A Calibration Manager's Guide to GLP

Principles of GLP and Compliance Monitoring - Good Laboratory Practice.

The purpose of this article is to explain the roles that instrument calibrations and calibration management play in GLP. It is a small, but highly important aspect of what is a very broad subject, but it's importance cannot be overstated.

On 1 April 1997, the United Kingdom’s voluntary Good Laboratory Practice Compliance programme was superseded by a Statutory Instrument (SI) entitled The Good Laboratory Practice Regulations 1997. The regulations were based on the 1981 version of the Organisation for Economic Co-operation and Development (OECD) principles of Good Laboratory Practice (GLP).

In 1998 the OECD issued the revised Principles of GLP and Compliance Monitoring. These were adopted by the EC in October 1998 and issued as Directives 99/11/EEC and 99/12/EEC. Consequently, in 1999, the UK Regulations were updated by SI 3106, as amended by SI 994, 2004, and are accompanied by a guide that interprets them and explains how compliance will be verified.

The primary objective of the OECD Principles of GLP is to ensure the generation of high quality and reliable test data related to the safety of industrial chemical substances and preparations. It harmonises testing procedures so that results and other data are acceptable between laboratories and organisations, a process referred to as Mutual Acceptance of Data (MAD). Do not think, however, that GLP applies to any one particular sector or type of laboratory. It is a fundamental framework for ensuring that, wherever laboratory studies are carried out, all data generated is reliable, and that the studies are planned, performed, monitored, recorded, reported and archived in such a way as to ensure this reliability.

For some laboratories, adherence to GLP is a statutory requirement. Other laboratories may follow the guidelines on a voluntary basis in order to demonstrate the rigour in which their work is carried out. However, test facilities that do not carry out regulatory studies (defined below) are not compelled to work in accordance with the principles of GLP. Such facilities are not eligible for admission to the UK GLP compliance programme.

2. Who Needs to Comply?

Compliance with the principles of Good Laboratory Practice (GLP) is a legal requirement for:

test facilities that undertake health and environmental safety studies, and some other testing, that will be submitted to regulatory authorities for the purposes of risk assessment.


	Test facilities that undertake health and environmental safety studies
	Other types of testing that will be submitted to regulatory authorities for the purposes of risk assessment

To comply with the GLP regulations, a test facility which conducts, or intends to conduct, regulatory studies must be a member of the UK GLP Compliance Monitoring Programme. These regulations define a 'regulatory study' as a non-clinical experiment or set of experiments in which:


	An item is examined under laboratory conditions or in the environment in order to obtain data on its properties or its safety (or both) with respect to human health, animal health or the environment
	The results of which are, or are intended, for submission to the appropriate regulatory authorities
	Compliance with the principles of GLP is required in respect of that experiment or set of experiments by the appropriate regulatory authorities

Work that does not constitute a regulatory study as defined above (or an integral part thereof) is not required to be conducted in compliance with the principles of GLP. Examples of these are:

	Work undertaken by Quality Control laboratories in support of final product release
	Laboratory work in support of human clinical trials, does not require to be conducted in compliance with the Principles of GLP

There are other regulations that cover the control of the quality of a manufactured product or service, examples being ISO 9001 and, for calibration laboratories, ISO 17025.

3. Who Governs and Monitors GLP?

The UK GLP Monitoring Authority (GLPMA) has responsibility for monitoring test facilities for compliance with the principles of GLP.

The work of the GLPMA is carried out by a unit within the Inspection and Enforcement Division of the Medicines Control Agency (MCA), which is an executive Agency of the Department of Health (DH). The range of test facilities monitored by the GLPMA include those involved in the health and environmental safety testing of human and veterinary pharmaceuticals, agrochemicals, cosmetics, food and feed additives and industrial chemicals.

The UK Government's website contains some very useful information on GLP. Here are some links that you might find informative:

MHRA: Good Laboratory Practice

Good laboratory practice (GLP)

MHRA - GLP: The UK GLP compliance monitoring programme

Good Laboratory Practice Regulations 1999

4. What is the Purpose of Calibration Management Within GLP?

Almost without exception, testing will involve the use of measuring equipment, scientific instruments and other hardware.

It is inconceivable that anyone would have confidence in the measurements produced by these instruments if they did not have a continuous record of traceable calibration. Furthermore, the calibration records must be readily available to all concerned including laboratory staff, inspectors and auditors, etc.

It is essential, therefore, that GLP compliant laboratories have in place an effective and accurate calibration management system which gives access to all relevant information including:

* Date of last calibration and calibration due date
* All relevant current calibration data
* Details of previous calibrations (historical data)
* Operating and calibration procedures
* Device details such as type, supplier, purchase date, etc
* The person with responsibility for the instrument
* The person who calibrated the instrument

It is perfectly acceptable for laboratories to devise their own calibration management systems but be warned: designing such systems from scratch can be a time-consuming process, particularly if a paperless (i.e. computerised) system is required. The majority of laboratories elect to use commercially available calibration management software such as Calibration Toolbox ADO, which was designed, from the outset, to be used by laboratories working to GLP, ISO 17025 and other internationally accepted standards.

4.1. A Validated Calibration Management System

OECD Series on Principles of GLP and Compliance Monitoring Number 5 (Revised) - ENV/JM/MONO(99)21

Computer systems, applications software:

All computer software, including that obtained from an external supplier, should normally be acceptance-tested before being put into service by a laboratory. From this requirement it can be inferred that it is acceptable for formal validation of applications software to be carried out by the supplier on behalf of the user, provided that the user undertakes the formal acceptance tests.

The Revised Principles of GLP (Section II.1.2.2g) place the responsibility to ensure that software programmes have been validated with the Study Director. The validation may be undertaken by the user or the supplier, but full documentation of the process must be available and should be retained in the archives.

In cases where the validation is performed by the user, Standard Operating Procedures should be available

The ultimate responsibility for the validation of your system lies with your own laboratory.

However, vendors of proprietary software, such as Calibration Toolbox ADO and Caliso Calibration Administrator, can play their part by providing you with validation documentation for their software, and tools for testing the software in its intended location, i.e. in your laboratory.

Calibration Toolbox ADO, which is widely used throughout the healthcare, pharmaceutical and biotechnology industries, is designed to automate parts of your company's quality control system and, because of this, has been subjected to strict validation/verification procedures. It is classed as "off the shelf" software in which by definition you, the end-user, played no direct part in the specification, development and testing. One of the key purposes of this document to demonstrate to you and any auditor, that the software has been designed, developed and tested in accordance with the internationally accepted guidelines for software validation.

Should you require external sources of reference for your software validation, there are several excellent sources of reference, in particular, the US Food & Drug Administration FDA web site and the web site of the US National Institute of Standards & Technology. NIST.

You will find more information on Calibration Toolbox ADO, and other Humpage Technology Software products, on this website, or please contact us if you require further information. Also please see our download page to get the software FREE.

4.2. Use, Calibration, and Maintenance of Equipment

OECD Principles of Good Laboratory Practice - Legislative basis Directive 87/18/EEC, Directive 88/320/EEC

Apparatus used in a study should be periodically inspected, cleaned, maintained, and calibrated according to Standard Operating Procedures. Records of procedures should be maintained.

OECD Series on Principles of GLP and Compliance Monitoring Number 5(Revised) - ENV/JM/MONO(99)21 Apparatus:

It is the responsibility of test facility management to ensure that instruments are adequate and functioning according to their intended use.

The test facility management should also ensure that instruments are inspected and calibrated at prescribed intervals. Calibration should be traceable to national or international standards of measurement as appropriate. If reference standards are kept by the user they should be calibrated by a competent body at prescribed intervals.

Equipment used to generate data should be appropriately located, safe, suitable for the purpose, of appropriate design, and of adequate capacity. It should be calibrated and serviced regularly by trained staff so that performance is optimal and the results can be trusted.

A designated person should be responsible for ensuring the proper use and maintenance of equipment and, where appropriate, for training staff in its use. When this is not possible, the users themselves should take on the responsibility. Records should be kept of calibration, servicing, faults, breakdowns, and misuse of equipment.

A standard operating procedure should be maintained for each piece of equipment; in some cases this might be the manufacturer’s instruction manual. There should be easily accessible instructions for the safe shutdown of equipment in case of emergency.

4.3. Standard Operating Procedures

Standard operating procedures (SOPs) should be documented for all routine methods and for individual items of equipment to ensure that data are collected consistently and accurately. When there is more than one approved technique for any given procedure, all should be covered by SOPs.

SOPs should be written in simple language, readily accessible, and ideally in a standardised format. They should be updated as necessary, and only the current version should be available.

Standard written protocols should also be available covering the process of seeking informed consent from patients or volunteers, to ensure clarity and consistency. Written protocols are likewise essential for ensuring strict adherance to regulations/licences, for example in research involving animals.

4.4. Maintenance of Calibration Records

OECD SERIES ON PRINCIPLES OF GOOD LABORATORY PRACTICE AND COMPLIANCE MONITORING

The following should be retained for the period specified by the appropriate authorities:

* The study plan, raw data, samples, specimens, and the final report of each study
* Records of all inspections and audits performed by the Quality Assurance Programme
* Summary of qualifications, training, experience and job descriptions of personnel
* Records and reports of the maintenance and calibration of equipment
* The historical file of Standard Operating Procedures

The above requirements are very clear and require no further explanation.

4.5. Measurement Uncertainties and Other Issues

As we have said, the primary objective of GLP is to ensure the generation of high quality data.

Essential to this is the ability to produce estimates for the measurement uncertainty associated with calibrations. Your calibration management system should enable you to perform all the necessary analysis in accordance with NIST/GUM guidelines, including Type A and Type B uncertainties, combined uncertainties, coverage factor and expanded uncertainties.

Other key GLP/GMP records to be maintained by our calibration management system are:

* Unique ID number to identify each instrument or device
* Calibration data storage and calibration histories
* Compliant calibration certificate design
* Easy access to standard operating procedures
* Secure Audit Trail

Acknowledgements

This paper has made use of information taken from the following sources:

The Medicines and Healthcare products Regulatory Agency (MHRA) (Various items)

OECD Series On Principles Of Good Laboratory Practice And Compliance Monitoring