FDA AND EU-GMP - ALWAYS IN BALANCE?

When working with the FDA-regulated US market, there is frequently the question about the differences to the European GMP requirements. This will also be valid after the MRA1 finally becomes effective next year. Any company that wants to distribute its products in the US market needs to know the specifics.

"The FDA is much stricter," you can often hear. But is it really true? And what differences are there? And where are the similarities?

To be able to answer these questions at least approximately, one should also consider the cultural differences.

The European Union (EU) is a federation of currently still 28 European states with its own influences. The EU countries' population today counts more than 510 million, sharing a variety of different cultures and languages. The individual member states delegate parts of their sovereignty so that decisions and specifications with regard to important common interests can be taken at the European level. We need to distinguish:

• EU Regulations: directly binding and effective, no modifications possible and no implementation in national legislation necessary
• EU Directives: binding in terms of goal, the implementation in national legislation is necessary, with slight modifications
• EU Decisions: they are legally binding on a case-by-case basis, the addressee is specifically named
• EU Guidelines: legally not directly binding, they document the status of scientific and technical knowhow and define expectations; justified deviations are possible

The most responsibilities and especially the medicinal product supervision is with the single member states. Due to federalist systems in the single states there are far more than 28 competent authorities within the EU. Although there are also many so-called "District Offices" with a supervising function in the US, they all are part of the same authority - the FDA.

Recommendation

Berlin, Germany4/5 December 2024

Root Cause Analysis

The United States of America comprise 50 states with a population of currently a little more than 300 million. In addition to English Spanish is spoken in some parts of the country and in some major cities. That means that the FDA does not need to coordinate activities with 28 sovereign states and is independent from political circumstances in doing its work. In the FDA's responsibilities is the approval of medicinal products as well as their supervision. Its authority is clearly defined and accepted.

Within the EU Member States, the GMP rules are not hundred percent the same. Mainly laid down in directives and guidelines, member states are permitted to adapt these requirements to the prevailing conditions and to existing state regulations. In addition there are also differences in the timing of implementation. The best example for this is the very late introduction of the Qualified Person in Germany and the prior separation of powers between the head of manufacturing and the head of quality control with virtually unregulated release responsibility.

But where are the differences now on the basis of GMP requirements?

The European requirements are for the most part described in more detail. The FDA was often criticized for this. Examples include process validation, self-inspection, requirements for personnel or the different roles of quality assurance and quality control. The actual GMP requirements in the US with a legal character (Code of Federal Regulations, CFR) have changed only marginally since 1978 and are not always entirely in line with the state of science and technology. A large number of guides and guidances (sometimes over years in the draft version) do not exactly facilitate the overview. However, the EU is in no way inferior with its multitude of documents.

For the FDA it is ultimately the industry's responsibility to keep up to date with the help of guides and guidances, inspectional guidelines, warning letters, FDA presentations and workshops, etc. Hence the terminology cGMP ("current GMP"). The expectations of the EU are determined more clearly.

There are also differences in the expectations for the manufacture of clinical investigational medicinal products. These are regulated more comprehensively and in more detail within the EU. Of course, this also results in differences. One example is the requirements for the labeling of investigational medicinal products. A (worldwide) harmonization is absolutely necessary here. In addition to some other details, the release is also regulated differently ("two-step release procedure"). One of the biggest differences in general lies in the release of medicinal products. The FDA does not know a direct personal responsibility comparable to the one of the Qualified Person. And it is always a challenge to explain this role to American colleagues. There are also far-reaching differences in the requirements for the manufacture of aseptic (parenteral) dosage forms and in process validation. One difference is e.g. the requirement in Annex 15 to the EU-GMP Guide to also list non-critical attributes and parameters in the validation plan. The FDA Process Validation Guideline only requires the specification of critical quality attributes and critical process parameters. For the FDA there is a further difference in the process validation approaches. Annex 15 lists three approaches (traditional, continuous process verification, hybrid), while no distinction is made in the FDA Process Validation Guideline. Furthermore, the requirements for statistics differ in both documents as well. Also, the FDA Process Validation Guideline requires a higher number of samples in step three of the process validation lifecycle (continued/ongoing process verification), at least until enough data is available to estimate variability. This requirement for an increased number of samples in the ongoing process verification does not exist in Annex 15. All of this can also be important in the approval for the US market.

Quality Reviews

The objective of the FDA "Annual Product Review" is to evaluate annually the quality standards of each drug product, but also to determine the need for changes in specifications or manufacturing or control procedures. For this a representative number of batches is reviewed. The objective of the EU ''Product Quality Review'' is to concentrate more on the overall manufacturing and quality system and to show that a company consistently produces products with the appropriate quality. But the PQR should include all batches which have been manufactured in the respective period. EU Inspectors are often requesting PQRs in advance of inspections!

Ultimately, APR and PQR have the same goal though: to evaluate the quality status of products regularly and up-to-date. However, the PQR also contains data about

• Manufacturing processes
• Changes to product specifications
• Process parameters
• Equipment and devices as well as their qualification and validation status

And so, going into the details of the wide world of regulations, there are further, often marginal differences. So, are the requirements of the FDA stricter? This everyone has to evaluate for himself. The way in which each authority organises its inspections possibly allows this conclusion. European inspectors are more likely to try to understand the process, to review its implementation on-site and to make sure that safe medicines can be manufactured in the future. In contrast, FDA inspectors are usually busy closely scrutinizing the documentation of already manufactured medicinal products and to uncover the fraud they expect. That's why perhaps they call themselves "investigators". But, as so often, the particular procedure also heavily depends on the personality and experience of the inspector, so that it is hard to generalize.

By and large the similarities prevail, though. The goal - which is to obtain safe, effective and qualitatively perfect medicinal products for the best of the population - is the same. There are many initiatives aiming at mostly harmonized requirements (e.g. ICH). In the international business it is of course important to exactly know the particular requirements and expectations and not to forget that it is the national laws and provisions that need to be considered. The pharmaceutical set of rules, especially in Europe, underlies a constant development, and it is important to understand and implement them in their overall context.

Recommendation

22/23 January 2025

HPLC Data Integrity - Live Online Training

Contamination Control

The 2015 revisions of EU-GMP Guide Chapter 3 and Chapter 5 put a lot of focus on contamination control. The main changes in the new Chapter 3 "Premises and Equipment" concern measures to prevent cross contamination. The changes are closely associated with the revision of Chapter 5 ("Production") and with the EMA-Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012). The new text asks for a risk-based assessment on the basis of toxicological data. Dedicated facilities are only required if the identified risks cannot be controlled using adequate technical or organisational measures.

Overall, a documented Contamination Control Strategy is required and QRM principles should be used to assess and control the risks of contamination.

GMP for Excipients

In the EU, there is a GMP Guidance for pharmaceutical excipient suppliers. The expectation is that MAHs perform a risk assessment to evaluate any risk associated with the excipient manufacturer/ supplier to further define appropriate GMP controls and supplier qualification.

 

Author:
Wolfgang Schmitt
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA, GMP and GDP.

Source:
¹ EU-FDA Mutual Recognition Agreement (MRA) for GMP inspections of manufacturers of medicinal products for use in humans