Do you know what Good Laboratory Practice stands for? In nonclinical animal studies, these requirements spell out the rules that must be followed when studying the safety of drugs. Following GLP rules not only makes sure that researchers treat animals with respect, but it also protects the validity, integrity, and reliability of nonclinical safety data. It is this nonclinical safety data that will be looked at by regulatory agencies when they decide if studies on humans should be done.

Background

The rules that make up have become an important part of making sure that drug research meets quality standards. Even though they've been widely adopted, they were only introduced fairly recently (in my timeline), and it's worth looking at their past. In 1978, the US Food and Drug Administration (FDA) put out "Guidance for Industry Good Laboratory Practices Regulations" because of worries about the quality and scientific accuracy of some nonclinical toxicology studies that were being done in the mid-1970s.

Our most recent Insider's Insight talks about how a scandal involving the business testing unit Industrial Bio-Test Laboratories was found to be a notable event [1]. After the investigations were over, several executives were accused of giving their clients false information, which was then used to show the government that the goods were safe. As it turns out, New Zealand and Denmark had already put out their own GLP rules in 1972, long before the FDA did. The Organization for Economic Co-operation and Development (OECD) adopted these principles in 1992 to promote a more ‘global’ compliance. Both regulations cover a broad range of considerations, including:

• General provisions such as organisation and personnel management Detailed records on company facilities and equipment as well as their operation
• Use and tracking of test and control animals
• Protocols to describe the conduct of all nonclinical laboratory studies/procedures
• Maintenance of thorough records and test reports
• Disqualification of testing facilities
• When required?

As a general rule, GLP rules will apply to most nonclinical studies. That being said, following GLP is not always necessary in the early parts of the pre-clinical phase. Exploratory genotoxicity, mutagenicity, safety pharmacology, and general invitro toxicology studies might not have to follow these rules.

Sponsors often choose to do many of their pre-clinical studies outside of GLP standards in order to save money. This is usually only done when the goal is to characterise preliminary drug safety by figuring out a drug's absorption, distribution, metabolism, and elimination profile. Most of the time, these studies check how well a drug works at first in a variety of settings. Most of the time, the results lead to more research being done in a project where GLP compliance is needed. Standard repeated dose toxicity, genotoxicity, and safety pharmacology studies are examples of studies that need to follow GLP. The way these studies are done needs to be properly documented in Investigator Brochures, Investigational New Drug submissions, and Investigational Medicinal Product Dossiers. Finally, all nonclinical study results that need to be sent with an IND or something similar must be done according to GLP rules.

The Quality Assurance Unit

A key aspect of GLP regulations is the need for a monitoring Quality Assurance Unit (QAU) that is independent of a facility’s operations. GLP Part 58.35 requires QAU’s to monitor the conduct of all studies to “assure management that all facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations.”

The QAU typically audits all nonclinical laboratory GLP studies. The aim of completing these audits is to ensure that the standard operating procedures (SOPs), protocols and GLP requirements have been followed and that the data summarised in the following reports accurately reflects the findings. An QAU audit may include:

• Source data vs. data imported into the analysis software
• Confirmation that all routine quality control (QC) checks were performed
• Confirm report data against analysis, tables/listings/figures
• Recording of protocol/amendments, SOPs and regulatory requirements
• Contract research organisation and compliance

Contract research organisations (CROs) can offer subject matter experts in specific processes who can give different operational perspectives. Independent from the Sponsor, CROs can provide an unbiased oversight since their focus is on the ‘service’ provided as opposed to the study findings and ultimate impact on a candidate’s development. In order to ensure compliance, CROs can monitor metrics such as:

• Number and frequency of deviations and reasons behind them
• Who submitted the deviation
• Planned vs. unplanned deviations

Each metric helps define a better understanding of why deviations are occurring and how processes can be improved as well as any potential impact on study findings. Metrics offer a means of reviewing how an organization is currently performing in terms of GLP compliance and overall quality as well as areas where improvements could be made.

Conclusion

In the pharmaceutical industry, GLP regulations provide the framework for assuring the quality and integrity of nonclinical drug safety studies. First introduced in the 1970s, they have become an integral part of nonclinical drug development.

References

1. Staying Fab in the Lab: An Insider’s Insight into Good Laboratory Practice