What Does Good Laboratory Practice (GLP) Mean?

The term Good Laboratory Practice (GLP) is a well known acronym for quality in the laboratory but how much do you know about the term, its background and what does it really mean in practice?

OK, let's start from the beginning: GLP is a formal regulation that was formulated in 1978¹ by the US Food and Drug Administration (FDA) that impacted the pharmaceutical industry. However, the primary focus of the regulation was not the chromatography laboratory nor even the analytical laboratory. GLP was intended to regulate non-clinical laboratory safety studies (i.e., animal toxicology testing) to ensure that any new molecular entities developed by the pharmaceutical industry were safe before administration to human volunteers and patients in clinical trials. This original aim has not changed since the regulation was issued as the title of the regulation makes clear: Good Laboratory Practice for Nonclinical Laboratory Studies.¹

While you may think that the "Laboratory" in GLP includes chromatography, the primary aim of the regulation does not. The main laboratories that were affected by the regulation were ones conducting clinical chemistry, histology and pathology, which are used to analyse the samples generated from toxicology studies. In addition to the FDA regulations, the Organization for Economic Cooperation and Development (OECD) has published GLP regulations² that we use in Europe that have the same overall intent as the FDA regulations but with some differences that we will discuss in this article.

Aims of GLP

The aims of the GLP regulations are fairly simple and for the most part do not differ from other quality schemes:

• Staff are trained and follow written instructions (standard operating procedures — SOPs) that reflect their actual working practices rather than being major works of artistic fiction.

• Equipment and computer systems used in studies are fit for the purpose that they are intended (this means that each is specified, installed correctly and is shown to work against the specification).

• Records generated during the course of any toxicology tests are verified and authenticated and can be used to reconstruct the study if required.

• There is an independent quality assurance unit (QAU) to check that work was performed in accordance with the regulations and the laboratory's internal procedures.

However, there are key differences:

• Some roles and responsibilities are unique to GLP, including study director and principal investigator.

• Studies must be planned and executed according to pre-approved plans (protocols) and changed by formal amendments or deviations.

• A list or master schedule is maintained of all studies and protocols running in the testing facility to help coordinate the running of the studies. This must be updated on a regular basis, typically monthly, and is a key item in any GLP regulatory inspection. The master schedule is raw data in its own right.

• Raw data is the concept used for the records generated in the course of a study.

• There is a formal archive with an archivist who is responsible for maintaining the study records stored within it.

I will discuss some of these differences in more detail so that you can get a better understanding of the concepts and principles of GLP.

GLP Organization Roles and Responsibilities

To understand some of the major differences in the way that GLP is organized we need to look at the key roles and responsibilities defined in the regulations. There are five key roles:

Study director (SD): This person has the sole responsibility for the design, conduct and reporting of the study including compliance with the regulations (in pharmaceutical manufacturing an equivalent role is the qualified person). As most GLP studies are multi-disciplinary the study director needs to coordinate with scientists in other organizational departments to conduct the study effectively.

Principal investigator (PI): These are the individuals who act on behalf of the study director and have defined responsibilities for the delegated phases of a study. They are usually scientists who have a functional responsibility for the work conducted, so for the bioanalytical portion of a protocol there will be a bioanalytical PI who is identified in the protocol and report, similarly there will be a PI responsible for the pharmacokinetic or toxicokinetic analysis. Note that the responsibilities of the study director for the overall conduct of the study cannot be delegated to the PIs including approval of the study protocol, any amendments, the final report and GLP compliance. Note that the PI concept is only found in OECD GLP regulations and not FDA GLP.

However, this is a practical way of dividing the multi-disciplinary work found in a non-clinical study. In a European GLP report the PIs sign for the scientific content of their portion of the study.

Test facility manager: This person has the authority and formal responsibility for the organization and functioning of the GLP test facility. Identification and documentation of the responsibilities of senior management in the GLP regulations contrasts with the omission in the pharmaceutical Good Manufacturing Practice (GMP) regulations.

Members of quality assurance unit (QAU)¹ or quality assurance programme:² These are independent individuals responsible to the test facility management for ensuring that studies were conducted according to the protocol and GLP. The key word is independent: they must not conduct any study work nor report to management responsible for conducting the study.

Archivist: This individual manages the GLP archive — a controlled area for storing records and regulatory documents generated during the execution of study protocols as well as regulatory documents written by the test facility. This will be discussed in the following section.

The Study Protocol

Each GLP study is conducted to a formal plan that must be pre-approved before execution and formally reported after completion. This is called either a study plan or protocol and is used to describe:

• how the study will be set up.

• doses that each group of animals will get and for how long.

• the route of administration.

• when (and how) the samples will be taken and analysed (e.g.,blood for measurement the clinical chemistry parameters such as cell counts, liver function and haematology or for the measurement of the experimental compound under development).

• how the data will be analysed: the comparison of the measured blood chemistry values against reference ranges to see if the experimental drug has altered anything, or the pharmacokinetic analysis of the concentration profiles of the experimental drug.

• how the study data and results will be collated and reported.

The plan will be written by the study director with input from the various principal investigators involved and then reviewed by management and the QA unit before being released for use.

During the laboratory phase of the study, changes to the protocol must be made by issuing protocol amendments that, similar to the approval of the protocol, must be formally issued and documented. Protocol changes come in two forms:

1. Amendments are planned changes from the study plan and occur before they occur.

2. As life cannot always be planned, study deviations document changes that were unplanned and are written and authorized after the event.

Raw Data

Raw data is one of the requirements of both the FDA and OECD GLP regulations. It is a frequently used term but what does it really mean?

OECD regulations state:

• Raw data means all original test facility records and documentation, or verified copies thereof, which are the result of the original observations and activities in a study.

• Raw data may also include, for example, photographs, microfilm or microfiche copies, computer readable media, dictated observations, recorded data from automated instruments, or any other data storage medium that has been recognized as capable of providing secure storage of information for the retention period of the study.²

FDA regulations state:

• Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a non-clinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study.

• In the event that exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data.

• Raw data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments.¹

Raw data are generated during the course of the execution of a protocol and they are the original observations. These can either be written in a laboratory notebook, printed from a chromatograph, LIMS or other computer system or be electronic records generated by a computer. This topic has been the written about in earlier "Questions of Quality" columns in 1996 and 2000.^3,4

In the FDA GLP A758.130, part (e) states

• All data generated during the conduct of a non-clinical laboratory study, except those that are generated by automated data collection systems, shall be recorded directly, promptly and legibly in ink.

• All data entries shall be dated on the date of entry and signed or initialled by the person entering the data.

• Any change in these entries shall be made so as not to obscure the original entry, shall indicate the reason for such change and shall be dated and signed or identified at the time of the change.

• In automated data collection systems, the individual responsible for direct data input shall be identified at the time of the data input. Any change in automated data entries shall be made so as not to obscure the original entry, shall indicate the reason for the change, shall be dated and the responsible individual shall be identified.

Hence, changes to GLP raw data both for paper and automated records have the following information associated with them:

• Original data must still visible.

• Corrections to the data added.

• Initialled by the individual.

• Dated (contemporaneously — at the time the change was made).

• The reason for the change must be documented.

The GLP Archive and the Archivist

One of the major differences between GLP and other quality systems is the concept of the archive. This is a secure storage facility (i.e., locked, with controlled environmental conditions and fireproof) designed to protect the records that are under the direction of an archivist. At the completion of a study all the raw data, protocols, amendments, analytical data and specimens are transferred to the archive.

There needs to be formal procedures for the transfer of study records into the archive: a log of accession describing what the records consist of and where they are located. If material is removed from the archive, there needs to be records of this and when it will be replaced. In the latter instance when the material is returned it must be checked to ensure that all records are returned. Many GLP archive facilities also have a log of visitors to the archive: they have to sign into the archive in a log, state the reason for the entry and sign out again at the end of the visit and be escorted by the archivist or a deputy.

Expansion of GLP Scope

The scope of GLP has expanded outside the original concept of nonclinical studies into drug metabolism, bioanalysis, as well as agrochemical and environmental studies.

Bioanalysis and drug metabolism: Expansion of the scope of GLP to include classic drug metabolism (excretion balance and metabolite identification) and bioanalytical studies occurred in the early 1980s. As many of the samples analysed in these laboratories were taken from animals during the course of toxicology studies it was logical to expand the laboratories to include those in drug metabolism and pharmacokinetic (DMPK) departments, so LC and LC–MS–MS techniques have been included.

Samples taken for bioanalysis are related to the dose groups of the animals in the study and, after LC or LC–MS analysis, are interpreted by pharmacokinetic analysis. The nearest equivalent in more conventional laboratories is a stability study, where samples are taken over time and must relate to the product batch from which they originate.

This difference in approach to GLP study samples has important considerations when trying to automate a bioanalytical laboratory by implementing a laboratory information management system (LIMS). Instead of the LIMS being sample-driven and the results generated being compared with a development or product specification, there needs to be a protocol driver that allows the study to be defined electronically and the samples to be taken in the various animal dose groups used in the protocol. This difference in the way the LIMS works is so important that any organization trying to implement a sample- driven LIMS for a bioanalytical laboratory is heading for failure before the ink is dry on the project proposal.

OECD GLP

In addition to the FDA's GLP regulations, Europeans use a slightly different variant developed and maintained by the OECD.² Based in Paris this organization appears at first a little strange as the originator of GLP regulations, but it is the work of the Environmental Directorate that produces the regulation. The original scope of toxicology studies remains but also extends to include environmental studies such as ecotoxicology, environmental behaviour and bioaccumulation, residue analysis and the impact on natural ecosystems. OECD defines GLP as a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.² So agrochemical and environmental studies are covered under these GLP regulations.

The OECD have also produced a number of guidance documents, some of which are listed in Table 1 and discussed in the next section.

Table 1: GLP Guidance Documents to help Interpretation of the Regulations.

GLP Guidance Documents

To help and interpret GLP regulations a number of organizations (FDA, OECD and the Swiss AGIT group) have published several guidance documents that are freely available on the internet. These are listed in Table 1 and some key ones discussed below.

FDA guidance for industry on bioanalytical method validation:

This document was published in 2001⁵ and is an update of an earlier consensus conference held in 1990 and published in 1992.⁶ The guidance is intended validation and application of bioanalytical methods used to generate data from both nonclinical and human studies used in regulatory submissions. It covers the criteria to be applied for quantitative chromatographic method validation: for example precision, accuracy and selectivity, as well as the stability of the analyte to be measured in biological matrices such as whole blood, plasma or urine.

In addition, what is expected when a validated method is applied to the analysis of GLP samples including reporting of the results. For example, instead of selecting the best chromatograms, the study plan needs to define which ones will be included in the report before the analysis starts so that a representative selection is used.

OECD GLP Guidance Documents

As you can see from Table 1, the OECD have produced a large number of guidance documents to help organizations interpret GLP, currently there are about 15 but I have omitted the more esoteric ones because they do not add much value for a chromatography audience.

Application of the principles of GLP to computerized systems: This provides an overview of the validation of computerized systems in a GLP environment, it is a consensus document that was published in 1995 as a collaboration between industry and the regulators.⁷ It is flawed in that there is no mention of the need for a requirements specification, which is recognized as the key for any system validation. It contains some good elements that are useful but look at the Swiss AGIT document for a better validation guide.⁸

Establishment and control of archives that operate in compliance with the principles of GLP: Issued in 2007 it looks at both electronic and paper archives, in a Part 11 world it is a useful document.⁹

Swiss GLP Guidance Documents

In Switzerland collaboration between a group of GLP inspectors and industry experts has resulted in the formation of the Working Group on Information Technology (AGIT in German) who have published a series of guidance documents over the past eight years. In my opinion, these documents are very practical and valuable additions to the GLP literature and can also be used outside of the GLP subject area. All the guidance documents are all listed in Table 1 but three of these are worth highlighting:

Validation of computerized systems: A more focused and up-to-date guidance on the validation of GLP computerized systems, the section on change control in the operational environment is very practical and recommended even outside of GLP.⁹

Electronic raw data archiving: Regulations always lag technological advances so the regulations look at paper- based archives when electronic records are created in abundance within our GLP laboratories. What mechanisms need to be in place for an electronic archive? Read the guidance in reference 10 and find out!

Acquisition and processing of electronic raw data: Read reference 11 if you are working with chromatography and need to comply with 21 CFR 11 (Electronic Records and Electronic Signatures regulations) because it has an excellent discussion when electronic records are created in chromatography.

Summary

In this "Questions of Quality" column I have looked at GLP regulations and their original aim of regulating nonclinical safety studies in the pharmaceutical industry. Over time these have extended into chromatography laboratories undertaking bioanalysis of samples from these studies, in vivo and in vitro metabolism studies, as well as human clinical trials. The aim of GLP is similar to other quality systems but there are differences such as the roles and responsibilities, the definition of raw data and the GLP archive.

Bob McDowall, PhD, is principal at McDowall Consulting, Bromley, Kent, UK. He is also a member of the Editorial Advisory Board for LCGC Europe.

References

1. Food and Drug Administration, 21 CFR 58 Good Laboratory Practice for Non-clinical Laboratory Studies, Federal Register 43 60013 (1978).

2. Organization for Economic Cooperation and Development, Principles Of Good Laboratory Practice (1999).

3. R.D. McDowall, LCGC Int., 9(12), 790–793 (1996).

4. R.D. McDowall, LCGC Eur., 13(9), 648–657 (2000).

5. FDA Guidance for Industry, Bioanalytical Methods Validation (2001)

6. V. Shah et al., Pharmaceutical Research, 9, 588–592 (1992).

7. Application of the Principles of GLP to Computerized Systems, OECD (1995).

8. Swiss AGIT: Validation of Computerized Systems (2000).

9. Establishment And Control Of Archives That Operate In Compliance With The Principles Of GLP, OECD (2007).

10. Swiss AGIT: Guidelines For The Archiving Of Electronic Raw Data In A GLP Environment (2003).

11. Swiss AGIT: Guidelines For The Acquisition And Processing Of Electronic Raw Data In A GLP Environment (2005).

Useful Websites

FDA web site:

www.fda.gov

OECD GLP web site: http://www.oecd.org/department/0,3355,en_2649_34381_1_1_1_1_1,00.html

Swiss AGIT web site: http://www.bag.admin.ch/themen/chemikalien/00253/00539/03300/index.html?lang=en