Differences in registration requirements for Europe and USA market

The Drug approval processes in the United States (USA) & Europe are the most demanding in the world.

North America (NA) and Europe follow different approval procedures and each of them is unique in its own way. Although they share the common goal of patient safety and preserving public health, there are notable differences in the regulations, the functions of the regulatory authorities, drug approval process.

The format for chemistry, manufacturing and control (CMC) information is presented in ICH guideline M4. US and Europe are both Founding Regulatory Members of the ICH Association. As both regions are members of the ICH, they share many scientific and regulatory guidelines. These guidelines are incorporated in the US as Guidance for Industry and Notice to Applicants in Europe. Also, both of these health authorities continuously make efforts to harmonize their compendial monographs’ content. Despite all these efforts, there are still some specific requirements which are unique for the respective region.

Let’s have an overview of the differences between the US and Europe’s regulatory expectations. First, we need to understand why there are differences in regulatory expectations. The main reason for the existence of significant differences in requirements for both regions are:

• How the regulatory guidelines are interpreted and implemented in these regions.
• The practical consideration of guidelines is significantly different in both regions.
• These differences originate from the varying circumstances faced by individual authorities and the mindsets of the authorities.
• The tradition and legislation already in place before the harmonization processes have also played a significant role in the Agency’s current expectations.
• Some historically grown differences greatly influence the presentation, anticipated content and terminology of the application dossier in both regions.

Below are a few examples showing the differences in understanding of both regions.

• Both regions follow their own Pharmacopoeia. The United States Pharmacopoeia (USP), has many finished product monographs while European Pharmacopoeia (EP) has only a few.
• USFDA accepts Drug Master File (DMF). In contrast, Europe accepts the Active Substance Master File (ASMF, formerly DMF) and Certificates of Suitability to the European Pharmacopoeia (CEP) monographs. There are several types of DMFs in the US such as active substances, colorants, flavors, excipients, packaging materials, intermediates and raw materials. In Europe, the ASMFs and CEPs are applicable only for Active Substances.
• FDA inspections are product specific while European health authorities opt for site-specific inspections for the product type (sterile, solid, etc.).
• The USFDA assessors expect to include full data in the application for their evaluation while the European assessors expect to have only the data critical for the product and abstract other information from GMP sources rather than presenting them directly. Therefore, a significant part of European CMC writing is summarizing and minimizing data. The CMC sections of the US application disclose every possible product flaw by presenting the maximum amount of available data. In contrast, the European quality part focuses on identifying the critical characteristics of the product and presenting data regarding these. For example; summarizing the manufacturing process is enough for Europe while USFDA requires batch manufacturing and packaging records in addition to manufacturing process descriptions.
• The bioequivalence study for generic drugs must be performed against US RLD for USFDA while against the EU reference product for Europe.
• USFDA follows the inactive ingredients database to identify acceptable excipient concentration.

Below are the few examples listing the differences in the requirements for both the regions.

The definitions and terms used to describe “Variations”; types and processes vary across both regions, however, all changes fall into three general definitions which share many similarities: administrative, minor and major.

The below comparative table summarizes a generalized understanding of different variation categories for Europe and the US.