaling: Use feedback from the pilot to refine the system before expanding to a broader network.

Table 2: Research Reagent Solutions: Essential Components for a Blockchain ATMP Platform

Component / Solution	Function / Rationale	Example Implementations
Permissioned Blockchain Platform	Provides the foundational distributed ledger; allows known participants and enables transaction privacy, which is crucial for commercial and patient data.	Hyperledger Fabric [63], Ethereum-based private chains [64].
Smart Contract Framework	Encodes the business logic and GDP rules; automates processes like compliance checking and status updates, reducing human error.	Solidity (Ethereum), Go (Hyperledger Fabric) [64].
IoT Sensors & API Gateways	Captures real-time, objective environmental (temperature, geolocation) and process data; feeds this data to the blockchain ledger.	GPS trackers, temperature loggers with cellular/wireless connectivity [61].
Zero-Knowledge Proof (ZKP) Module	Enables regulatory compliance verification without exposing full datasets, protecting commercial IP and patient privacy while streamlining audits.	zk-SNARKs, zk-STARKs cryptographic libraries [64].
Digital Identity & Consent Management	Manages secure, patient-controlled digital identities and consent for data sharing, ensuring alignment with GDPR/HIPAA.	Self-sovereign identity (SSI) solutions [63].

The future of ATMP distribution lies at the intersection of robust regulatory adherence and technological innovation. The EudraGMDP database will continue to be the central validator of GMP/GDP compliance, and preparation for its evolving requirements is non-negotiable. By proactively integrating blockchain technology, drug development professionals and researchers can not only meet these requirements but exceed them. The result will be a supply chain that is not only compliant and secure but also more efficient, transparent, and resilient—a critical foundation for delivering the life-saving promise of advanced therapies to patients worldwide. The journey requires strategic investment and cross-stakeholder collaboration, but the payoff is a future-proofed operation capable of leading the next wave of pharmaceutical innovation.

Leveraging EudraGMDP for Due Diligence and Strategic Decision-Making

For researchers, scientists, and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), verifying the regulatory compliance of partners and suppliers is a critical component of quality assurance and risk management. ATMPs, which include gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines, represent a complex and rapidly evolving category of biological medicinal products [14]. The European regulatory framework mandates that any company involved in manufacturing or importing ATMPs within the European Economic Area must hold appropriate authorizations and comply with Good Manufacturing Practice (GMP) principles [7]. The EudraGMDP database, maintained by the European Medicines Agency (EMA), serves as the primary tool for verifying the compliance status of manufacturers and suppliers in this sector [8] [1]. This technical guide provides a comprehensive methodology for leveraging this database to ensure regulatory compliance throughout the ATMP supply chain, a crucial consideration given the specific regulatory challenges and stringent quality requirements for these innovative therapies.

Understanding the EudraGMDP Database

Purpose and Functionality

The EudraGMDP database is the official Community database for manufacturing, import, and wholesale-distribution authorizations, along with GMP and Good Distribution Practice (GDP) certificates [1]. This database represents a centralized information hub that aims to improve information sharing between regulators and the public, including the pharmaceutical industry. Its key functions include aiding the coordination of inspections of manufacturers in third countries among national competent authorities, eliminating the need for industry to submit paper documents to support marketing-authorization applications, and helping protect the medicine distribution chain and active-substance supply chain by facilitating the verification of legitimate actors [1]. For ATMP professionals, this database provides transparent access to the compliance status of potential partners and suppliers, a critical factor given the complex manufacturing processes and specialized materials involved in advanced therapy production.

Legal Framework and Governance

The legal framework for the EudraGMDP database was established by Directive 2004/27/EC amending Directive 2001/83/EC on human medicinal products [8]. The database operates under the management of the EMA, with content provided by the National Competent Authorities (NCAs) of the EEA member states [8]. This structure ensures that the information available reflects the official regulatory status of manufacturing sites as determined through inspections conducted by authorized regulatory bodies. The Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG), chaired by the EMA and composed of senior GMP inspectors from the EEA, provides guidance and recommendations on the harmonization and coordination of GMP and GDP matters, ensuring consistent application of standards across the region [7].

Compliance Document Types in EudraGMDP

The EudraGMDP database contains several categories of regulatory documents essential for verifying partner and supplier compliance. Understanding these document types is fundamental to effective due diligence in the ATMP sector.

Table 1: Key Compliance Documents in the EudraGMDP Database

Document Type	Description	Relevance to ATMPs
Manufacturing and Importation Authorisation (MIA)	Authorization issued by NCA permitting manufacturing or import of medicinal products in the EEA [8]	Mandatory for all ATMP manufacturers operating within or importing to the EEA [7]
GMP Certificate	Certificate issued after successful inspection confirming compliance with GMP principles [8]	Confirms adherence to specific GMP guidelines for ATMPs published by European Commission [7]
GDP Certificate	Certificate for wholesale distributors confirming compliance with Good Distribution Practice [8]	Important for verifying distributors in ATMP supply chain
Statement of Non-Compliance	Document issued when inspection identifies serious GMP/GDP failures [8]	Critical risk indicator for supplier selection
API Registration	Registration of active substance manufacturers, importers, and distributors [8] [24]	Relevant for ATMPs utilizing biological active substances

For ATMPs specifically, manufacturers must demonstrate compliance with EU GMP rules and principles, including the specific GMP guidelines for ATMPs published by the European Commission in accordance with Article 5 of Regulation (EC) No 1394/2007 [7]. The regular and repeated on-site inspections conducted by NCAs evaluate whether all manufacturing operations are performed in line with GMP and the relevant marketing authorization, with the outcomes documented in the EudraGMDP database [7].

Step-by-Step Verification Methodology

Verification Workflow

The process for verifying partner and supplier compliance follows a systematic workflow that ensures comprehensive due diligence. The diagram below illustrates this logical verification process:

Practical Implementation Guide

• Database Access: Navigate to the public EudraGMDP database accessible through the EMA website [8]. The database is updated regularly with information provided directly by NCAs [1].

• Entity Identification: Search for the manufacturing site or supplier using precise naming conventions and location details. Since January 2022, organization-related details are drawn from EMA's Organisation Management Service (OMS), ensuring consistency in identification [1].

• Authorization Verification: Confirm the existence of a valid Manufacturing and Importation Authorisation (MIA) for the specific site and activities relevant to your ATMP [8]. For ATMPs, this authorization should cover the specific category of product (gene therapy, somatic-cell therapy, or tissue-engineered medicine) [14].

• GMP Certificate Assessment: Verify that current GMP certificates are present, indicating recent successful inspections. Note that GMP certificates are issued when the inspection outcome confirms compliance with GMP principles [8]. For ATMP manufacturers, specific GMP guidelines apply, as published by the European Commission [7].

• Non-Compliance Screening: Actively check for any statements of non-compliance, which are entered when serious GMP failures are identified [8]. The discovery of non-compliances may result in health protection measures, including prohibition of manufacture or suspension of authorizations [7].

• Documentation and Audit Trail: Maintain comprehensive records of all verification checks, including dates of access, specific documents reviewed, and any identified concerns. This documentation forms part of the pharmaceutical quality system required under EU GMP [7].

• Risk Assessment Integration: Incorporate verification findings into your supplier qualification and risk management processes. The supply chain for each active substance must be established back to the manufacture of the active substance starting materials, and the risks associated with this supply chain should be formally documented [5].

Essential Research Toolkit for Compliance Verification

Table 2: Research Reagent Solutions for Regulatory Compliance Verification

Tool/Resource	Function/Purpose	Application in Verification Process
EudraGMDP Database	Primary database for GMP/GDP compliance status [8] [1]	Central tool for verifying authorizations and certificates of manufacturers and suppliers
OMS (Organisation Management Service)	EMA master database for organization details [1]	Ensuring correct identification of entities in EudraGMDP searches
EMA GMP/GDP Q&A Documents	Interpretive guidance on EU GMP guidelines [5]	Clarifying regulatory requirements and inspection standards for complex scenarios
Compilation of Union Procedures (CoUP)	Standardized procedures and templates for inspections [66]	Understanding basis for national inspection procedures and certificate formats
ATMP-Specific GMP Guidelines	European Commission guidelines on GMP for ATMPs [7]	Assessing compliance with ATMP-specific manufacturing requirements

This toolkit provides the essential resources for comprehensive compliance verification. The EudraGMDP database serves as the cornerstone tool, while the supporting resources provide context and clarification for proper interpretation of the information obtained. The EMA and NCAs provide additional support and scientific advice to ensure respect of EU GMP, with manufacturers able to access guidelines reflecting a harmonized approach across EU Member States [7].

Analysis of Quantitative Data in EudraGMDP

While the EudraGMDP database itself primarily contains qualitative compliance information, systematic analysis of the data permits quantitative assessment of supplier compliance profiles. This analysis can inform risk-based decision making in partner selection.

Table 3: Quantitative Metrics for Supplier Compliance Assessment

Metric Category	Specific Parameters	Interpretation in Risk Assessment
Inspection History	Number of successful inspections, Frequency of inspections, Time since last inspection	Consistent positive outcomes indicate robust quality systems; gaps may signal compliance issues
Authorization Scope	Types of manufacturing activities authorized, Geographical coverage, Product categories covered	Confirms suitability for specific ATMP type and intended market
Compliance Timeline	Certificate issue and expiry dates, History of regulatory actions, Pattern of authorization updates	Identifies potential compliance deterioration or improvement trends
Supply Chain Complexity	Number of contracted sites, Presence of multiple jurisdictions, Depth of supply chain documentation	Higher complexity may require more extensive verification efforts

For ATMPs specifically, the regulatory landscape is characterized by a high number and diversity of guidance documents, with our analysis finding 126 guidance documents applicable to ATMPs from July 1990 to September 2023 [67]. This regulatory complexity underscores the importance of thorough compliance verification for all partners in the ATMP development and manufacturing continuum.

Advanced Technical Considerations for ATMPs

ATMP-Specific Verification Challenges

Verifying compliance for ATMP partners presents unique challenges beyond conventional pharmaceutical manufacturing. The substantial manipulation of cells or tissues defines many ATMPs and triggers specific regulatory requirements [14]. When verifying suppliers for these products, particular attention should be paid to whether the manufacturing authorization specifically covers the type of manipulation being conducted. Additionally, combined ATMPs that incorporate medical devices as integral components, such as cells embedded in biodegradable matrices or scaffolds, require verification of compliance with both medicinal product and device regulations [14].

The regulatory framework for ATMPs continues to evolve, with the European Commission and EMA publishing a joint action plan on ATMPs in October 2017 to streamline procedures and better address specific requirements of ATMP developers [14]. This dynamic regulatory environment necessitates ongoing monitoring of compliance status rather than one-time verification. Furthermore, the EMA's Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs, and understanding their recommendations and classifications can inform more sophisticated verification approaches [14].

Contractual Compliance Verification

The complex manufacturing processes for ATMPs frequently involve multiple contracted entities, creating additional verification requirements. According to EU GMP guidance, a direct written contract should be in place between the Marketing Authorization Holder (MAH) and the Manufacturing and Importation Authorization (MIA) holder responsible for Qualified Person (QP) certification of the product [5]. A similar direct contract should exist between the MIA holder and sites involved in various manufacturing stages [5].

While a "chain of contract" setup may be acceptable in exceptional cases, this arrangement requires robust documentation and verification to ensure: timely communication between all parties; access to relevant contracts for all entities; written acceptance of arrangements by the MIA holder; and comprehensive auditing of all parties [5]. These contractual verification steps are essential for maintaining supply chain integrity and regulatory compliance for ATMPs with distributed manufacturing models.

For professionals involved in ATMP research and development, rigorous verification of partner and supplier compliance status represents both a regulatory necessity and a critical quality assurance measure. The EudraGMDP database provides the foundational tool for this verification process, offering transparent access to authorization and compliance information for manufacturers and distributors across the EEA. By implementing the systematic verification methodology outlined in this guide—incorporating comprehensive database searches, careful document analysis, and ongoing monitoring—organizations can effectively mitigate regulatory risks while advancing the development of innovative advanced therapies. The dynamic nature of the ATMP regulatory landscape necessitates continued vigilance and adaptation of verification practices as new guidelines and requirements emerge in this rapidly evolving field.

Using the Database for Regulatory Intelligence and Inspection Planning

The EudraGMDP database, maintained by the European Medicines Agency (EMA) in partnership with EU National Competent Authorities, serves as a critical repository for good manufacturing practice (GMP) and good distribution practice (GDP) compliance information [43]. For researchers, scientists, and drug development professionals working with Advanced Therapy Medicinal Products (ATMPs), this database provides indispensable regulatory intelligence for strategic planning and compliance assurance. The system contains inventory on the status of pharmaceutical manufacturers of both active substances and finished medicinal products that have been subject to inspection by National Competent Authorities within the EU or in third countries [43].

EudraGMDP functions as a dual-access system: while confidential access is reserved for inspectors and regulatory bodies, a public portal allows internet users to search for GMP compliance information using certificate numbers or site details such as DUNS Number, site name, city, and country [43]. This makes it an essential tool for due diligence during vendor selection, partnership development, and regulatory strategy formulation for ATMP manufacturing licenses.

Database Structure and Information Taxonomy

Core Data Modules

The EudraGMDP database architecture comprises several interconnected modules that collectively provide a comprehensive view of regulatory compliance status [43]:

• GMP Certificates and Planned Inspections: Documents compliance with Good Manufacturing Practice standards
• GMP Non-Compliance Reports: Identifies facilities failing to meet regulatory requirements
• Manufacturing/Importation Authorisations (MIA): Records authorizations for manufacturing and import activities
• Good Distribution Certificates (GDP): Tracks compliance along the distribution chain
• Wholesale Distribution Authorisations (WDA): Records authorizations for wholesale distribution
• Active Substance Registrations: Registers manufacturers, importers and distributors of active substances for human use

Legal Framework and Governance

The Union format for the GMP Certificate is established in accordance with Article 47 of Directive 2001/83/EC and Article 93(2) of Regulation (EU) 2019/6 [10]. GMP Certificates are entered into EudraGMDP as referred to in Article 111(6) of Directive 2001/83/EC and Article 91(3) of Regulation (EU) 2019/6 [10]. This legal foundation ensures the standardized presentation and recognition of compliance documentation across the European Economic Area.

Table: EudraGMDP Certificate Types and Regulatory Applications

Certificate Type	Legal Basis	Primary Use in ATMP Research	Data Accessibility
GMP Certificate	Directive 2001/83/EC Art. 47	Verification of manufacturing compliance	Public access
GDP Certificate	Directive 2001/83/EC	Distribution chain quality assurance	Public access
Non-Compliance Report	Regulation (EU) 2019/6	Risk assessment of suppliers	Public access
Manufacturing/Import Authorisation	Directive 2001/83/EC	Due diligence for partnership decisions	Restricted access

Methodological Framework for Database Utilization

Experimental Protocol 1: Supplier Qualification Assessment

Objective: To systematically evaluate potential ATMP manufacturing partners using EudraGMDP compliance data.

Materials and Reagents:

• EudraGMDP Public Access Portal: Primary data source for compliance verification [43]
• Site Identifier Information: DUNS Number, site name, and geographical details [43]
• Regulatory Database: Compilation of Union Procedures on Inspections and Exchange of Information [10]
• Documentation System: For maintaining audit trails of regulatory assessments

Methodology:

• Initiate Search Query: Access the EudraGMDP application at eudragmdp.ema.europa.eu
• Input Search Parameters: Utilize site identifiers including DUNS Number, site name, city, and country [43]
• Retrieve Compliance Documentation: Extract GMP certificates, inspection reports, and non-compliance records
• Cross-Reference Legal Status: Verify certificate validity against the Compilation of Union Procedures [10]
• Document Assessment: Record findings with certificate numbers, dates, and any restrictions or conditions

Validation Criteria:

• Current, valid GMP certificates with no unresolved non-compliance reports
• History of successful inspections with no critical findings
• Consistency between claimed capabilities and regulatory documentation

Experimental Protocol 2: Inspection Planning and Readiness

Objective: To proactively prepare for regulatory inspections by analyzing historical inspection patterns and common deficiencies.

Materials and Reagents:

• Historical Inspection Data: Non-compliance reports and inspection outcomes from EudraGMDP [49]
• Quality Risk Management Framework: As referenced in EU GMP guidance [5]
• Comparative Analysis Tools: For benchmarking against industry standards

Methodology:

• Data Extraction: Collect non-compliance reports relevant to ATMP manufacturing facilities
• Deficiency Categorization: Classify findings based on EU GMP chapters and criticality
• Trend Analysis: Identify recurring compliance issues across the ATMP sector
• Gap Assessment: Compare findings against internal quality systems
• Remediation Planning: Develop targeted corrective actions based on regulatory patterns

Validation Criteria:

• Comprehensive coverage of relevant regulatory requirements
• Alignment with most recent regulatory focus areas
• Implementation of preventive measures for commonly cited deficiencies

Data Interpretation and Analysis Framework

Quantitative Assessment Metrics

The EudraGMDP database enables quantitative analysis of regulatory compliance status through structured data elements. The following table outlines key metrics for regulatory intelligence:

Table: Quantitative Metrics for ATMP Regulatory Intelligence

Metric Category	Data Source	Calculation Method	Interpretation in ATMP Context
Inspection History Density	GMP Certificate Records	Number of inspections per timeframe	High frequency may indicate compliance issues or complex operations
Non-Compliance Incidence	Non-Compliance Reports	Ratio of non-compliance to total inspections	Elevated ratios signal systemic quality issues
Certification Latency	Certificate Issue Dates	Time between inspection and certification	Extended delays may indicate significant remediation requirements
Geographic Compliance Variance	Regional Inspection Data	Comparison of findings across regions	Identifies regional regulatory emphasis differences

Case Study: Data Integrity Assessment

A recent GDP Non-Compliance Report from January 2025 illustrates the application of EudraGMDP data for risk assessment [49]. The Hungarian competent authority issued a report following a January 17, 2025 inspection that identified critical violations including data integrity problems and unauthorized personnel performing quality-related decisions [49]. Specific findings included:

• Unauthorized Access: Personnel without proper authorization accessed accounts and performed critical quality decisions
• Credential Sharing: Responsible Persons' credentials were shared with other personnel
• Inadequate IT Controls: Systems failed to regulate access permissions and lacked sufficient monitoring, logging, and user identification
• Poor Remote Access Controls: Inadequate security for remote system access [49]

The regulatory outcome included partial suspension of the wholesale distribution license, with limitations on activities except for medicines deemed critical by the authority [49]. This case demonstrates how EudraGMDP data can reveal systemic weaknesses relevant to ATMP manufacturing environments where data integrity is paramount.

Advanced Technical Implementation

Regulatory Intelligence Workflow

The following diagram illustrates the systematic approach to extracting regulatory intelligence from EudraGMDP for ATMP development:

Research Reagent Solutions for Regulatory Assessment

Table: Essential Research Materials for Regulatory Intelligence Activities

Research Material	Technical Function	Application in EudraGMDP Analysis
EudraGMDP Public Access Portal	Primary regulatory data source	Direct extraction of GMP certificates, non-compliance reports, and authorization status [43]
Compilation of Union Procedures	Reference for regulatory standards	Interpretation of certificate formats and legal requirements [10]
GMP/GDP Q&A Documentation	Interpretive guidance for standards	Contextual understanding of inspection findings and compliance expectations [5]
Non-Compliance Report Database	Historical compliance data	Pattern analysis of regulatory enforcement trends and common deficiencies [49]
Quality Risk Management Framework	Systematic risk assessment tool	Evaluation and prioritization of identified compliance gaps [5]

Strategic Implementation for ATMP Development

Integration with Quality Systems

The intelligence gathered from EudraGMDP should be systematically integrated into the Pharmaceutical Quality System as required by EU GMP Chapter 1 [5]. This includes:

• Documented Supply Chain Verification: Establishing the supply chain for each active substance back to the manufacture of the active substance starting materials, with formal documentation of associated risks [5]
• Comprehensive Quality Agreements: Implementing direct written contracts between the Marketing Authorization Holder (MAH) and the Manufacturing Importation Authorization (MIA) holder responsible for Qualified Person (QP) certification, with clearly defined activities and responsibilities for each entity [5]
• Robust Change Control Systems: Ensuring that contracts in "chain of contracts" setups are reviewed as part of the product quality review (PQR) process, with changes notified to and accepted by the MIA holder responsible for QP release [5]

Advanced Analytical Techniques

For comprehensive regulatory intelligence, implement these advanced analytical approaches:

• Comparative Regulatory Mapping: Analyze inspection outcomes across different National Competent Authorities to identify regional variations in regulatory emphasis or interpretation
• Temporal Trend Analysis: Track changes in inspection focus areas and deficiency patterns over time to anticipate evolving regulatory expectations
• Cross-Functional Impact Assessment: Evaluate how identified compliance issues in similar facilities might impact specific ATMP manufacturing processes, particularly for novel therapeutic platforms
• Supplier Risk Stratification: Develop risk-based categorization of potential partners based on compliance history, inspection density, and deficiency patterns

The strategic application of EudraGMDP data enables ATMP researchers to make evidence-based decisions regarding manufacturing partnerships, identify potential compliance vulnerabilities in advance of inspections, and maintain current understanding of regulatory expectations in this rapidly evolving field.

For researchers and developers in the advanced therapy medicinal product (ATMP) space, navigating the European Union's regulatory landscape is a critical component of bringing new therapies from the lab to the clinic. Central to this landscape is the EudraGMDP database, a key tool for ensuring the quality and safety of medicinal products. EudraGMDP, which stands for the European Union Drug Good Manufacturing and Distribution Practice database, serves as the community database for manufacturing and import authorisations, as well as good manufacturing practice (GMP) and good distribution practice (GDP) certificates [1]. For ATMP manufacturers, whose products often involve complex biological materials and processes, understanding and utilizing EudraGMDP is not merely a regulatory obligation but a fundamental aspect of quality assurance and regulatory strategy.

This technical guide examines the unique position of EudraGMDP within the broader EU regulatory ecosystem, with particular emphasis on its critical role for ATMP manufacturing licenses. Unlike more general regulatory databases, EudraGMDP provides a specialized focus on the quality systems and manufacturing standards that are particularly challenging for ATMP developers, from academic institutions to commercial enterprises. The database's evolution since its initial launch in 2007 reflects the growing complexity of medicinal product manufacturing, especially with the inclusion of active substance registrations and GDP information in subsequent releases [1].

EudraGMDP's Core Architecture and Functionality

System Purpose and Scope

EudraGMDP functions as a centralized repository for quality-related compliance information across the European Economic Area (EEA). Its primary objective is to improve information sharing between regulators and the public, aid in coordinating inspections of manufacturers in third countries, eliminate the need for industry to submit paper documents to support marketing-authorisation applications, and help protect the medicine distribution chain by facilitating verification of legitimate actors [1]. The system is maintained and operated by the European Medicines Agency (EMA), with content provided by national competent authorities of EU Member States [1].

The database encompasses several key areas of regulatory oversight:

• Manufacturing and Importation Authorisations (MIAs)
• GMP and GDP Compliance Certificates
• Non-Compliance Reports
• Registration of active substance manufacturers, importers, and distributors [43]

For ATMP researchers, this centralized approach provides unprecedented visibility into the quality standards and compliance status of manufacturing facilities, which is particularly valuable when establishing contracts with contract manufacturing organizations (CMOs) or when scaling up from research-grade to clinical-grade production.

Key Users and Access Levels

EudraGMDP employs a tiered access model that serves different stakeholder groups with appropriate levels of information:

Table: EudraGMDP User Access Levels

User Category	Access Level	Key Permissions
EEA National Competent Authorities	Read & Write	Full access to create, enter, and edit GMP certificates, non-compliance reports, and authorisations [43]
International Regulatory Partners	Unrestricted Read	Access to information supporting mutual recognition agreements [1]
Pharmaceutical Industry & Public	Restricted Public Access	Search functionality for GMP/GDP compliance by certificate number or site details [43]

This multi-layered access framework ensures that sensitive information is protected while maintaining transparency in the regulatory environment. For ATMP developers, the public access component provides a valuable due diligence tool when evaluating potential manufacturing partners or suppliers.

Comparative Analysis: EudraGMDP in the EU Regulatory Ecosystem

Distinguishing EudraGMDP from EUDAMED

A critical distinction for researchers to understand is the fundamental difference between EudraGMDP and the European Database on Medical Devices (EUDAMED). While both are European regulatory databases, they govern entirely different product categories and regulatory frameworks:

Table: EudraGMDP vs. EUDAMED Comparison

Feature	EudraGMDP	EUDAMED
Regulatory Scope	Medicinal Products for human/veterinary use [1]	Medical Devices and In Vitro Diagnostics [68]
Governance	Good Manufacturing/Distribution Practice (GMP/GDP) [5] [1]	Medical Device Regulation (MDR) / In Vitro Diagnostic Regulation (IVDR) [68]
Key Focus	Manufacturing quality, authorization, and compliance [1]	Device traceability, clinical investigation, post-market surveillance [68]
Product Examples	ATMPs, chemical drugs, biological medicines [3] [4]	Hip implants, pacemakers, blood glucose monitors [68]

This distinction is particularly important for combined ATMPs, which incorporate both a medicinal product and a medical device component. Developers of such products must navigate both regulatory frameworks, utilizing EudraGMDP for the medicinal product aspects and EUDAMED for the device components [4].

Interconnection with Other Regulatory Systems

EudraGMDP does not operate in isolation but functions as part of an integrated network of regulatory systems. A key integration is with the Organisation Management Service (OMS), which since January 2022 has served as the master data source for organization-related details such as name and address [1]. This integration aims to ensure more reliable data in EudraGMDP through consistent use of organization master data, reducing the need for data entry and cleansing while enhancing IT system interoperability.

The diagram below illustrates EudraGMDP's position within the broader EU regulatory infrastructure for medicinal products:

EudraGMDP's Critical Role in ATMP Manufacturing and Licensing

The ATMP Manufacturing Authorization Process

For ATMP developers, the journey from research concept to clinically available product requires obtaining a manufacturing authorization, which EudraGMDP centrally records. According to Directive 2001/83/EC, any legal entity wishing to manufacture a medicinal product in the EU must hold this authorization issued by the national competent authority of the Member State where the manufacturing activities occur [3]. The manufacturing authorization process for ATMPs involves particularly stringent requirements due to the complexity of these products and the use of substances of human origin like blood, tissues, and cells [3].

The European Commission has published detailed GMP guidelines specific to ATMPs, recognizing their unique challenges including the use of biological materials with short shelf lives, maintaining sterility throughout complex manufacturing processes, and demonstrating product consistency despite biological variability [3]. All manufacturing sites for ATMPs must comply with these GMP standards and are subject to regular inspections by national competent authorities, with the outcomes documented in EudraGMDP.

Regulatory Framework and Oversight

The regulatory framework governing ATMP manufacturing involves multiple entities with distinct responsibilities, all connected through EudraGMDP:

Table: Key Entities in ATMP Manufacturing Oversight

Entity	Role in ATMP Manufacturing	Connection to EudraGMDP
National Competent Authorities	Assess manufacturing authorization applications; conduct regular GMP inspections [3]	Input inspection results, authorizations, and non-compliance reports [1]
EMA	Scientific assessment of ATMPs; coordinates GMP harmonization [3]	Maintains database; chairs GMP/GDP Inspectors Working Group [5] [3]
GMP/GDP Inspectors Working Group	Provides harmonized interpretation of GMP/GDP requirements [5]	Issues Q&A guidance reflected in EudraGMDP content [5]
Manufacturing Authorization Holder	Complies with GMP standards and maintains quality systems [3]	Subject of records in EudraGMDP; uses database for due diligence

This interconnected system ensures that ATMP manufacturers are held to consistent standards across the EEA, with EudraGMDP serving as the transparent record-keeping mechanism that supports regulatory coordination.

Practical Research Methodology: Utilizing EudraGMDP in ATMP Development

Experimental Protocol for Manufacturing Site Selection

For ATMP researchers selecting manufacturing partners or establishing their own GMP-compliant facilities, EudraGMDP provides critical due diligence information. The following methodology outlines a systematic approach to utilizing the database for this purpose:

Objective: To identify and evaluate potential GMP manufacturing sites for ATMP production through analysis of regulatory compliance status in EudraGMDP.

Step-by-Step Protocol:

• Define Search Parameters: Identify potential manufacturing sites by name, location, or specific activities (e.g., "sterile manufacturing," "cell therapy production").
• Access Public EudraGMDP Portal: Navigate to the public interface at eudragmdp.ema.europa.eu [43].
• Execute Search Queries: Utilize available search filters including:
  • Site name or company name
  • Country or city
  • DUNS Number (where available)
  • Certificate number (if referencing specific documentation) [43]
• Analyze Compliance Status: Review returned records for:
  • Current GMP certificates and their expiry dates
  • Manufacturing authorizations and their scope
  • Any non-compliance reports or statements
  • Historical inspection frequency and outcomes
• Verify Supply Chain Legitimacy: Confirm that active substance manufacturers and suppliers appear in the registry where required [1].
• Cross-Reference with Additional Sources: Correlate EudraGMDP findings with other regulatory assessments and scientific advice.

This methodology enables data-driven decision making when establishing manufacturing strategies for ATMP development, potentially reducing regulatory risks and timelines.

Table: Essential Research Resources for ATMP Regulatory Compliance

Research Tool	Function in ATMP Development	Access Method
EudraGMDP Public Database	Verification of manufacturing authorizations and GMP compliance status of potential partners [1]	Public portal: eudragmdp.ema.europa.eu [43]
EMA GMP/GDP Q&A Documents	Interpretation of specific technical requirements for complex ATMP manufacturing scenarios [5]	EMA website: "Guidance on good manufacturing practice" [5]
OMS Organisation Lookup	Verification of correctly registered organization details mandatory for EudraGMDP records [1]	EMA Organisation Management Service
Community Procedures on Inspections	Understanding inspection processes and standards applied by regulatory authorities [69]	EMA Inspections > GMDP/GDP compliance > Community procedures [69]

Advanced Applications in ATMP Research and Development

Navigating Complex Supply Chains

ATMPs frequently involve complex global supply chains for starting materials, particularly when using human tissues or cells. EudraGMDP supports supply chain verification through its registration of active substance manufacturers, importers, and distributors [1]. The EU GMP guide requires that "the supply chain for each active substance must be established back to the manufacture of the active substance starting materials" and that "this should be documented and must be kept current" [5]. For ATMP developers, this translates to a regulatory obligation to map and verify their entire supply chain, with EudraGMDP serving as a critical verification tool.

The database also facilitates the coordination of inspections between regulatory authorities, which is particularly valuable for manufacturers in third countries [1]. This function helps prevent duplication of inspection efforts and promotes consistent standards across international borders—a significant advantage for ATMP developers working with contract manufacturing organizations outside the EEA.

Regulatory Strategy and Market Access

From a strategic perspective, EudraGMDP plays a crucial role in regulatory planning and market access for ATMPs. The database provides visibility into the regulatory status of similar products or manufacturing approaches, helping developers anticipate potential regulatory challenges. Furthermore, the public nature of the database means that investors, partners, and other stakeholders can independently verify the regulatory standing of manufacturing facilities, making EudraGMDP an indirect factor in business development and financing discussions.

For ATMPs designated as priority medicines (PRIME) by the EMA, which includes 19 ATMPs as of 2018 [4], robust manufacturing and quality systems documented in EudraGMDP become even more critical. The PRIME scheme leverages existing regulatory tools including scientific advice, conditional approval, and accelerated assessment to expedite development of promising therapies [4]. In this context, a clean compliance record in EudraGMDP supports the overall regulatory strategy for these priority products.

Future Directions and Strategic Implications

The regulatory landscape for ATMPs continues to evolve, with ongoing discussions about decentralized manufacturing models that would place production closer to patients [3]. Such models present significant challenges for the current regulatory framework, where "each production site must hold a manufacturing authorisation and comply with GMP specific to ATMPs" [3]. Future adaptations of EudraGMDP may need to accommodate more flexible manufacturing paradigms while maintaining appropriate oversight.

The 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions that would exempt "decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site" from requiring separate manufacturing authorizations [3]. If adopted, this change would fundamentally alter how such manufacturing networks are recorded and monitored in EudraGMDP.

For ATMP researchers and developers, understanding both the current functionality and future trajectory of EudraGMDP is essential for strategic planning. As the database continues to evolve, it will likely incorporate new modules and functionalities to address emerging challenges in ATMP manufacturing, particularly as these innovative therapies become more mainstream and their manufacturing processes more complex.

In the tightly regulated pharmaceutical sector, Mutual Recognition Agreements (MRAs) serve as critical trade and public health instruments that allow regulatory authorities to rely on each other's inspection systems and quality controls. For researchers and developers working with Advanced Therapy Medicinal Products (ATMPs), understanding these agreements is paramount for navigating international regulatory pathways. The EudraGMDP database (the European Union Database for Good Manufacturing and Distribution Practice) operates as the central technological infrastructure enabling these agreements. This technical guide examines the operational integration between the European Union and Japan, detailing how this MRA partner utilizes the EudraGMDP system to facilitate regulatory cooperation, share critical manufacturing compliance data, and ensure the integrity of the global medicinal product supply chain, with specific implications for ATMP research and development [70] [1].

EU-Japan MRA: Scope and Operational Framework

The EU-Japan MRA on Good Manufacturing Practice (GMP), initially effective from 29 May 2004, underwent a significant scope extension in July 2018. This expansion broadened the agreement to cover more complex product categories, reflecting evolving regulatory science and increased trust between the systems. The agreement is specifically designed to eliminate duplicative inspections and waive batch testing requirements for products manufactured in the EU and Japan, thereby streamlining market access while upholding the highest quality standards [70].

The following table summarizes the human medicinal products covered under the EU-Japan MRA, illustrating its comprehensive scope:

Product Category	Status	Key Exclusions
Chemical Pharmaceuticals	Included	Veterinary medicines
Biological Pharmaceuticals (from non-transgenic sources)	Included	Stable medicines from human blood/plasma
Active Pharmaceutical Ingredients (APIs)	Included	Advanced Therapy Medicinal Products (ATMPs)
Sterile Medicines	Included	Medicinal gases
Homeopathic Medicines (if classified as medicines)	Included	Investigational Medicinal Products (IMPs) for clinical trials
Vitamins, Minerals, and Herbal Medicines (if classified as medicines)	Included

A critical point for ATMP researchers is that the EU-Japan MRA, like most other MRAs detailed by the EMA, explicitly excludes Advanced Therapy Medicinal Products from its scope [70]. This means that for ATMPs, separate and specific regulatory approvals and inspections are required. Nonetheless, the operational model and data exchange protocols established for other biologicals under the MRA serve as a foundational framework for regulatory collaboration.

EudraGMDP: The Technical Infrastructure for MRA Implementation

The EudraGMDP database is the cornerstone for implementing MRAs. Developed and hosted by the European Medicines Agency (EMA), it serves as the community database for manufacturing and import authorisations, as well as GMP and GDP compliance certificates [1]. Its primary functions in the context of international MRAs are:

• Information Sharing between Regulators: It allows EU National Competent Authorities and international partners with MRAs to share GMP inspection reports and compliance statuses seamlessly [1].
• Public Transparency: A public version of the database allows pharmaceutical manufacturers and the broader public to verify the GMP compliance status of manufacturing sites, enhancing supply chain security [43].
• Inspection Planning: A non-public module enables authorities to coordinate their inspection plans for manufacturers in third countries, optimizing global regulatory resources [1].

For MRA partners like Japan, the database facilitates a direct electronic link, replacing the need for exchanging paper-based certificates. The Japanese Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) were among the first international regulators to be granted unrestricted read access to EudraGMDP, and they have had write access since October 2013, allowing them to directly input inspection data [1]. This deep integration is fundamental to the agreement's operation.

Japan's Integration with EudraGMDP: Technical Protocols and Data Flows

The integration of Japanese regulatory agencies into the EudraGMDP ecosystem establishes a structured, automated workflow for data exchange. This technical interoperability is what makes the mutual recognition principle a practical reality. The process ensures that GMP compliance verified by one party is instantly accessible and trusted by the other.

The following diagram illustrates the logical workflow and data exchange between the EU and Japan via the EudraGMDP database:

Diagram: EU-Japan EudraGMDP Data Exchange Workflow

The operationalization of this workflow relies on several key technical protocols and data points, which are summarized in the table below:

Exchange Element	Technical Protocol	Function in MRA
GMP Compliance Certificates	Electronic exchange via EudraGMDP	Replaces on-site inspections by the importing party's regulators [70].
Batch Certificates	Electronic exchange	Enables the waiver of re-testing upon product importation [70].
Two-Way Alert System	Immediate notification	Activates upon discovery of quality defects or non-compliance to protect public health [70].
Inspection Planning Data	Access to non-public EudraGMDP module	Coordinates oversight of manufacturers in third countries to avoid duplication [1].

This structured exchange creates a robust system of mutual oversight. For example, when a Japanese inspector uploads a GMP certificate for a Tokyo-based API manufacturer, that certificate becomes visible to an EU Qualified Person (QP). The QP can then rely on that certification for batch release in the EU without requiring a separate EU inspection, thereby facilitating smoother trade and focusing inspectional resources on higher-risk facilities [70].

For drug development professionals and researchers, particularly those operating in the ATMP space, navigating the intersection of science and regulation requires a specific set of resources. The following toolkit comprises essential databases and documents critical for planning international development pathways and ensuring compliance.

Tool/Resource	Function & Utility for Researchers
EudraGMDP Public Database	Verifies GMP compliance status of potential manufacturing partners and active substance suppliers within the EU and MRA countries [43] [1].
EMA MRA Overview Pages	Provides the official scope, legal text, and operational status of each MRA (e.g., with Japan, Switzerland, U.S.), which is vital for strategic planning [70].
GMP/GDP Inspectors Working Group Q&A	Offers authoritative, harmonized interpretation of EU GMP guidelines, clarifying complex technical requirements for quality systems [5].
Organisation Management Service (OMS)	Ensures consistent identification of legal entities in all regulatory submissions to the EU system, a mandatory step for applications from 2022 [1].

The integration of MRA partners like Japan into the EudraGMDP database represents a sophisticated and highly functional model of international regulatory cooperation. While ATMPs are currently outside the scope of most MRAs, the established technical infrastructure and trusted data exchange protocols for biological products set a powerful precedent. For researchers and developers, mastering the use of tools like EudraGMDP is not merely an administrative task but a core component of strategic drug development. As the regulatory landscape for advanced therapies evolves, the principles of mutual recognition and database-driven transparency are likely to extend further into the ATMP field, potentially streamlining the path to market for these innovative treatments across global jurisdictions.

The development and commercialization of Advanced Therapy Medicinal Products (ATMPs) represent a frontier in modern medicine, offering innovative treatments for genetic disorders, cancer, and other serious conditions. ATMPs are categorized into three main types: gene therapy medicines, which introduce recombinant genes for therapeutic effects; somatic-cell therapy medicines, which utilize manipulated cells to treat diseases; and tissue-engineered medicines, containing cells or tissues designed to repair or regenerate human tissue [14]. A fourth category, combined ATMPs, incorporates one or more medical devices as integral components of the medicine, such as cells embedded in a biodegradable scaffold [14].

The transition from research-grade to clinical-grade manufacturing poses significant challenges. Unlike conventional pharmaceuticals, ATMPs possess complex pharmacological characteristics where the living cells themselves are the product [51]. This complexity makes their pharmacological properties more difficult to define and standardize. Maintaining consistent product characteristics and activity during the scaling-up from research to Good Manufacturing Practice (GMP)-grade production is a critical hurdle that can hinder rapid patient access to these therapies [51]. Consequently, assessing and selecting manufacturing facilities with robust quality systems is paramount for successful ATMP development.

Within the European Union, the European Medicines Agency (EMA) provides a centralized authorization procedure for all ATMPs [71]. The EudraGMDP database serves as a crucial tool for regulators and industry professionals alike, enhancing information sharing and providing transparency about the compliance status of manufacturing sites [1]. This case study demonstrates how to strategically utilize this public database to perform a rigorous assessment of a potential ATMP manufacturing site, a critical step in the drug development lifecycle.

The Regulatory Framework for ATMPs and GMP Compliance

The Centralized Role of the European Medicines Agency

The European regulatory framework for ATMPs is centralized and rigorous. The EMA is statutorily responsible for the scientific evaluation of marketing authorisation applications for all ATMPs across the European Economic Area (EEA) [71]. The Committee for Advanced Therapies (CAT), a dedicated committee within the EMA, provides the specialized expertise required to evaluate these complex products. The CAT prepares draft opinions on the quality, safety, and efficacy of ATMPs, which then form the basis for the Committee for Medicinal Products for Human Use (CHMP) opinion and the European Commission's final authorization decision [14].

This centralized oversight ensures a uniform standard of assessment across the EEA. Furthermore, the EMA actively supports developers through initiatives like the ATMP pilot for academia and non-profit organizations, which offers dedicated regulatory guidance and financial incentives to encourage the development of promising therapies targeting unmet medical needs [14].

The Critical Importance of GMP Certification

For any manufacturing site producing ATMPs, compliance with Good Manufacturing Practice (GMP) is not optional; it is a legal mandate. A GMP certificate is issued by a national competent authority following a successful inspection that confirms the manufacturer's adherence to the principles of GMP as stipulated in EU legislation [8]. The EudraGMDP database is the official repository for these certificates, providing a public-facing window into the compliance status of manufacturers both within and outside the EU [1].

The absence of a valid GMP certificate for a manufacturing site, or the presence of a statement of non-compliance in the database, represents a significant regulatory risk. It can halt clinical trials and prevent market authorization. The database aims to improve information sharing, aid in the coordination of inspections—particularly for manufacturers in third countries—and help protect the medicine supply chain by facilitating the verification of legitimate operators [1].

Methodological Protocol for Interrogating the EudraGMDP Database

Protocol for Database Interrogation and Site Assessment

A systematic approach to searching the EudraGMDP database ensures a comprehensive due diligence assessment of a potential ATMP manufacturing partner. The following protocol outlines the key steps, from initial preparation to final decision-making.

Step 1: Preliminary Information Gathering Before accessing the database, compile all known identifiers for the potential manufacturing site. This includes the company's legal name and any associated trading names, its precise physical address, and any known Manufacturing Importation Authorisation (MIA) number. This information is crucial for performing precise searches and accurately interpreting the results.

Step 2: Database Navigation and Search Execution Access the public EudraGMDP database. Utilize the search functionality to query the site using the gathered identifiers. It is advisable to perform multiple searches using slight variations of the company name to ensure no relevant records are missed. The database allows searching by company name, country, and type of document (e.g., GMP certificate, MIA).

Step 3: Data Extraction and Analysis For any identified records, extract the following key data points meticulously:

• Document Type: Is it a GMP certificate, Manufacturing Importation Authorisation, or a statement of non-compliance?
• Status and Validity: The issue date and, critically, the expiry date of the certificate or authorisation.
• Scope of Approval: The specific activities and products the certificate covers. For ATMPs, verify that the scope explicitly includes the relevant product type (e.g., "sterile products", "advanced therapy medicinal products").
• Issuing Authority: The national competent authority that performed the inspection.
• Any Specific Conditions or Remarks: Notes that may indicate limitations or special provisions attached to the manufacturing license.

Step 4: Corroboration with National Registers Cross-reference the findings with national registers of authorised medicines [72]. This provides an additional layer of verification and may reveal further details about products manufactured at the site that have received marketing authorization.

Step 5: Risk Assessment and Decision Matrix Synthesize the collected data to evaluate the level of regulatory risk associated with the site. The table below outlines a simplified decision matrix based on GMP status.

Table 1: GMP Compliance Status and Associated Risk Level

GMP Status	Risk Level	Recommended Action
Valid Certificate with ATMP-relevant scope	Low	Proceed; site is acceptable from a GMP compliance standpoint.
Valid Certificate with unclear scope	Medium	Seek clarification from the site and the issuing NCA on scope applicability to ATMPs.
Expired Certificate	High	Do not proceed until the site provides evidence of a recent successful re-inspection.
Statement of Non-Compliance	Critical	Eliminate site from consideration.

Workflow Visualization of the Site Assessment Process

The following diagram illustrates the logical workflow for assessing a potential manufacturing site, from initial research to the final partnership decision.

Diagram 1: Site Assessment Workflow

Essential Research Toolkit for ATMP Manufacturing Assessment

Successful assessment of an ATMP manufacturer extends beyond database checks. The following toolkit outlines key regulatory and material components critical for the evaluation process.

Table 2: The Scientist's Toolkit for ATMP Manufacturing Site Assessment

Tool / Resource	Function / Purpose	Relevance to Site Assessment
EudraGMDP Database	Public database for GMP/GDP certificates and manufacturing authorisations.	Primary source for verifying a site's regulatory compliance status and inspection history [8] [1].
National Competent Authorities (NCAs)	Regulatory bodies in EU/EEA Member States responsible for inspections and issuing licenses.	The issuing body for GMP certificates; source of truth for clarifying ambiguous database information [8].
Organisation Management Service (OMS)	EMA's master database for organisation-related details.	Ensures consistent and accurate identification of manufacturers in EudraGMDP, reducing data errors [1].
National Medicine Registers	Country-specific databases of authorised medicines (e.g., Germany's PharmNet.Bund, Spain's CIMA).	Allows verification of which specific ATMPs are authorized for production at a given site [72].
EMA ATMP Classification	Procedure to confirm a product's status as an ATMP prior to marketing authorization application.	Confirms the product's regulatory pathway and the associated manufacturing requirements [71].

Analysis of Regulatory Findings and Visualization of Compliance Relationships

Interpreting the data from the EudraGMDP database requires an understanding of the relationships between different regulatory entities and documents. The following diagram maps these key relationships and the flow of regulatory authority that governs ATMP manufacturing site compliance.

Diagram 2: Regulatory Compliance Relationships

The relational map in Diagram 2 clarifies that a manufacturing site's compliance is not a static event but a dynamic outcome of a structured regulatory system. The National Competent Authority (NCA) acts as the primary inspector and issuer of the Manufacturing Importation Authorisation and GMP certificate [8]. The EMA, supported by the CAT, provides overarching scientific evaluation and maintains the EudraGMDP database where the compliance data is published [14] [1]. Both entities operate under the framework of EU Legislation. A robust site assessment must therefore verify that the site has been evaluated by this system and possesses the valid, scope-appropriate documentation to prove it.

The pathway from ATMP discovery to patient administration is fraught with regulatory and manufacturing complexities. A meticulous assessment of the manufacturing site is a non-negotiable component of the development process. The EudraGMDP database, as demonstrated in this case study, is an indispensable public tool that provides transparent access to critical compliance data. By following a structured methodological protocol—involving precise database interrogation, cross-referencing with national registers, and careful analysis of certificate scope and validity—drug developers and researchers can effectively de-risk their selection of manufacturing partners. In the rapidly evolving field of advanced therapies, leveraging these public data resources is not just a best practice but a fundamental requirement for ensuring that groundbreaking treatments are manufactured to the highest standards of quality, safety, and efficacy.

Conclusion

The EudraGMDP database is an indispensable tool for ATMP developers, serving as both a public-facing verification system and a backbone for regulatory coordination. Success hinges on a thorough understanding of its data, a proactive approach to the MIA and GMP certification process, and diligent use of the system for ongoing supply chain oversight. As the ATMP field evolves with trends like decentralized manufacturing and advanced traceability, the database's role in ensuring quality and safety will only grow. Integrating EudraGMDP checks into routine operational and strategic planning is no longer optional but a fundamental requirement for successful ATMP development and commercialization in the European market.

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