Understanding and complying with GLP guidelines

Good Laboratory Practice (GLP) deals with the organization, process and conditions under which laboratory studies are planned, performed, monitored, recorded and reported. GLP data are intended to promote the quality and validity of test data.

David Weller, an analyst, has rightly said: “If experimental work is conducted in compliance with GLP, with or without the aid of computer, it should be possible for an inspector, maybe four or five years hence, to look at the records of the work and determine easily why, how and by whom the work was done, who was in control, what equipment was used, the results obtained, any problems that were encountered and how they were overcome”.

As far as pharmaceutical development is concerned, the GLP principles, in their regulatory sense, apply only to studies which:

• are non-clinical, i.e. mostly studies on animals or in vitro, including the analytical aspects of such studies;
• are designed to obtain data on the properties and/or the safety of items with respect to human health and/or the environment;
• are intended to be submitted to a national registration authority with the purpose of registering or licensing the tested substance or any product derived from it.

Depending on national legal situations, the GLP requirements for non-clinical laboratory studies conducted to evaluate drug safety cover the following classes of studies :

• Single dose toxicity
• Repeated dose toxicity (sub-acute and chronic)
• Reproductive toxicity (fertility, embryo- foetal toxicity and teratogenicity, peri-/post natal toxicity)
• Mutagenic potential
• Carcinogenic potential
• Toxicokinetics (pharmacokinetic studies which provide systemic exposure data for the above studies)
• Pharmacodynamic studies designed to test the potential for adverse effects (Safety pharmacology)
• Local tolerance studies, including phototoxicity, irritation and sensitisation studies, or testing for suspected addictive and/or withdrawal effects of drugs.

GLP principles are independent of the site where studies are performed as they only apply to the studies planned and conducted in a manufacturer’s laboratory, at a contract or subcontract facility, or in a university or public sector laboratory. It is not directly concerned with the scientific design of studies. The scientific design may be based on test guidelines and its scientific value is judged by the (Drug) Regulatory Authority that provides marketing authorization. However, adherence to GLP will remove many sources of error and uncertainty, adding to the overall credibility of the study.

Regulatory requirements, inspection and enforcement practices are quite dynamic. What is appropriate today may not need to be appropriate tomorrow. Regulations change but more often it is the inspection practices that change. In the early 90’s the focus of inspections was on basic requirements of GLP , but then it changed to equipment hardware and later on to software and computer systems. Hence at present the clear focus is on data security, traceability and integrity of electronic records. FDA has two types of inspection:
1)    Routine inspection: It involves periodic determination of facility’s compliance with regulations. Data audit may be done.
2)    Cause inspection: It is less frequently conducted without notifying the laboratories beforehand. It can be initiated when serious non-compliance is found with GLP.

During the inspection, if the testing facility fails to comply with one or more regulations implemented by the GLP manual which affects the validity of the data leading to adverse outcomes, it can be disqualified. This can also result due to ignorance of warnings or rejection of the previous studies, falsifying information for permit, registration or any required records, related to testing protocols, ingredients, observations, data equipment etc. Failure to prepare, retain or submit written records required by law is also not permitted. Before a workplace can experience the consequences of noncompliance, an explanation of disqualification is needed. The FDA states the purpose of disqualification as the exclusion of a testing facility from completing laboratory studies or starting any new studies due to not following the standards of compliance set by the Good Laboratory Practice manual. The FDA commissioner then sends a written proposal of disqualification to the testing facility. A regulatory hearing on the disqualification is scheduled and if it is found out after hearing that the facility has complied, then a written statement with an explanation of termination of disqualification is sent to the facility or study may also be reinstated at the will of the commissioner. But if the commissioner finds that the facility was non-compliant on any of the grounds after the hearing, then he sends a final order of noncompliance to the facility with explanations and thus any studies done before or after the disqualification will need to be determined as essential to a decision. If the study is determined unacceptable, then the facility itself may need to show that the study was not affected by the noncompliance that led to the disqualification. Once finally disqualified, the facility may not receive or be considered for a research or marketing permit and the study is rejected.

Whatever the industry targeted, GLP principles stresses the following main points which must be considered before inspection by regulatory authorities:

Personnel must clearly understand the functions they need to perform.

Test article mixtures should be appropriately tested for stability.

Standard operating procedures (SOPs) need to be implemented in writing setting forth nonclinical laboratory study methods that are adequate to ensure the quality and integrity of the data generated in the course of a study.

The Study Director should ensure that all applicable GLP regulations are followed and all experimental data, including observations of unanticipated responses of the test system, are accurately recorded and verified.

The Quality Assurance Unit (QAU) should be entirely separate from and independent of the personnel engaged in the conduct of that study.

The QAU must maintain an accurate master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director.

The QAU must ensure that no deviations from SOPs are made without proper authorization and documentation.

Equipment used for the generation, measurement, or assessment of data should be adequately inspected, cleaned, maintained, tested, calibrated, and standardized.

Final reports should be properly dated, amended and signed by the study directors.

The study directors must be educated or trained in both scientific and organizational aspects to ensure compliance.

The laboratory records must include complete data derived from all tests necessary to ensure compliance with established specifications and standards.

All deviations from standard operating procedures in a study must be authorized by the study director and documented in the raw data.

Testing facilities should establish standard operating procedures for data handling, storage, and retrieval.

Archives and retrieval processes must be adequate, test items and test systems must be adequately characterized, Resources should be adequate, standardized procedures must be followed and also one should have good animal husbandry.

The maintenance logs or daily quality control records of equipment must be complete without lack of adherence to maintenance schedules.

The procedures for equipment maintenance & cleaning must be written and followed adequately. It is also necessary to record maintenance or performance checks.

An example of QAU checklist items to ensure GLP compliance is as follow:

• Item Attributes
• Study SOPs used (list) - Approval status
• Laboratory methods used (list) - Validation status
• Test and control articles (list) - Storage requirements
• Stability and rationale
• Equipment used (list) - Maintenance and calibration
• Environmental control (list) - Temperature monitoring records
• Lab reports -

Completeness

• Data included
• Identification of
• Training (list individual and requirements) - Complete and documented
• Thus GLP regulates all non-clinical safety studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA or other similar national legislation. The implementation of GLP must be a collaborative effort, enthusiastically supported by top management and involving personnel from a variety of disciplines to avoid warning letters and for regulatory compliance of the GLP guidelines.