Good Manufacturing Practice (GMP) Inspections (veterinary medicines)

In general, a manufacturer will be notified 4-6 weeks in advance of a planned inspection. In relation to for cause or triggered inspections, a shorter notice period may be given. The notification will outline the legal basis for the inspection, what will be reviewed as part of the inspection (the scope), names of the inspectors and the planned number of inspection days. The notification will include an initial list of pre-inspection requests for information and documentation which must be provided to the HPRA in advance. This may include:

• Current site master file (SMF),
• Details of any significant changes to premises and equipment, key personnel and manufacturing processes in the period since the last inspection

This information will be reviewed by the HPRA and used to develop an inspection plan 1-2 weeks in advance of the inspection. If requested, the lead inspector may provide the plan to the site prior to the start of the inspection.

The duration of the inspection and the number of inspectors conducting it will vary depending on the complexity of the operations and the activities conducted at the site. Typically, they are scheduled for 3-5 days and will be performed at the site that was chosen for the inspection. Where appropriate, certain types of inspections may also be conducted remotely.

The activities conducted during an inspection, including areas of the building inspected and the type of documentation reviewed, will vary depending on the type of inspection and the scope. However, inspections usually consist of an opening meeting, document review, walk through of the facilities, sessions with key personnel and a closing meeting.

The scope and activities reviewed during some of the more common types of GMP inspections conducted by the HPRA are outlined below. This list is not exhaustive, but provides an overview of areas that would typically be reviewed.

Manufacturing site inspections may include a review of:

• Production areas
• Facilities and equipment (including computerised systems)
• Management of starting materials
• Laboratory premises, procedures and test results
• Pharmaceutical quality system documents and records
• Controls in place to prevent contamination and mix ups
• Personnel and training
  

A written report outlining issues identified during the inspection will be sent to the site within three weeks of the end of the inspection.

Issues that are identified (known as deficiencies) are classified into three categories: critical, major and other.

A critical deficiency is one which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal.

A major deficiency is a non-critical deficiency, which has produced or may produce a product, which does not comply with its marketing authorisation, 

or 

which indicates a major deviation from EU Good Manufacturing Practice, 

or

(within EU) which indicates a major deviation from the terms of the manufacturing authorisation, 

or 

which indicates a failure to carry out satisfactory procedures for release of batches

or

(within EU) a failure of the Qualified Person to fulfill their legal duties

or

a combination of several 'other' deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such.

'Other' deficiencies are those which cannot be classified as either critical or major, but which indicate a departure from good manufacturing practice. A deficiency may be 'other' either because it is judged as minor, or because there is insufficient information to classify it as a major or critical.

The site will be requested to provide a response to the issues outlined in the report within approximately three weeks. The report will outline the deadline for response and will contain instructions to assist with responses. A response for each finding should be provided, outlining a root cause analysis of the deficiency (e.g. what caused the issue) and a proposal for corrective and preventative actions (CAPA). Specific actions are expected to be provided as part of this response, including what is going to be done, who will be responsible and when it will be completed.

The responses will be reviewed by the inspection team to determine if they are acceptable to address the issues identified and to prevent them occurring in future. The inspectors will routinely send follow up questions or request further clarification before the responses are finalised. When the responses to the inspection report are judged to be acceptable, the inspection will be closed and a close out letter is issued by day 120.

If an inspection finds that the GMP compliance at a manufacturing site is significantly lower than the required standard the manufacturer will be informed at the end of the inspection that the deficiencies identified are being referred by them to a Compliance Regulatory Group (CRG). A CRG meeting will be convened and the grading of the most significant deficiencies agreed. If necessary, a case management strategy will be developed and implemented with the aim of making the most senior person within the company aware that there is an urgent need to improve compliance. Actions that may be taken include holding meetings with key people, sending a cautionary letter to the company to explain what is expected and what action is being considered if compliance does not improve at the site.