European Country Differences

As an American Pharmaceutical Quality professional who has worked in and with European colleagues for decades, I am used to hearing, “But the requirements in country X are different,” to which my response is always, “Prove it.”

EudraLex represents the cornerstone of Good Manufacturing Practice (GMP) regulations within the European Union, providing a comprehensive framework that ensures medicinal products meet stringent quality, safety, and efficacy standards. You will understand the fundamentals if you know and understand Eudralex volume 4. However, despite this unified approach, a few specific national differences exist in how a select few of these regulations are interpreted and implemented – mostly around Qualified Persons, GMP certifications, registrations and inspection types.

EudraLex: The European Union Pharmaceutical Regulatory Framework

EudraLex serves as the cornerstone of pharmaceutical regulation in the European Union, providing a structured approach to ensuring medicinal product quality, safety, and efficacy. The framework is divided into several volumes, with Volume 4 specifically addressing Good Manufacturing Practice (GMP) for both human and veterinary medicinal products. The legal foundation for these guidelines stems from Directive 2001/83/EC, which establishes the Community code for medicinal products for human use, and Directive 2001/82/EC for veterinary medicinal products.

Within this framework, manufacturing authorization is mandatory for all pharmaceutical manufacturers in the EU, whether their products are sold within or outside the Union. Two key directives establish the principles and guidelines for GMP: Directive 2003/94/EC for human medicinal products and Directive 91/412/EEC for veterinary products. These directives are interpreted and implemented through the detailed guidelines in the Guide to Good Manufacturing Practice.

Structure and Implementation of EU Pharmaceutical Regulation

The EU pharmaceutical regulatory framework operates on multiple levels. At the highest level, EU institutions establish the legal framework through regulations and directives. EU Law includes both Regulations, which have binding legal force in every Member State, and Directives, which lay down outcomes that must be achieved while allowing each Member State some flexibility in transposing them into national laws.

The European Medicines Agency (EMA) coordinates and harmonizes at the EU level, while national regulatory authorities inspect, license, and enforce compliance locally. This multilayered approach ensures consistent quality standards while accommodating certain national considerations.

For marketing authorization, medicinal products may follow several pathways:

Authorizing body	Procedure	Scientific Assessment	Territorial scope
European Commission	Centralized	European Medicines Agency (EMA)	EU
National authorities	Mutual Recognition, Decentralized, National	National competent authorities (with possible additional assessment by EMA in case of disagreement)	EU countries concerned

This structure reflects the balance between EU-wide harmonization and national regulatory oversight in pharmaceutical manufacturing and authorization.

National Variations in Pharmaceutical Manufacturing Requirements

Austria

Austria maintains one of the more stringent interpretations of EU directives regarding Qualified Person requirements. While the EU directive 2001/83/EC establishes general qualifications for QPs, individual member states have some flexibility in implementing these requirements, and Austria has taken a particularly literal approach.

Austria also maintains a national “QP” or “eligible QP” registry, which is not a universal practice across all EU member states. This registry provides an additional layer of regulatory oversight and transparency regarding individuals qualified to certify pharmaceutical batches for release.

Denmark

Denmark has really flexible GMP certification recognition, but beyond that no real differences from Eudralex volume 4.

France

The Exploitant Status

The most distinctive feature of the French pharmaceutical regulatory framework is the “Exploitant” status, which has no equivalent in EU regulations. This status represents a significant departure from the standard European model and creates additional requirements for companies wishing to market medicinal products in France.

Under the French Public Health Code, the Exploitant is defined as “the company or organization providing the exploitation of medicinal products”. Exploitation encompasses a broad range of activities including “wholesaling or free distribution, advertising, information, pharmacovigilance, batch tracking and, where necessary, batch recall as well as any corresponding storage operations”. This status is uniquely French, as the European legal framework only recognizes three distinct positions: the Marketing Authorization Holder (MAH), the manufacturer, and the distributor.

The Exploitant status is mandatory for all companies that intend to market medicinal products in France. This requirement applies regardless of whether the product has received a standard marketing authorization or an early access authorization (previously known as Temporary Use Authorization or ATU).

To obtain and maintain Exploitant status, a company must fulfill several requirements that go beyond standard EU regulations:

The company must obtain a pharmaceutical establishment license authorized by the French National Agency for the Safety of Medicines and Health Products (ANSM).
It must employ a qualified person called a Chief Pharmaceutical Officer (Pharmacien Responsable).
It must designate a local qualified person for Pharmacovigilance.

The Pharmacien Responsable: A Unique French Pharmaceutical Role

Another distinctive feature of the French health code is the requirement for a Pharmacien Responsable (Chief Pharmaceutical Officer or CPO), a role with broader responsibilities than the “Qualified Person” defined at the European level.

According to Article L.5124-2 of the French Public Health Code, “any company operating a pharmaceutical establishment engaged in activities such as purchasing, manufacturing, marketing, importing or exporting, and wholesale distribution of pharmaceutical products must be owned by a pharmacist or managed by a company which management or general direction includes a Pharmacien Responsable”. This appointment is mandatory and serves as a prerequisite for any administrative authorization request to operate a pharmaceutical establishment in France.

The Pharmacien Responsable holds significant responsibilities and personal liability, serving as “a guarantor of the quality of the medication and the safety of the patients”. The role is deeply rooted in French pharmaceutical tradition, deriving “directly from the pharmaceutical monopoly” and applying to all pharmaceutical companies in France regardless of their activities.

The Pharmacien Responsable “primarily organizes and oversees all pharmaceutical operations (manufacturing, advertising, information dissemination, batch monitoring and recalls) and ensures that transportation conditions guarantee the proper preservation, integrity, and safety of products”. They have authority over delegated pharmacists, approve their appointments, and must be consulted regarding their departure.

The corporate mandate of the Pharmacien Responsable varies depending on the legal structure of the company, but their placement within the organizational hierarchy must clearly demonstrate their authority and responsibility. This requirement for clear placement in the company’s organization chart, with explicit mention of hierarchical links and delegations, has no direct equivalent in standard EU pharmaceutical regulations.

Germany

While Germany has many distinctive elements—including the PZN identification system, the securPharm verification approach, specialized distribution regulations, and nuanced clinical trial oversight—the GMPs from Eudralex Volume 4 are the same.

Italy

Italy has implemented a highly structured inspection system with clearly defined categories that create a distinctive national approach to GMP oversight.

National Preventive Inspections
- Activating new manufacturing plants for active substances
- Activating new manufacturing departments or lines
- Reactivating departments that have been suspended
- Authorizing manufacturing or import of new active substances (particularly sterile or biological products)
National Follow-up Inspections to verify the GMP compliance of the corrective actions declared as implemented by the manufacturing plant in the follow-up phase of a previous inspection. This structured approach to verification creates a continuous improvement cycle within the Italian regulatory system.
Extraordinary or Control Inspections: These are conducted outside normal inspection programs when necessary for public health protection.

Spain

The differences in Spain are mostly on the way an organization is registered and has no impacts on GMP operations.

Regulatory Recognition and Mutual Agreements

EU member states have received specific recognition for their GMP inspection capabilities from international partners individually.

The Challenge of Cleanroom Classification Harmonization

In the world of pharmaceutical manufacturing, cleanroom classifications play a crucial role in ensuring product quality and patient safety. However, a significant hurdle in the global harmonization of regulations has been a pain in our sides for a long time, that highlights the persistent differences between major regulatory bodies, including the FDA, EMA, and others, despite efforts to align through organizations like the World Health Organization (WHO) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

The Current Landscape

United States Approach

In the United States, cleanroom classifications are primarily governed by two key documents:

The FDA’s “Sterile Drug Products Produced by Aseptic Processing” guidance
ISO 14644-1 standard for cleanroom classifications

The ISO 14644-1 standard is particularly noteworthy as it’s a general standard applicable across various industries utilizing cleanrooms, not just pharmaceuticals.

European Union Approach

The European Union takes a different stance, employing a grading system outlined in the EU GMP guide:

Grades A through D are used for normal cleanroom operation
ISO 14644 is still utilized, but primarily for validation purposes

World Health Organization Alignment

The World Health Organization (WHO) aligns with the European approach, adopting the same A to D grading system in its GMP guidelines.

The Implications of Disharmony

This lack of harmonization in cleanroom classifications presents several challenges:

Regulatory Complexity: Companies operating globally must navigate different classification systems, potentially leading to confusion and increased compliance costs.
Technology Transfer Issues: Transferring manufacturing processes between regions becomes more complicated when cleanroom requirements differ.
Inspection Inconsistencies: Differences in classification systems can lead to varying interpretations during inspections by different regulatory bodies.

The Missed Opportunity in Annex 1

The recent update to Annex 1, a key document in GMP regulations, could have been a prime opportunity to address this disharmony. However, despite involvement from WHO and PIC/S (and through them the FDA), the update failed to bring about the hoped-for alignment in cleanroom classifications.

Moving Forward

As the pharmaceutical industry continues to globalize, the need for harmonized regulations continues to be central. I would love to see future efforts towards harmonization here that would:

Prioritize alignment on fundamental technical specifications like cleanroom classifications
Consider the practical implications for manufacturers operating across multiple jurisdictions

While the journey towards full regulatory harmonization may be long and challenging, addressing key discrepancies like cleanroom classifications would represent a significant step forward for the global pharmaceutical industry.

EMA GMP Plans for Regulation Updates

Like one does, I watch upcoming regulations like a hawk. Here are a few of the forthcoming GMP changes coming from the 3-year work plan for the Inspectors Working Group.

Document	Intended Changes	When	My Thoughts
GMP Guide: Chapter 4 (Documentation)	Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Annex 11 (Computerised Systems).	Q1 2026	An update is needed to align with current thinking. Data Integrity has advanced significantly in the last five years, and Chapter 4 could benefit from alignment with the PIC/S guidance.
GMP Guide: Annex 11 (Computerised Systems)	Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Chapter 4 (Documentation).	Q1 2026	A necessary update. Will be curious to see how it aligns with the FDA’s CSA approach (which isn’t really all that new). We pretty much know what will be in it from the concept paper. At least it will solidify this requirement for cloud systems “Regulated users should 26 have access to the complete documentation for validation and safe operation of a system and be able to present this during regulatory inspections, e.g. with the help of the service provider.”
Guidelines on GMP specific to ATMPS	Review the Guidelines in collaboration with CAT and the European Commission following the publication of a new regulation on standards of quality and safety for substances of human origin intended for human application and need to update legal references and definitions. Review the Guidelines in the light of new Annex 1 Manufacture of Sterile Medicinal Products and consider whether any updates are necessary.	Q4 2026	This is a fast area of change, and this update is called for. Aligning to Annex 1 is overdue.
GMP Guide: Annex 3 Manufacture of Radiopharmaceuticals	A review and update of the Annex to reflect current state of the art.	Q4 2026	I’ve never worked in radiopharmaceuticals. Maybe someday.
GMP Guide: Annex 15 Qualification and Validation	In the context of new technology in facilities, products and processes and following up on LLE recommendations, and extend the scope to APIs.	Q4 2025	LLE is the EMA’s lessons learnt report (LLE) on Nitrosamines. I’d love to see significant changes to finally align with ATSM E2500 and other recent challenges in validation.
GMP Guide: Annex 16 Certification by a Qualified Person and Batch Release	Following up on LLE recommendations.	Q4 2025	I’m not a massive fan of QPs as structured. Not expecting that to change.
GMP and Marketing Authorisation Holders	To revise the paper in line with recommendations from the Nitrosamines LLE, to strengthen guidance for MAHs in terms of having adequate quality agreement with manufactures.	Q4 2025	Anything to strengthen quality agreements is probably a good thing.

Anytime we see a major chapter update in the Eudralex Volume 4 is an exciting year, and the next few promise to be big. Maybe not Annex 1 big, but maybe the EMA and PIC/S will surprise us.

Leveraging Inspection Manuals for GMP Inspection Readiness

The various agency inspection manuals are critical tools for inspection readiness. I want to lay out where to find some of these manuals and then go deep into pre-approval inspections, focusing on data integrity.

European Medicines Agency

The European Medicines Agency (EMA) has established detailed procedures and work instructions for coordinating and conducting Good Clinical Practice (GCP), Good Manufacturing Practice (GMP), and pharmacovigilance inspections. Here are the key points regarding EMA’s inspection procedures:

GCP Inspection Procedures

EMA identifies applications for GCP inspections based on risk assessment criteria and exchanges information on shared applications with the FDA.
Inspections can be joint (conducted concurrently by EMA and FDA inspectors) or sequential (conducted separately by each agency).
EMA notifies the applicant/marketing authorization holder (MAH) and inspects sites about upcoming inspections through the IRIS industry portal instead of formal letters.
Applicants/MAHs must provide a signed statement accepting the inspection and granting direct access to documents and medical records.
Requested documents should be provided directly to inspectors in electronic format after consulting the reporting inspector.
After the inspection, EMA receives the draft inspection report, finalizes it with the inspectee’s responses, and publishes it in IRIS.

GMP Inspection Procedures

EMA coordinates GMP inspections based on risk assessment for marketing authorization applications, variations, and routine re-inspections.
Work instructions cover areas such as inspection announcement, fee calculation, product sampling/testing, and report circulation.

Pharmacovigilance Inspection Procedures

EMA has specific procedures for coordinating pharmacovigilance inspections and managing non-compliance notifications from MAHs.
Work instructions detail the inspection program creation, data entry in databases, and interactions with third-country inspectorates.

The EMA aims to harmonize inspection processes with the FDA and other regulatory bodies to streamline collaboration and information sharing while ensuring clinical trial subject protection and product quality.

FDA

The FDA Investigations Operations Manual (IOM) is the primary inspection manual used by FDA personnel when performing inspections and investigations.

The key points about the IOM are:

It provides comprehensive instructions, procedures, and policies for FDA investigators and inspectors to follow when conducting inspections, surveys, and investigations.
It covers inspectional activities for foods, drugs, medical devices, biologics, cosmetics, and other FDA-regulated products.
The manual details procedures for inspections of manufacturing facilities, sampling, import operations, recalls, consumer complaints, and other compliance activities.
It aims to ensure inspections are conducted consistently across FDA field offices and provide clear guidance to the industry on the FDA’s inspection approach.
The IOM is updated periodically to incorporate new laws, regulations, policies, and technological changes impacting FDA’s operations.
While not legally binding, the IOM represents the FDA’s current thinking and policies on inspections and investigations.

The FDA Investigations Operations Manual serves as the comprehensive inspection reference and procedure manual for FDA field staff carrying out the agency’s oversight and enforcement activities across all regulated product areas.

Pre-Approval Inspections

For new facilities, CPGM 7346.832, the FDA’s Compliance Program Guidance Manual for Pre-Approval Inspections (PAIs) of drug manufacturing facilities, is critical to spend time with. It outlines the objectives and procedures for FDA inspectors to evaluate a facility’s readiness for commercial manufacturing before approving a new drug application.

The key objectives of CPGM 7346.832 are:

Assess if the facility has a quality system capable of controlling commercial manufacturing operations.
Verify that the manufacturing processes, formulation, and analytical methods conform to the application details.
Audit raw data integrity to authenticate the data submitted in the application.
Evaluate the facility’s commitment to quality in pharmaceutical development (new objective added in 2022 revision).

The guidance instructs inspectors on evaluating the firm’s quality systems, process validation, data integrity, laboratory controls, change management, investigations, batch release procedures, and compliance with current Good Manufacturing Practices (cGMPs). It aims to ensure the facility can reliably produce the drug product described in the application.

Data Integrity

CPGM 7346.832 has specific requirements for data integrity audits during drug manufacturing facility pre-approval inspections (PAIs). Utilizing this document is an excellent way to evaluate your data integrity program.

The key points are:

Objective 3 of the guidance is “Data Integrity Audit”—auditing and verifying raw data associated with the product to authenticate the data submitted in the application.
Inspectors must audit the accuracy and completeness of data reported by the facility for the product. This involves verifying the factual integrity (data matches what was submitted) and contextual integrity (supporting data is complete).
Inspectors should examine raw data, such as chromatograms, analyst notebooks, electronic data, etc., and compare it to the summary data in the application’s Chemistry, Manufacturing, and Controls (CMC) section.
The data integrity audit should focus on finished product stability, dissolution, content uniformity, API impurities, etc.
Inspectors must identify any unreported relevant data, data falsification, improper invalidation of results, or unexplained data discrepancies.
Indications of data integrity issues include altered raw data, references to failing studies, discrepancies between samples, and missing records.

The data integrity audit aims to ensure the CMC data submitted to FDA is complete, reliable, and can be fully authenticated from the raw data at the manufacturing site. Robust data integrity is critical for the FDA to decide on the application’s approval.

European Guideline on Data Integrity in GCP Studies

The EMA has published “Guideline on computerised systems and electronic data in clinical trials.”

Anyone familiar with Annex 11 of Eudralex Annex 4 won’t be surprised by the content, but frankly I expect a lot of folks who have primarily experience on the clinical side will be scratching their heads. The fact that the authors felt the need to have an entire paragraph dedicated to unique user names is telling.

This is a great resource for sponsors who need to figure out just what to evaluate at investigators sites, a requirement this guideline repeats multiple times.

I’ll be very curious how effective sponsors are in ensuring this requirement is met “The investigator should receive an introduction on how to navigate the audit trail of their own data in order to be able to review changes.”