What are 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!

Tracking & Trending and Key Process Indicators (KPIs)

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.

Supply Chain Traceability

The qualification of (all) suppliers is a legal obligation of the marketing authorisation holder (MAH). Already when applying for a marketing authorisation (MA), the respective API suppliers need to be audited (and qualified) by the manufacturer. And this is the start of an ongoing qualification.

Article 46 of EU-Directive 2001/83/EC requires that (to comply with the GMP guidelines) the product manufacturer shall verify compliance of the API manufacturer it uses by conducting audits at manufacturing and distribution premises. For excipient suppliers, a formalised risk assessment is the minimum (see next paragraph).

Chapter 7 of the EU-GMP Guide ("Outsourced Activities") then requires that "the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities" prior to outsourcing activities [7.5] and that "the Contract Giver should monitor and review the performance of the Contract Acceptor (…)" [7.7].

According to Annex 16 of the EU-GMP Guide, the QP has to ensure that "all audits of sites involved in the manufacture and the testing of the medicinal products and in the  manufacture of the active substance have been carried out and that the audit reports are available to the QP performing the certification." [1.7.3]

GMP for Excipients

In the EU, there is GMP Guidance for pharmaceutical excipient suppliers: Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use. The expectation is that Manufacturing Authorisation Holders perform a risk assessment to evaluate any risk associated with the excipient manufacturer/ supplier to further define appropriate GMP controls and a classification of the manufacturer's risk profile for the supplier qualification.

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