IEC Guide 25: Schisms and

Chapter 5

The OECD GLP Principles and ISO/IEC Guide 25: Schisms and Bridges

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Theo Helder GLP Monitoring Unit, Veterinary Public Health Inspectorate, Ministry of Health, Welfare and Sport, P.O. Box 5406, 2280 HK Rijswijk, the Netherlands

Both the Good Laboratory Practice Principles and the ISO/IEC Guide 25 are quality systems to be applied to research. Because of this the systems are quite comparable and have much in common. Basic differences between the criteria, like the independent QA function, the study director concept and archiving requirements, arise from the distinct scopes of GLP and ISO 25. The application of GLP is legally required for research in the regulatory area, whereas ISO 25 serves almost exclusively the private market. Therefore, only a few laboratories need to implement both quality systems. As a result of the distinction of scope, the monitoring of GLP compliance and ISO-type laboratory accreditation serve different purposes and are performed in quite different ways. GLP compliance has to be monitored by government inspectors with investigational powers and authority, and ISO-conformityassessment is conducted by private bodies. Some monitoring authorities issue "Statements of Compliance" after satisfying inspections, which is essentially differentfromthe formal accreditation performed by accreditation bodies. Theoretically, it is possible to perform laboratory "accreditations" for OECD GLP compliance; however, the task of performing directed inspections and study audits is and must remain the responsibility of government bodies. Therefore, the practicality of contracting out part of the monitoring programmes to private bodies is implausible.

The implementation of rules or principles of Good Laboratory Practice in the conduct of non-clinical and safety studies became a legal requirement in almost all of the OECD countries in the late seventies until the mid eighties. Monitoring programmes were subsequently set up by the OECD Member Countries. Not long after, industry became

© 1999 American Chemical Society

In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

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32 aware of the advantages of also having a quality system for the non-regulated area, as a result of which the ISO 9000 series standard and, more specifically, for laboratories, ISO Guide 25 and its equivalent European standard, EN 45001, were developed. Governmental or private organisations took up the task to accredit the laboratories implementing these quality systems. Because of the similarities between the requirements of both the Principles of GLP and the ISO/IEC Guide 25, and the purported burden of multiple inspections, a movement has developed to bring together the ISO 25 and GLP quality systems. Although it is clear that on paper both quality systems are much alike, the differences between their origins, scope, purpose and legal position make a merger virtually impossible. Implementation and Monitoring When comparing the GLP system with the ISO or EN system, the veryfirstthing to be done is to discriminate between the rules or principles to be applied in the laboratory or test facility and the surveillance of their application by third parties or authorities. This is very much neglected by those in favour of merging the two quality systems. It is of major importance to separate implementation and surveillance in order to get a clear overall picture. The "GLP-system is based on the Council Decision of the OECD Council on Mutual Acceptance of Data [C(81)30(Final)] and Council Decision C(89)87(Final). These decisions stipulate that data of safety research produced in one Member Country will be accepted in any other Member Country, if the Principles are applied and an appropriate monitoring is in place. The principles to be applied are laid down as Annex Π to the C(81)30(Final) Decision (/), whereas the guide for monitoring procedures and the guidance for laboratory inspections and study audits are to be found as the Annexes I and II of the Council Decision C(89)87(Final) (2, 3). A similar partition is to be found in the area of laboratory accreditation. The standard, EN 45001, that is equivalent to ISO/IEC Guide 25, sets out the requirements that laboratories have to meet; EN 45002 and 45003 set out the rules for the assessment of testing laboratories and for laboratory accreditation bodies, respectively. H

Comparison of Requirements Several efforts to compare GLP and ISO/EEC Guide 25, or its equivalent EN 45001, have been made. From these, it is quite obvious that GLP and ISO/IEC 25 have different starting points and different endpoints. Whereas ISO 25 requirements are fully in line with the laboratory accreditation requirements, i.e. aimed to demonstrate the compe tence to carry out a specific task and, therefore, is test method oriented, GLP is study oriented and designed to fulfill governmental requirements to demonstrate that a study is fully reconstructiblefromthe study plan, SOPs, raw data andfinalreport. This means that GLP has stringent requirements related to a study plan, study director,finalreport, study director's GLP statement, and the QA statement that cannot be found in ISO 25. Also there is a requirement for an independent QA programme, which is considered a very strong requirement for GLP, very much unlike the ISO's self assessment scheme. Furthermore, GLP requires complete recording of all events and has strict archiving rules, which also cannot be found in ISO 25. To be compliant, a laboratory, therefore,



33 should apply the GLP principles over the full width of its activities. For each study, it should be decided if GLP rightfully can be claimed, dependent on whether or not there is full adherence to the GLP Principles. It should not be forgotten here that adherence to the GLP Principles is a legal requirement for safety studies. ISO 25 laboratory accreditation is aiming at the assessment of the competence to perform specified tests. These tests are of a repetitive nature unlike GLP studies. The laboratory is free to decide which and how many types of tests are to be assessed. This makes it possible that a laboratory is accredited for only a fraction of the types of tests conducted. Because of these differences, ISO 25-type testing might only be used instead of GLP where it concerns repetitive testing activities like urinalysis, blood chemistry, etc., as part of sizable studies. Also, it might be feasible for very short term studies as physical-chemical studies, Ames testing, etc., as long as all GLP requirements are fulfilled. The OECD GLP Panel, consisting of the heads of all monitoring units of the OECD Member Countries, has considered also the use of laboratory accreditation with reference to GLP monitoring and has issued a position paper (4), stating that "data, generated solely under ISO/EEC Guide 25 or equivalent standards is unlikely to be accepted by regulatory authorities ". Simultaneous Implementation of GLP and ISO 25 The fact that ISO 25 and GLP are not equivalent does not mean that simultaneous implementation of both systems is impossible. A EUROLAB-EURACHEM Working Group has published a helpful guide to simultaneous implementation (5). Almost all OECD Member Countries' monitoring units have reported successful simultaneous implementation of both GLP and ISO 25 in a number of test facilities. However, the number is quite limited when compared with the total number of laboratories in the Table L Number of Test Facilities in the European Union Implementing GLP and GLP Plus EN 45001 (1996) Country

GLP

GLP

Belgium Denmark Finland France Germany Greece Ireland Italy Netherlands Portugal Spain Sweden United Kingdom

26 17 8 94 170 6 6 25 50 2 6 30 160

2 2 0 ?

10 ?

0 ?

3 0 ? ?

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34 respective Member Countries in the EU. Table 1 shows the results of a survey among the EU Member States. Because of these low numbers, it was concluded by the European Commission, in a meeting of the EU Working Party on GLP, that the search for possibilities of merging GLP and EN 45001 would be given low priority.


Scope of GLP and EN 45001 Internationally, the scope of GLP has been well defined. According to several European directives, to be incorporated in EU Member-States' legislations, all preclinical and safety studies on industrial chemicals, pharmaceuticals, veterinary drugs, animal feed additives, pesticides, and cosmetics have to be carried out in compliance with the OECD Principles of GLP. Basically, the same requirements exist in the other OECD Member Countries. Some countries have even a more extended scope; e.g., the USA requires application of GLP for medical devices and implants. The European Directives on medical devices and active implants just require the application of a quality system; both GLP and EN 45001 are acceptable. The scope for ISO/IEC 25 and EN 45001 is not very well defined, since these standards are almost exclusively applied in the nonregulated area. These standards are used mainly in thefieldsof analytical chemistry, physical chemistry, physics and clinical (pathological) chemistry, where there is a link with the regulated GLP area. In the European Union, there is only one legal requirement to apply EN 45001, i.e., in Directive 93/99/EEC on the supervision of foodstuffs. The Directive requires the application of EN 45001 plus OECD GLP Principles 2 (on QA) and 7 (on SOPs), which is quite incomprehensible since EN 45001 has definite paragraphs on SOPs. Monitoring and Surveillance According to Annex I to the OECD Council Decision, monitoring of GLP compliance has to be carried out by or on behalf of the governments of the OECD Member countries. This is understandable since governments are responsible for the admission of chemicals on their markets. Most governments have charged governmental or government-related bodies with this task. In some countries these bodies also have been charged with the task of laboratory accreditation, like in Australia (NATA), Ireland (ICLAB), New Zealand (Telarc) and Norway (NMS). In some other countries accreditation bodies perform GLP inspections only where it concerns industrial chemicals. This is the case in Denmark (DANAK), France (Cofrac), Portugal (IPQ) and Sweden (Swedac). Of the total of 32 monitoring authorities, 2 are private, 3 are government-related, and 27 are fully governmental. All these monitoring authorities perform their inspections according the relevant OECD Guidance (3). The purpose of GLP monitoring is to determine that a study is reliable and reconstructible from the study plan and raw data and that it is reported correctly. The purpose of laboratory accreditation is to assess if the laboratory is competent to perform the tests as specified in their documentation. Therefore, other than in laboratory accreditation, GLP monitoring authorities have 2 major instruments. One is the typical test facility inspection, always including the limited auditing of studies. The other tool


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is the in-depth study audit requested by regulatory authorities (directed study audit). Since the application o f G L P is legally mandatory, the inspectors performing such inspections and study audits should have investigational powers, for instance to enter the test facility's premises and inspect confidential material. In many legal systems it is not possible to grant such powers to private (laboratory accreditation) bodies. Many monitoring authorities inspect the test facilities in their programmes on a regular basis, e.g. once in two years. Apart from the study audits, these inspections might be considered as "accreditations", since inspectors are assessing the general performance and the competence o f the test facility. Many monitoring authorities even issue a "Statement or Endorsement o f Compliance" when a test facility is judged to operate in compliance at the time of the inspection. This is not equivalent to certification as in the accreditation environment where it means an acknowledgement o f competence; however, there is a tendency to use it in that way. It is thinkable to contract out this part o f the monitoring programme to third parties, for instance accreditation bodies. These bodies then must follow the O E C D Guide and Guidance. However, the task o f performing study audits, being a regulatory task, must remain with the governmental authorities. For practical reasons it is preferable to leave both instruments in one hand: the governmental or government-related inspectorate. Conclusions 1. 2. 3. 4. 5. 6.

I S O / I E C Guide 25 and equivalent standards are not equivalent to the G L P Principles. Simultaneous implementation o f G L P and I S O / I E C Guide 25 is quite possible. Adherence to the G L P Principles is a legal requirement and should be monitored by governmental authorities. O E C D procedural guides Environmental Monographs Nos. 110 and 111 must be followed for G L P monitoring. Monitoring authorities must have legal investigational powers. Accreditation to O E C D G L P is possible, but can only be part o f G L P compliance monitoring.

Literature Cited 1. 2. 3. 4.

5.

The OECD Principles of Good Laboratory Practice, Environment Monograph No. 45, OECD, Paris, 1992. Revised Guide for Compliance Monitoring Procedures for Good Laboratory Practice, Environment Monograph No. 110, OECD, Paris, 1995. Revised Guidance for the Conduct of Test Facility Inspections and Study Audits, Environment Monograph No.111,OECD, Paris, 1995. The Use of Laboratory Accreditation with Reference to GLP Compliance Monitoring: Position of the OECD Panel on Good Laboratory Practice, OECD, Paris, 1994. Quality Assurance According to EN 45001 and OECD GLP. A guide to simultaneous implementation. The Joint EUROLAB-EURACHEM Working Group, EUROLAB T-QA WG2/EURACHEM, Netherlands WG3.


IEC Guide 25: Schisms and

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