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.

Understanding Some International Organizations – ICH, ICMRA and PIC/S

The ICH, ICMRA, and PIC/S are three important international organizations in the pharmaceutical regulatory space that folks should pay attention to and understand how they shape our profession’s future.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a global initiative that brings together regulatory authorities and the pharmaceutical industry to discuss and establish common guidelines and standards for developing, registering, and post-approval pharmaceutical products.

History and Evolution

Establishment: ICH was established in 1990 by the regulatory authorities and pharmaceutical industry associations from Europe, Japan, and the United States. The goal was to harmonize the regulatory requirements for pharmaceutical product registration across these regions.
Reformation: In 2015, ICH was reformed and became a legal entity under Swiss law, transforming from the International Conference on Harmonisation to the International Council for Harmonisation. This change aimed to create a more robust and transparent governance structure and to expand its global reach.

Objectives and Goals

Harmonization: The primary goal of ICH is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.
Efficiency: By harmonizing technical requirements, ICH aims to improve the efficiency of the drug development and registration process, reduce duplication of clinical trials, and minimize the use of animal testing without compromising safety and effectiveness.

Structure and Governance

ICH Assembly: This is the overarching governing body, which includes all members and observers. It adopts decisions on guidelines, membership, work plans, and budgets.
ICH Management Committee: This committee oversees the operational aspects, including administrative and financial matters and working group activities.
MedDRA Management Committee: This committee manages the Medical Dictionary for Regulatory Activities (MedDRA), standardizing medical terminology for adverse event reporting and clinical trial data.
ICH Secretariat: Handles the day-to-day management and coordination of ICH activities.

Guidelines and Categories

ICH guidelines are categorized into four main areas:

Quality: Covers topics such as stability testing, analytical validation, and good manufacturing practices (GMP).
Safety: Includes guidelines on genotoxicity, reproductive toxicity, and other safety evaluations.
Efficacy: Focuses on the design, conduct, safety, and reporting of clinical trials, including novel drug classes and pharmacogenetics.
Multidisciplinary: Encompasses cross-cutting topics like the Common Technical Document (CTD) and electronic standards for regulatory information transfer.

Global Impact and Implementation

Membership: ICH includes regulatory authorities and industry associations from around the world. It currently has 20 members and 36 observers.
Implementation: Regulatory members are committed to adopting and implementing ICH guidelines within their jurisdictions, ensuring consistent regulatory standards globally.

Key Activities

Guideline Development: ICH develops harmonized guidelines through a consensus-based process involving regulatory and industry experts.
Training and Support: Provide training materials and support to facilitate the consistent implementation of guidelines across different regions.

The ICH plays a crucial role in the global pharmaceutical regulatory landscape by promoting harmonized standards, improving the efficiency of drug development, and ensuring the safety and efficacy of medicines worldwide.

International Coalition of Medicines Regulatory Authorities (ICMRA)

The International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level, strategic coordinating, advocacy, and leadership entity. It brings together heads of national and regional medicines regulatory authorities worldwide to address global and emerging human medicine regulatory and safety challenges.

Objectives and Goals

Global Coordination: ICMRA provides a global architecture to support enhanced communication, information sharing, crisis response, and addressing regulatory science issues.
Strategic Direction: It offers direction for areas and activities common to many regulatory authorities’ missions and identifies areas for potential synergies.
Leveraging Resources: ICMRA leverages existing initiatives, enablers, and resources to maximize the global regulatory impact wherever possible.

Membership

Voluntary Participation: Membership is voluntary and open to all medicines regulatory authorities. It includes prominent entities such as the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and many others worldwide.
Global Representation: The coalition includes regulatory authorities from various regions, with the World Health Organization (WHO) participating as an observer.

Key Activities and Projects

Antimicrobial Resistance (AMR): Developing a coordinated global approach to tackle AMR.
COVID-19 Response: During the COVID-19 pandemic, ICMRA has been pivotal in expediting and streamlining the development, authorization, and availability of COVID-19 treatments and vaccines worldwide.
Innovation and Pharmacovigilance: Ongoing investigations and case studies relating to emerging regulatory challenges and working on real-world evidence, adverse event reporting, and vaccine confidence.
Supply Chain Integrity: Ensuring the integrity of the global supply chain for medicines.

Strategic Importance

Enhanced Collaboration: ICMRA fosters international collaboration among medicine regulatory authorities to ensure the safety, quality, and efficacy of medicinal products globally.
Regulatory Agility: The coalition promotes regulatory agility and rapid response to global health emergencies, ensuring patients have timely access to safe and effective medical products.

The ICMRA plays a crucial role in the global regulatory landscape by enhancing communication and cooperation among medicines regulatory authorities, addressing shared challenges, and promoting the safety and efficacy of medicinal products worldwide.

Pharmaceutical Inspection Co-operation Scheme.

PIC/S stands for the Pharmaceutical Inspection Co-operation Scheme, a non-binding, informal co-operative arrangement between regulatory authorities in Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. Its main purpose is to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the pharmaceutical field.

History: PIC/S was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It was created to overcome legal limitations that prevented new countries from joining the original PIC due to incompatibilities with European law.

Membership: PIC/S is open to any regulatory authority with a comparable GMP inspection system. As of 2023, it comprises 56 participating authorities worldwide, including Europe, Africa, America, Asia, and Australasia.

Structure: PIC/S operates as an association under Swiss law, registered in Geneva, Switzerland. It has a committee, an executive bureau, and various working groups.

Relationship with Other Organizations: PIC/S works closely with other international bodies, including the European Medicines Agency (EMA), to promote GMP harmonization and share resources.

Objectives

Harmonizing inspection procedures worldwide
Providing training opportunities for inspectors
Developing common standards in GMP
Facilitating cooperation between competent authorities and international organizations

Activities

Developing and promoting harmonized GMP standards and guidance documents
Training competent authorities, particularly inspectors
Assessing and reassessing inspectorates
Facilitating networking among regulatory authorities

Benefits

Ensures high standards among members
Provides training and networking opportunities
May facilitate pharmaceutical exports indirectly
Increases confidence in medicines manufactured in member countries

PIC/S plays a crucial role in global pharmaceutical regulation by promoting harmonized standards, facilitating cooperation between regulatory authorities, and working towards ensuring the quality and safety of medicinal products worldwide.

The Three in Overview

Aspect	ICH	ICMRA	PIC/S
Full Name	International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use	International Coalition of Medicines Regulatory Authorities	Pharmaceutical Inspection Co-operation Scheme
Established	1990 (reformed in 2015)	2013	1995
Primary Focus	Harmonization of technical requirements for drug development and registration	Strategic coordination and leadership in global human medicine regulation	Harmonization of Good Manufacturing Practice (GMP) standards and inspections
Main Objectives	Develop harmonized guidelines for drug development, registration, and post-approval	Enhance communication, information sharing, and crisis response among regulators	Develop common GMP standards and train inspectors
Membership	20 members, 36 observers (regulatory authorities and industry associations)	Heads of medicines regulatory authorities worldwide	Guideline development, training, and implementation support
Scope	Global, with emphasis on technical aspects of drug development	Global, focusing on high-level strategic issues	Global, concentrating on GMP and quality systems
Key Activities	Guideline development, training, implementation support	Strategic direction, crisis response, addressing emerging challenges	Inspector training, assessment of inspectorates, developing GMP guidance
Legal Status	Legal entity under Swiss law	Voluntary coalition	Non-binding, informal co-operative arrangement
Industry Involvement	Direct involvement of pharmaceutical industry associations	Limited direct industry involvement	No direct industry involvement
Main Output	Harmonized guidelines (Quality, Safety, Efficacy, Multidisciplinary)	Strategic initiatives, position papers, statements	GMP guidelines, inspection reports, training programs

This table highlights the distinct roles and focuses of these three important international pharmaceutical regulatory organizations. While they all contribute to global harmonization and cooperation in pharmaceutical regulation, each has a unique emphasis:

ICH primarily develops technical guidelines for drug development and registration.
ICMRA focuses on high-level strategic coordination among regulatory authorities.
PIC/S concentrates on harmonizing GMP standards and inspection practices.

Their complementary roles contribute to a more cohesive global regulatory environment for pharmaceuticals.

How to Monitor

Organization	What to Monitor	How to Monitor	Frequency
ICMRA	– COVID-19 updates and guidance – Statements on regulatory issues – Reports on emerging topics (e.g., AI, RWE) – Strategic meetings and workshops	– Check ICMRA website regularly – Subscribe to ICMRA newsletter – Follow ICMRA on social media – Attend public workshops when possible	Monthly
ICH	– New and updated guidelines – Ongoing harmonization efforts – Implementation status of guidelines – Training materials and events	– Monitor ICH website for updates – Subscribe to ICH news alerts – Participate in public consultations – Attend ICH training programs	Bi-weekly
PIC/S	– GMP guide updates – New guidance documents – Training events and seminars – Inspection trends and focus areas	– Check PIC/S website regularly – Subscribe to PIC/S newsletter – Review annual reports – Participate in PIC/S seminars if eligible	Monthly

Key points for monitoring:

Set up automated alerts or RSS feeds where available
Create a calendar reminder for regular check-ins on each organization’s website
Collaborate with regulatory affairs colleagues to share insights and updates
Implement a system to disseminate relevant information within your organization
Consider joining industry associations that actively engage with these organizations

Key Links

Well this was a dizzy ride – thanks SCOTUS for everything (not)

The 2024 U.S. Supreme Court decisions have had significant impacts on the Food and Drug Administration (FDA) and other federal agencies. I don’t think we will truly understand the impact for years as matters move through the courts. This increased uncertainty has led to new questions arising as we assess risk.

Overturning the Chevron Doctrine

A significant decision was made to overturn the Chevron doctrine, a longstanding precedent that mandated courts to defer to federal agencies’ expertise when interpreting unclear statutes. This doctrine has played a crucial role in enabling agencies such as the FDA to establish and enforce regulations based on their specialized knowledge.

Reduced Authority: With the Chevron doctrine overturned, the FDA’s ability to interpret and enforce regulations without judicial interference is significantly curtailed. This change makes it easier for regulations to be challenged in court, potentially leading to increased litigation and uncertainty in regulatory enforcement.

Challenges to Regulatory Actions

The decisions made by the Supreme Court have made it harder for federal agencies to effectively carry out their regulatory functions. The court’s rulings have extended the time frames for challenging agency actions, leading to delays in implementing new regulations and enforcement actions. This could particularly affect the FDA’s ability to respond promptly to emerging public health issues.

Specific Cases Affecting the FDA

Several other cases have also directly impacted the scope of FDA regulations:

Environmental and Safety Regulations: Recent court decisions have impacted the FDA’s ability to enforce regulations concerning food safety and environmental protection. For example, the decision to block certain EPA regulations on cross-state pollution indirectly affects the FDA’s responsibility to ensure the safety of food and drugs that might be affected by environmental factors. It’s still uncertain how significant this impact will be, but I am more concerned about this issue than I am about the weakening of the Chevron defense.
The Supreme Court’s decision to protect access to the abortion medication mifepristone is an important exception. The court upheld the FDA’s regulatory decision, which ensures that the FDA can continue to regulate and approve medications important to public health. However, it’s worth noting that this ruling was specifically about the legal standing of the case, so it’s not an entirely straightforward situation.

Broader Implications

The recent decisions signal a change in the balance of power between the judiciary and federal agencies. The Supreme Court’s decision to limit the deference typically given to agencies such as the FDA has altered the federal regulatory landscape. This change could result in a more restricted and litigious regulatory environment.

Laboratory diagnostic testing regulations

The recent Supreme Court rulings, especially the overturning of the Chevron doctrine in Loper Bright Enterprises v. Raimondo, will first impact the FDA’s new laboratory diagnostic testing regulations.

Increased Legal Challenges: The removal of Chevron deference means that courts will no longer automatically defer to the FDA’s interpretation of ambiguous statutes. This change might result in more legal disputes regarding the FDA’s power to regulate laboratory-developed tests (LDTs) as medical devices. The American Clinical Laboratory Association (ACLA) has already filed a lawsuit against the FDA over the new LDT rule, and this Supreme Court decision could strengthen their case.
Uncertainty in Regulatory Framework: The FDA’s final rule, published on May 6, 2024, regulates Laboratory Developed Tests (LDTs) as medical devices, similar to in vitro diagnostics. However, due to a new Supreme Court ruling, the FDA’s authority to regulate LDTs may face greater scrutiny by the courts. This could lead to uncertainty in the regulatory framework for clinical laboratories.
Potential Delays in Implementation: The Supreme Court’s decision in Corner Post v. Board of Governors extends the timeframe for challenging agency rules. This could lead to delays in the implementation of the FDA’s LDT regulations because stakeholders may now have more time to challenge the rules in court.
Stricter Scrutiny of FDA Decisions: The new ruling emphasizes that courts should exercise independent judgment in deciding whether an agency has acted within its statutory authority. This could lead to stricter scrutiny of FDA decisions regarding LDT approvals and regulations.

Keep in mind that although these potential impacts are meaningful, the complete effects of the Supreme Court’s rulings on FDA regulations will likely become more apparent over time as cases are presented in court and as the agency adjusts its approach. The situation is still evolving, and those of us involved in FDA regulated industries should be prepared for significant changes ahead.

FDA Reorganization

FDA’s Reorganization Approved for Establishing Unified Human Foods Program, New Model for Field Operations and Other Modernization Efforts

The FDA’s reorganization has been unveiled and will be implemented on October 1st. As a total wonk, this is exciting.

There are two major changes:

Forming a Human Food Program (HFP) to consolidate a preventive approach will not have much impact on me professionally, but I’m hoping that as a consumer, we see significant dividends from this refocus.
ORA is being renamed the Office of Inspections and Investigations (OII) and will focus on inspections, investigations, and imports as its core mission. If nothing else, this will make explaining the structure of the FDA a heck of a lot easier.

Everything else seems to be mostly a lot of shuffling of the deck chairs that will have little impact.