What is the Procedure for GMP Inspections (EU GMP inspections and FDA Inspections)?

The "Compilation of Union Procedures on Inspections and Exchange of Information" is an official EU reference document that brings together all harmonised procedures, templates, and guidelines used by the GMP/GDP inspectorates of the EU/EEA, the European Medicines Agency (EMA), and the European Commission for the coordination and performance of regulatory inspections. It contains procedures for carrying out inspections by EU inspectorates.

Procedure of a EU-GMP Inspection

1. Planning and Preparation

Before a GMP inspection, the competent authority performs risk-based planning and establishes an inspection programme. Inspections may take place at any time; however, they are usually announced so that the company can make relevant personnel and documents available.

Based on the risk assessment and other available information, the responsible inspector prepares the inspection. This preparation may include, for example:

• Site Master File
• Review of previous inspection reports and follow-up actions
• Review of relevant authorisation documentation (manufacturing and marketing authorisations, variations)
• Review of recalls and product defects
• Review of significant changes in facilities, processes, or key personnel
• Review of databases such as EudraGMDP or FDA Warning Letters

An inspection plan is then created, defining objectives, scope, and timeline.

2. Opening Meeting

At the beginning of the inspection, an opening meeting takes place. The inspector introduces her/himself and any accompanying persons, explains the objective, purpose, and scope of the inspection, discusses the planned agenda, and identifies the documents required. During the inspection, adjustments to the schedule and required documentation may be made at any time.

The company has the opportunity to briefly present itself and its quality management system, report on relevant changes since the last inspection and introduce the persons who will accompany the inspector.

3. Conduct of the Inspection

3.1 Facility Tour

A tour of the site (warehouse, manufacturing, laboratories) serves for orientation, identification of changes, and detection of initial risk signals. If necessary, the tour and subsequent steps are flexibly adapted.

The inspection often follows the material and process flow:

• Goods receipt
• Storage areas
• Manufacturing
• Packaging
• Quality control / microbiology
• Utility systems (HVAC, water, steam, etc.)

Inspectors evaluate layout, equipment, condition, and processes, discuss observations directly with personnel, assess staff competence and understanding, and identify potential weaknesses.

3.2 Document Review and Assessment of GMP Systems

Based also on the findings of the tour, the inspector reviews, on a sample basis, for example:

• Documented evidence for individual observations
• Specifications
• Manufacturing instructions and batch records
• Quality control documentation
• Relevant parts of the marketing authorisation dossiers
• Technical documentation on rooms and equipment
• Quality management systems and related SOPs
• Deviations and CAPA measures
• Qualification documentation for suppliers and contractors
• Recall procedures and complaint management
• Personnel training
• Self-inspections

4. Closing Meeting

At the end of the inspection, the inspector summarises all observations. Depending on the inspectorate, deficiencies may already be classified (critical / major / other):

• Critical deficiencies (critical, F1):
  The deficiency potentially or actually affects the product in such a way that it may become life-threatening or cause serious health damage.
• Major deficiencies (major, F2):
  The deficiency potentially or actually affects the product but does not fall into the F1 category.
• Other deficiencies (minor, F3):
  Deviations from EU GMP that are not classified as critical or major.

Recommendations may also be made if improvement potential is identified during the inspection. These do not represent non-compliance with GMP requirements.

The company has the opportunity to comment on the observations and, where appropriate, discuss possible corrective approaches. In the case of critical deficiencies, immediate actions must be taken.

5. Inspection Report

After the inspection, the inspector prepares a report that includes, among others:

• Description of the company and its activities
• Course of the inspection
• Observations and deficiencies
• Overall assessment of the inspection

The "Compilation of Union Procedures on Inspections and Exchange of Information" contains an example format: Good Manufacturing Practice (GMP) Inspection Report - Union format.

6. Issuance of a GMP Certificate / Non-Compliance Statement

Based on the company's GMP compliance, the severity of deficiencies, and the proposed corrective actions, the authority issues either a GMP Certificate or a Non-Compliance Statement. Both are entered into the EudraGMDP database. Templates are also provided in the "Compilation of Union Procedures".

GMP Inspections by the US FDA

FDA GMP inspections follow an independent, system-oriented process that differs in some respects from EU GMP inspections. A very good source for FDA inspections is the "FDA Compliance Program, Chapter 56 - Drug Quality Assurance".

The FDA mainly distinguishes between two types of inspections:

• Pre-Approval Inspections (PAI):
  Conducted as part of the approval process for a new product (NDA/BLA/ANDA). Despite the MRA between the EU and the USA, the FDA still conducts these in Europe.
• Routine / Surveillance inspections:
  To verify ongoing GMP compliance. These are less frequent in the EU because the FDA recognises EU inspections under the MRA, but they still take place.

The FDA uses a system-based approach and therefore evaluates individual quality systems in the areas of:

• Quality system
• Facilities and equipment
• Materials system (controls of finished products, components, including water or gases, containers and closures)
• Packaging and labelling
• Production
• Laboratory controls

A key difference from the EU approach: the FDA considers a company "out of control" if any one system fails: "An establishment is out of control if any one system is out of control. A system is out of control if the quality, identity, strength, and purity of the products resulting from one or more systems cannot be adequately ensured. Documented CGMP deficiencies provide the evidence for concluding that a system is not operating in a state of control."

If observations are made, the inspector hands over a Form 483 at the end of the inspection, without evaluation or classification of the observations. The company may discuss the points on site, but the Form 483 is still issued.
Afterwards, the FDA expects the company to respond within 15 working days, describing appropriate corrective actions.

Additionally, the inspector prepares an "Establishment Inspection Report (EIR)" within about 30 days and submits it to the District Office for evaluation. Based on the Form 483, the company's response, and the EIR, the inspection status is determined:

• NAI - No Action Indicated
• VAI - Voluntary Action Indicated
• OAI - Official Action Indicated

In OAI cases, formal actions may follow, such as:

• Warning Letter
• Import Alert
• Debarment
• Complete Response Letter
• Consent Decree

After all deficiencies have been corrected, the FDA issues a Close-Out Letter.

For preparation for inspections, ECA offers a dedicated training course, also available as a recording.