EU and FDA GMP

Food and Drug Administration (FDA)

The Food and Drug Administration (FDA) is a government agency established in 1906 with
the passage of the Federal Food and Drugs Act. The agency is separated into divisions that
oversee a majority of the organization's obligations involving food, drugs, cosmetics, animal
food, dietary supplements, medical devices, biological goods, and blood products.

Employees: 14,824 (2010)

Headquarters: White Oak Campus 10903 New Hampshire Avenue Silver Spring, Maryland

European Medicines Agency

The European Medicines Agency is an agency of the European Union in charge of the
evaluation and supervision of medicinal products. Prior to 2004, it was known as the
European Agency for the Evaluation of Medicinal Products or European Medicines

The Differences between EU and FDA GMP

While EU and FDA GMP Guidance is very similar, there are also some areas where there are
known differences. It is worthwhile being aware of these differences and how to prepare for
inspections and interaction with companies and authorities from the "other side".

Some examples:

The objective of the FDA "Annual Product Review" (APR) 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'' (PQR) 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!

According to EU-GMP Chapter 1, "a Pharmaceutical Quality System appropriate for the
manufacture of medicinal products should ensure that (…) a state of control is established
and maintained by developing and using effective monitoring and control systems for
process performance and product quality." It is important to use KPIs to demonstrate a state
of control but also to initiate and control potential continuous improvement processes. This
should be periodically reviewed by senior management (1.6). Overall, all manufacturing
processes should be "clearly defined, systematically reviewed in the light of experience and
shown to be capable of consistently manufacturing medicinal products of the required
quality and complying with their specifications."

So the EU will have an eye on quality metrics data mainly in the course of GMP inspections
whereas the FDA has a different approach: The draft "Submission of Quality Metrics Data
Guidance for Industry" was issued in November 2016. The FDA wishes that, after it has
come into force, manufacturers will submit defined quality metrics to the FDA via an
electronic portal. The FDA will use these to calculate specific statistics which are supposed
to allow for risk-based inspection planning by the FDA.

Role of the QP
In the EU, a named Qualified Person (QP) must certify the GMP compliance for each batch
of a drug product, either commercial or investigational (IMPs). The responsibilities of the
Qualified Person are defined in Annex 16 to the EU-GMP Guidelines. If commercial products
or IMPs are manufactured or packaged in the US and then imported into the EU, additional
analytical testing in the EU is needed. Additionally a successful supplier qualification is
needed including initial and periodic compliance audits which are conducted according to
the respective EU-GMP Guidance. These audits are performed by the QP or on behalf of the
QP. An inspection by a competent authority does not replace the need for an audit. So US
companies will still need to face EU audits, even after full implementation of the MRA.

In the US, the Quality Control Unit is responsible for conducting a production record review
according to CFR Part 211.192 and for ensuring contractors meet GMPs (211.22 a). 

In the US, the Quality Control Unit is responsible for conducting a production record review
according to CFR Part 211.192 and for ensuring contractors meet GMPs (211.22 a).

Validation
There is growing conformity between the FDA Process Validation Guideline and the
revised Annex 15 ("Qualification and Validation"). A better match with the FDA Guideline
was also one of the reasons for the revision of EU-GMP Guide Annex 15.

As one difference the Annex 15 asks to also list non-critical attributes and parameters in the
validation protocol. The FDA Process Validation Guideline only requires the specification of
critical quality attributes and critical process parameters. The FDA sees another difference in
the number of validation batches. Annex 15 refers to the minimum number of three,
whereas the FDA Process Validation Guideline does not mention a number. For the FDA
there is another difference in terms of process validation approaches. In Annex 15 three
approaches are mentioned (traditional, continuous process verification, hybrid), while the
FDA Process Validation Guideline makes no distinction. Further, the requirements for
statistics also differ in the two documents. This topic is emphasized more in the FDA Process
Validation Guideline. The FDA even recommends that a statistician should create the data
collection plans and should also be consulted with regard to the use of statistical methods.
The FDA also sees differences regarding the subject of sampling in stage 3 of the process
validation life cycle (continued/ongoing process verification) and demands a higher number
of samples - at least until sufficient data exist to assess variability. There is no such demand
for an increased number of samples in the ongoing process verification in Annex 15.

EU Specifics

Contamination Control
The 2015 revision 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. This means that dedicated facilities
are only required if the identified risks can not be controlled using adequate technical or
organisational measures.

This is also supported by EMAs Toxicological Guideline, mentioned above. It has been valid
since 1 June 2015 and describes a risk assessment based on the toxicological evaluation of
the products manufactured in the shared facilities/production areas. The revised chapter 5
"Production" also has a high focus on the technical and organisational measures to prevent
cross-contamination.

Overall, a documented Contamination Control Strategy is required and QRM principles

should be used to assess and control the risks of contamination & cross contamination.

Specific Differences in Technical GMP

Expectations
Whilst the EU and FDA GMP Guidelines are very similar, there are some areas where there
have been known differences in technical and GMP expectations:

Reverse Osmosis is permitted in the USA as a means of producing Water for Injection. Only
WFI by distillation is permitted in the EU.

Final capping of vials in the EU is expected to be performed in a classified environment,

ideally under Grade A laminar flow, whereas in the USA the FDA have accepted an
unclassified environment for this activity.

Clean room classification for manufacturing sterile or low bioburden products. The EU uses
Grade A – D and the USA uses Class 100 – Class 100,000 to indicate the particulate levels
required for the various room classifications.
The approach in the USA to the validation and management of steam sterilisers for
equipment and porous loads has encountered severe criticism from EU inspectors. The
importance of air removal in particular has not been well understood and applied in the
USA.

The EU approach to basing sampling plans for raw materials on risk and knowledge of the
supplier is not a typical USA approach. Raw materials in the USA are often sampled on a –.ln
+ 1 approach regardless of risk.

The FDA focuses heavily on the blending operation and validation for solid dose products
and has issued quite specific guidance on this subject.

The FDA has set many trends and this has been very evident with their very thorough and
rigid approach to the use of computers in the pharmaceutical industry, in particular to the
use of electronic signatures.

CFR 21 Part 11 has encountered heavy criticism from the industry in its requirements for
electronic signatures which has been onerous.

The FDA focuses heavily on the company procedures for dealing with Out Of Specification
results and their OOS Guidance finalised in 2006 has led the way in this issue and the EU
Inspectors will apply the same requirements.

The manufacture of Over the Counter (OTC) products in the USA does not appear to be as
important as prescription medicines with respect to GMP compliance, in that these
manufacturers are not inspected as often as prescription only medicine manufacturers. In
the EU the inspection frequency has been the same.

Conclusion:
In practice, GMPs applied throughout the world are all about ensuring that medicinal
products are made consistently to the quality specification required, by implementing
controls over all factors that could affect the product quality during manufacturing.

There have been considerable differences in the past between the EU and USA in the
approach to inspections and in some specific areas of GMP.

Hopefully the new FDA initiatives, the ICH process and the recent API inspection
collaboration project will promote a better internationally agreed approach to quality
systems in the pharmaceutical industry worldwide, and a more consistent interpretation
of GMPs

References
http://qp.solutions/pharmaceutical-gmp/gmps-eu-usa-overview-comparison/
https://www.gmp-compliance.org/gmp-news/what-are-the-differences-between-eu-and-fda-gmp

https://www.investopedia.com/terms/f/fda.asp