FDA versus EMA: Two Key Differences in Regulatory Approach for Quality Filing

Understanding key differences in pharmaceutical filings and guidelines between the FDA and EMA starts with exploring each organization's history and culture. These factors have shaped their structures and thought processes, impacting how business and science are conducted in their respective regions, particularly in terms of pharmaceutical regulatory approaches of the Common Technical Document (CTD) filings of Module 3. Two examples are provided in the context of cGMP documentation and product quality management.

Historical, Legal, and Cultural Contexts

The United States Constitution has established a system of government in which power is divided between a national or federal government and state governments. This system is known as federalism. Federalism allows both levels of government to operate within their respective spheres of influence, meaning that the balance of power allows both levels of government to operate effectively within their jurisdiction. For example, states can address local issues that directly affect their residents, while the federal government manages affairs that impact the nation as a whole. The US is a young nation, 249 years-old this year, with a population of almost 347 million as of January 2025 according to Worldometer.info (https://www.worldometers.info/world-population/us-population/?form=MG0AV3). Its vast cultural diversity has influenced the way business and science are carried out within its borders, as well as how laws are crafted and enforced to govern these activities. With respect to pharmaceutical products regulations, the US Federal government, not individual states, is responsible for ensuring their safety, efficacy, and quality through the regulatory instrument called the Federal Food, Drug, and Cosmetic Act, passed in 1938. This is the foundational law that gives the Food and Drug Administration (FDA) the authority to oversee the safety of food, drugs (as medicines), medical devices and cosmetics. This act is codified under Title 21 Chapter 9 of the United States Code of Laws. Additional acts have refined and expanded the FD &C act to address the pharmaceutical product lifecycle needs from development to post-market surveillance along with legal requirements.

The European Union (EU) has roots that trace back to the aftermath of World War II, with the objective of fostering peace and economic cooperation in Europe. The European Coal and Steel Community (ECSC) was established in 1951, followed by the Treaties of Rome in 1957, which created the European Economic Community (EEC) and the European Atomic Energy Community (Euratom). The 1960s saw further economic integration and the establishment of the European Parliament. The 1970s brought the first new members (Denmark, Ireland, and the UK), and the 1980s saw the beginning of the single market. The Maastricht Treaty in 1992 formally established the European Union, introducing new policies and the Euro currency, which was launched in 1999. The EU expanded significantly in the early 21st century, with 12 new countries joining between 2000 and 2009. The Lisbon Treaty in 2007 streamlined EU institutions and introduced new governance mechanisms (History of the EU, EU pioneers | European Union). Overall, the EU evolved from a small group of 6 countries to a union of 27 member states. As of January 2024, the EU has a total population of around 449 million people (Demography of Europe – 2024 edition - Interactive publications - Eurostat).

While heads of state play a crucial role in decision making for the Union, they also must balance the interests and needs of their citizens. Member states can opt out of certain EU policies. However, member states have committed to shared sovereignty in specific areas covered by EU treaties. Thus, the EU is not a “country made up of states” with a federal government like the US; it is a political and economic union of 27 member states that retain their sovereignty. Each member state is a distinct country with its own historical significance, official language(s), and long-standing cultural heritage. Each country has a unique history that has shaped identities, culture, language, thought processes and interrelationships over centuries, affecting their way of conducting business and science.

With respect to pharmaceutical regulation, the European Medicines Agency (EMA) was introduced by Regulation (EC) No 726/2004. This regulation established the EMA in 1995 to harmonize the work of existing national medicine regulatory bodies within the European Union. So, the EMA only has a 25-year track record of ensuring efficacy and safety of medicines and of promoting research and innovation in their development. Yet, in that short period of time, it has encouraged and promoted, not imposed, the exchange of knowledge, ideas, and best practices to meet their regulatory standards in the quality of medicines developed, manufactured, and marketed in the European zone while balancing the interests, requirements, and needs of the individual member states ((EMA's history | European Medicines Agency (EMA)).

A Couple of Noteworthy Differences in FDA and EMA Regulatory Approaches

In the US, the FDA is responsible for inspecting pharmaceutical manufacturing sites in terms of documentation and manufacturing processes to verify compliance with cGMP regulations. If a site meets these standards, the FDA includes this information in its inspection reports and can issue a cGMP Declaration upon request (Pharmaceutical Inspections and Compliance | FDA).

In the EU, the EMA does not inspect manufacturing sites for cGMP compliance and does not issue any documentation pertaining to a site complying with cGMPs because it coordinates and oversees the inspections carried out by the national competent authorities (NCAs) of the individual EU member states. The inspections cover the documentation and activities related to the manufacturing process. The EMA plays a key role in harmonizing GMP activities at the EU level and ensures that inspections are conducted consistently across member states. The EMA then can focus on the scientific review of the pharmaceutical product’s quality, safety, and efficacy submitted in the Marketing Authorization Application (MAA). Thus, when putting together a US filing, the FDA requires the inclusion of batch records in the CMC section of the Common Technical Document (CTD) while the EMA requests that no GMP documentation like batch records be included in an EU filing. The EMA works with the national authorities to confirm that the manufacturing site and processes meet cGMP standards. This information is then included in the dossier.

Another distinction that stems more from a different mindset between FDA and EMA regulatory agencies rather than a difference in infrastructure and oversight, is the approach taken for product design, risk assessment and management.? FDA guidance typically outlines more specific and detailed expectations, whereas the EMA tends to allow pharmaceutical companies greater flexibility to develop their own risk management processes within the framework of ICH guidelines. For example, the FDA's guidelines incorporate ICH Q8 (R2) for pharmaceutical development, ICH Q9 for quality risk management, and ICH Q10 for the pharmaceutical quality system. These guidelines together form a comprehensive framework that emphasizes Quality by Design (QbD) principles throughout the product lifecycle. While the EMA also acknowledges and uses ICH Q8 and ICH Q10, its guidance is especially rooted in ICH Q9, which centers on Quality Risk Management (QRM). The EMA's approach often provides more flexibility for pharmaceutical companies to define their risk management processes within the broad principles established by QRM. This distinction is helpful when drafting CMC documentation as part of the CTD Module 3 section (Essential Guide to Module 3 of the CTD | Educo, M4Q pages 5-16).

In summary, the couple of significant differences discussed here in the FDA and EMA frameworks—stemming from historical, cultural, and political factors unique to their regions—result in varying quality filings, despite following the same legal format and regulatory guidance (ICH:M4Q). This divergence influences which documentation must be included and how it should be drafted.