---

ANNEX I

The provisions for the inspection and verification of GLP which are contained in Parts A and B are those contained in Annexes I (Guides for compliance monitoring procedures for good laboratory practice) and II (Guidance for the conduct of test facility inspections and study audits) respectively of the OECD Council Decision-Recommendation on compliance with principles of good laboratory practice (C(89)87(Final)) of 2 October 1989 as revised by the OECD Council Decision amending the Annexes to the Council Decision-Recommendation on compliance with principles of good laboratory practice of 9 March 1995 (C(95)8(Final)).

PART A

REVISED GUIDES FOR COMPLIANCE MONITORING PROCEDURES FOR GLP

To facilitate the mutual acceptance of test data generated for submission to Regulatory Authorities of the OECD member countries, harmonisation of the procedures adopted to monitor GLP compliance, as well as comparability of their quality and rigour, are essential. The aim of this part of this Annex is to provide detailed practical guidance to the Member States on the structure, mechanisms and procedures they should adopt when establishing national GLP compliance monitoring programmes so that these programmes may be internationally acceptable.

It is recognised that Member States will adopt GLP principles and establish compliance monitoring procedures according to national legal and administrative practices, and according to priorities they give to, for example the scope of initial and subsequent coverage concerning categories of chemicals and types of testing. Since Member States may establish more than one GLP Monitoring Authority due to their legal framework for chemicals control, more than one GLP compliance programme may be established. The guidance set forth in the following paragraphs concerns each of these Authorities and compliance programmes, as appropriate.

Definitions of terms

The definitions of terms in the OECD principles of good laboratory practice adopted in Article 1 of Directive 2004/10/EC of the European Parliament and of the Council are applicable to this part of this Annex. In addition, the following definitions apply:

—	GLP principles : principles of good laboratory practice that are consistent with the OECD principles of good laboratory practice as adopted in Article 1 of Directive 2004/10/EC,

—	GLP compliance monitoring : the periodic inspection of test facilities and/or auditing of studies for the purpose of verifying adherence to GLP principles,

—	(national) GLP compliance programme : the particular scheme established by a Member State to monitor GLP compliance by test facilities within its territories, by means of inspections and study audits,

—

(national) GLP Monitoring Authority : a body established within a Member State with responsibility for monitoring the GLP compliance of test facilities within its territories and for discharging other such functions related to GLP as may be nationally determined. It is understood that more than one such body may be established in a Member State,

—

test facility inspection : an on-site examination of the test facility's procedures and practices to assess the degree of compliance with GLP principles. During inspections, the management structures and operational procedures of the test facility are examined, key technical personnel are interviewed, and the quality and integrity of data generated by the facility are assessed and reported,

—

study audit : a comparison of raw data and associated records with the interim or final report in order to determine whether the raw data have been accurately reported, to determine whether testing was carried out in accordance with the study plan and standard operating procedures, to obtain additional information not provided in the report, and to establish whether practices were employed in the development of data that would impair their validity,

—	inspector : a person who performs the test facility inspections and study audits on behalf of the (national) GLP Monitoring Authority,

—	GLP compliance status : the level of adherence of a test facility to the GLP principles as assessed by the (national) GLP Monitoring Authority,

—	Regulatory Authority : a national body with legal responsibility for aspects of the control of chemicals.

Components of good laboratory practice compliance monitoring procedures

Administration

A (national) GLP compliance programme should be the responsibility of a properly constituted, legally identifiable body adequately staffed and working within a defined administrative framework.

Member States should:

Confidentiality

(National) GLP Monitoring Authorities will have access to commercially valuable information and, on occasion, may even need to remove commercially sensitive documents from a test facility or refer to them in detail in their reports.

Member States should:

Personnel and training

(National) GLP Monitoring Authorities should:

Inspectors may be:

In the latter two cases, the (national) GLP Monitoring Authority should have ultimate responsibility for determining the GLP compliance status of test facilities and the quality/acceptability of a study audit, and for taking any action based on the results of test facility inspections or study audits which may be necessary.

(National) GLP compliance programmes

GLP compliance monitoring is intended to ascertain whether test facilities have implemented GLP principles for the conduct of studies and are capable of assuring that the resulting data are of adequate quality. As indicated above, Member States should publish the details of their (national) GLP compliance programmes. Such information should, inter alia:

Follow-up to test facility inspections and study audits

When a test facility inspection or study audit has been completed, the inspector should prepare a written report of the findings.

Member States should take action where deviations from GLP principles are found during or after a test facility inspection or study audit. The appropriate actions should be described in documents from the (national) GLP Monitoring Authority.

If a test facility inspection or study audit reveals only minor deviations from GLP principles, the facility should be required to correct such minor deviations. The inspector may need, at an appropriate time, to return to the facility to verify that corrections have been introduced.

Where no, or where only minor deviations have been found, the (national) GLP Monitoring Authority may:

Where serious deviations are found, the action taken by (national) GLP Monitoring Authorities will depend on the particular circumstances of each case and the legal or administrative provisions under which GLP compliance monitoring has been established within their countries. Actions which may be taken include, but are not limited to, the following:

Appeals procedures

Problems, or differences of opinion, between inspectors and test facility management will normally be resolved during the course of a test facility inspection or study audit. However, it may not always be possible for agreement to be reached. A procedure should exist whereby a test facility may make representations relating to the outcome of a test facility inspection or study audit for GLP compliance monitoring and/or relating to the action the GLP Monitoring Authority proposes to take thereon.

PART B

REVISED GUIDANCE FOR THE CONDUCT OF TEST FACILITY INSPECTIONS AND STUDY AUDITS

Introduction

The purpose of this part of this Annex is to provide guidance for the conduct of test facility inspections and study audits which would be mutually acceptable to OECD member countries. It is principally concerned with test facility inspections, an activity which occupies much of the time of GLP inspectors. A test facility inspection will usually include a study audit or review as a part of the inspection, but study audits will also have to be conducted from time to time at the request, for example, of a Regulatory Authority. General guidance for the conduct of study audits will be found at the end of this Annex.

Test facility inspections are conducted to determine the degree of conformity of test facilities and studies with GLP principles and to determine the integrity of data to assure that resulting data are of adequate quality for assessment and decision-making by national Regulatory Authorities. They result in reports which describe the degree of adherence of a test facility to the GLP principles. Test facility inspections should be conducted on a regular, routine basis to establish and maintain records of the GLP compliance status of test facilities.

Further clarification of many of the points in this part of this Annex may be obtained by referring to the OECD consensus documents on GLP (on, e.g., the role and responsibilities of the study director).

Definitions of terms

The definitions of terms in the OECD principles of GLP adopted in Article 1 of Directive 2004/10/EC and in Part A of this Annex are applicable to this part of this Annex.

Test facility inspections

Inspections for compliance with GLP principles may take place in any test facility generating health or environmental safety data for regulatory purposes. Inspectors may be required to audit data relating to the physical, chemical, toxicological or ecotoxicological properties of a substance or preparation. In some cases, inspectors may need assistance from experts in particular disciplines.

The wide diversity of facilities (in terms both of physical layout and management structure), together with the variety of types of studies encountered by inspectors, means that the inspectors must use their own judgment to assess the degree and extent of compliance with GLP principles. Nevertheless, inspectors should strive for a consistent approach in evaluating whether, in the case of a particular test facility or study, an adequate level of compliance with each GLP principle has been achieved.

In the following sections, guidance is provided on the various aspects of the testing facility, including its personnel and procedures, which are likely to be examined by inspectors. In each section, there is a statement of purpose, as well as an illustrative list of specific items which could be considered during the course of a test facility inspection. These lists are not meant to be comprehensive and should not be taken as such.

Inspectors should not concern themselves with the scientific design of the study or the interpretation of the findings of studies with respect to risks for human health or the environment. These aspects are the responsibility of those Regulatory Authorities to which the data are submitted for regulatory purposes.

Test facility inspections and study audits inevitably disturb the normal work in a facility. Inspectors should therefore carry out their work in a carefully planned way and, so far as practicable, respect the wishes of the management of the test facility as to the timing of visits to certain sections of the facility.

Inspectors will, while conducting test facility inspections and study audits, have access to confidential, commercially valuable information. It is essential that they ensure that such information is seen by authorised personnel only. Their responsibilities in this respect will have been established within their (national) GLP compliance monitoring programme.

Inspection procedures

Pre-inspection

Purpose: to familiarise the inspector with the facility which is about to be inspected in respect of management structure, physical layout of buildings and range of studies.

Prior to conducting a test facility inspection or study audit, inspectors should familiarise themselves with the facility which is to be visited. Any existing information on the facility should be reviewed. This may include previous inspection reports, the layout of the facility, organisation charts, study reports, protocols and curricula vitae (CVs) of personnel. Such documents would provide information on:

Inspectors should note, in particular, any deficiencies from previous test facility inspections. Where no previous test facility inspections have been conducted, a pre-inspection visit can be made to obtain relevant information.

Test facilities may be informed of the date and time of inspector's arrival, the objective of their visit and the length of time they expect to be on the premises. This could allow the test facility to ensure that the appropriate personnel and documentation are available. In cases where particular documents or records are to be examined, it may be useful to identify these to the test facility in advance of the visit so that they will be immediately available during the test facility inspection.

Starting conference

Purpose: to inform the management and staff of the facility of the reason for the test facility inspection or study audit that is about to take place, and to identify the facility areas, study(ies) selected for audit, documents and personnel likely to be involved.

The administrative and practical details of a test facility inspection or study audit should be discussed with the management of the facility at the start of the visit. At the starting conference, inspectors should:

Before proceeding further with a test facility inspection, it is advisable for the inspector(s) to establish contact with the facility's quality assurance (QA) unit.

As a general rule, when inspecting a facility, inspectors will find it helpful to be accompanied by a member of the QA unit.

Inspectors may wish to request that a room be set aside for examination of documents and other activities.

Organisation and personnel

Purpose: to determine whether the test facility has sufficient qualified personnel, staff resources and support services for the variety and number of studies undertaken; the organisational structure is appropriate, and management has established a policy regarding training and staff health surveillance appropriate to the studies undertaken in the facility.

The management should be asked to produce certain documents, such as:

The inspector should check, in particular:

Quality assurance programme

Purpose: to determine whether the mechanisms used to assure management that studies are conducted in accordance with GLP principles are adequate.

The head of the QA unit should be asked to demonstrate the systems and methods for QA inspection and monitoring of studies, and the system for recording observations made during QA monitoring. Inspectors should check:

Facilities

Purpose: to determine if the test facility, whether indoor or outdoor, is of suitable size, design and location to meet the demands of the studies being undertaken.

The inspector should check that:

Care, housing and containment of biological test systems

Purpose: to determine whether the test facility, if engaged in studies using animals or other biological test systems, has support facilities and conditions for their care, housing and containment, adequate to prevent stress and other problems which could affect the test system and hence the quality of data.

A test facility may be carrying out studies which require a diversity of animal or plant species as well as microbial or other cellular or sub-cellular systems. The type of test systems being used will determine the aspects relating to care, housing or containment that the inspector will monitor. Using his judgment, the inspector will check, according to the test systems, that:

Apparatus, materials, reagents and specimens

Purpose: to determine whether the test facility has suitably located, operational apparatus in sufficient quantity and of adequate capacity to meet the requirements of the tests being conducted in the facility and that the materials, reagents and specimens are properly labelled, used and stored.

The inspector should check that:

Test systems

Purpose: to determine whether adequate procedures exist for the handling and control of the variety of test systems required by the studies undertaken in the facility, for example, chemical and physical systems, cellular and microbic systems, plants or animals.

Physical and chemical systems

The inspector should check that:

Biological test systems

Taking account of the relevant aspects referred to above relating to care, housing or containment of biological test systems, the inspector should check that:

Test and reference substances

Purpose: to determine whether the test facility has procedures designed (i) to ensure that the identity, potency, quantity and composition of test and reference substances are in accordance with their specifications, and (ii) to properly receive and store test and reference substances.

The inspector should check that:

Standard operating procedures

Purpose: to determine whether the test facility has written SOPs relating to all the important aspects of its operations, considering that one of the most important management techniques for controlling facility operations is the use of written SOPs. These relate directly to the routine elements of tests conducted by the test facility.

The inspector should check that:

Performance of the study

Purpose: to verify that written study plans exist and that the plans and the conduct of the study are in accordance with GLP principles.

The inspector should check that:

Reporting of study results

Purpose: to determine whether final reports are prepared in accordance with GLP principles.

When examining a final report, the inspector should check that:

Storage and retention of records

Purpose: to determine whether the facility has generated adequate records and reports and whether adequate provision has been made for the safe storage and retention of records and materials.

The inspector should check:

Study audits

Test facility inspections will generally include, inter alia, study audits, which review on-going or completed studies. Specific study audits are also often requested by Regulatory Authorities, and can be conducted independently of test facility inspections. Because of the wide variation in the types of studies which might be audited, only general guidance is appropriate, and inspectors and others taking part in study audits will always need to exercise judgment as to the nature and extent of their examinations. The objective should be to reconstruct the study by comparing the final report with the study plan, relevant SOPs, raw data and other archived material.

In some cases, inspectors may need assistance from other experts in order to conduct an effective study audit, for example, where there is a need to examine tissue sections under the microscope.

When conducting a study audit, the inspector should:

In studies in which animals (i.e., rodents and other mammals) are used, the inspectors should follow a certain percentage of individual animals from their arrival at the test facility to autopsy. They should pay particular attention to the records relating to:

Completion of inspection or study audit

When a test facility inspection or study audit has been completed, the inspector should be prepared to discuss his findings with representatives of the test facility at a closing conference and should prepare a written report, i.e., the inspection report.

A test facility inspection of any large facility is likely to reveal a number of minor deviations from GLP principles but, normally, these will not be sufficiently serious to affect the validity of studies emanating from that test facility. In such cases, it is reasonable for an inspector to report that the facility is operating in compliance with GLP principles according to the criteria established by the (national) GLP Monitoring Authority. Nevertheless, details of the inadequacies or faults detected should be provided to the test facility and assurances sought from its senior management that action will be taken to remedy them.

The inspector may need to revisit the facility after a period of time to verify that necessary action has been taken.

If a serious deviation from the GLP principles is identified during a test facility inspection or study audit which, in the opinion of the inspector, may have affected the validity of that study, or of other studies performed at the facility, the inspector should report back to the (national) GLP Monitoring Authority. The action taken by that Authority and/or the Regulatory Authority, as appropriate, will depend on the nature and extent of the non-compliance and the legal and/or administrative provisions within the GLP compliance programme.

Where a study audit has been conducted at the request of a Regulatory Authority, a full report of the findings should be prepared and sent via the relevant (national) GLP Monitoring Authority.

---

ANNEX II

PART A

PART B

---

ANNEX III