Good Laboratory Practice (GLP), are federal regulations that require implementation of a robust quality management system to ensure the validity, integrity and reliability of non-clinical safety data submitted for regulatory evaluation and approval.
US Food and Drug Administration (FDA) GLP regulations (21 CFR parts 11 and part 58) were first issued by the US in 1978 (1), and, at that time, safety data was mainly obtained from in vivo animal test systems.
Since then, researchers have continued to develop alternative ways to assess drug safety, and now, good laboratory practice regulations can be applied to all non-clinical laboratory safety studies, including in vitro and ex vivo test systems. In short, GLP-compliant studies require documentation (eg standard operating procedures) and are overseen by quality assurance units that perform process-, facility- and study-based inspections.
In this article, we provide an overview of which studies require Good Laboratory Practice (GLP) compliance, which do not, and why in some cases the choice is unclear.
Understanding the details of your prospective contract research organisation’s (CRO) GLP-compliant and non-GLP compliant study conduct is key. Once you know exactly what to expect, you can select the level of study you need to achieve your project’s objectives – and possibly, depending upon the CRO, save time and funds by choosing non-GLP.
Which studies require Good Laboratory Practice (GLP)?
With formal regulations in place, you’d think the answer to this question would be simple. It is, and it isn’t.
In summary, the FDA guidelines for GLP compliance are as follows:
1. Evidence that their products are safe in research and/or marketing applications (21 CFR 58.1) must be submitted by sponsors of nonclinical laboratory studies to support the safety of:
– Food and colour additives
– Animal food additives
– Animal drugs
– Human drugs and biological products
– Medical devices for human use
– Electronic products
2. Non-clinical laboratory studies that must comply with FDA GLP regulations include:
– Toxicity profiles
– Observed no adverse effect levels
– Risks of clinical studies involving humans or animals
– Potential teratogenic, carcinogenic or other adverse effects
– Safe levels of use
3. Compliance with GLP regulations is NOT required for these studies:
– Basic research
– Any other in vitro studies in which the safety of the product is not being assessed
Mixed messages for drug interaction and reaction phenotyping
While non-GLP studies do not need to fulfill GLP requirements, they must still produce high-quality, reviewed and reliable data.
In particular, multiple nations’ regulatory agencies and the pharma industry have singled out in vitro drug interaction studies (such as CYP inhibition, induction or reaction phenotyping data, or transporter inhibition or substrate potential) as especially important in assessing drug safety – even though these are technically non-GLP studies.
Moreover, the pharmaceutical industry states that drug interaction studies must be “performed with high quality and consistency, particularly when the studies ultimately influence the design of clinical trials” (2). Furthermore, the US FDA recommended that these studies be carried out “in the spirit of GLP” (3), with the investigator “taking necessary steps to assure the quality and integrity of the data”.
In light of these statements, sponsors often feel they must deliver the same level of data integrity and validity for in vitro drug interaction studies as they would for non-clinical safety studies. To achieve this, when outsourcing, they frequently request GLP-compliant studies as a matter of course. But is GLP truly the only way to be certain these non-GLP studies meet the guidelines above? Depending upon the rigour of the non-GLP study conduct, perhaps not.
Waste not, want not: scrutinise your options
Unnecessary GLP studies squander both time and money. Before you decide on GLP or non-GLP enzyme inhibition, enzyme induction, drug transport or drug metabolism studies, analyse your proposed CRO’s study options for in vitro and ex vivo test systems. Once you consider the exact differences between the GLP and non-GLP studies, you will be able to decide whether the CRO’s non-GLP conduct will fulfill the research objectives of your particular project. In the end, you may decide on non-GLP studies – or those in compliance with US FDA GLP regulations, Japan MHLW GLP regulations or OECD GLP guidance.
Considerations when evaluating how your prospective CRO applies GLP regulations to in vitro and ex vivo studies
Most elements of the GLP regulations are constant, regardless of test system. For in vitro studies, though, a few points require interpretation in view of intent and applicability.
It’s useful to compare:
– Specific, relevant GLP regulations from 21 CFR Part 58
– How the CRO interprets these regulations in FDA GLP-compliant studies
– How the CRO handles these regulations in non- GLP studies
In vitro and ex vivo drug metabolism and drug interaction studies are critical to evaluate the safety of existing drugs or drug candidates and to assess the risk of toxicity and adverse drug-drug reactions in vivo. Nonetheless, they are not considered safety studies. In the end, the sponsor must choose whether to conduct them in GLP-compliant or non-GLP-compliant fashion.
The degree to which your chosen CRO conducts GLP and non-GLP studies identically will affect the likelihood that you will be able to utilise non-GLP drug metabolism and interaction studies.
Specific aspects of GLP versus non-GLP study conduct you may want to compare are listed below:
– Personnel roles and functions
– Laboratory space
– Standard operating procedures
– Protocol and study conduct and documentation
– Hard copy and electronic records storage, retrieval and retention
– Bioanalytical method validation
Selecting a CRO that conducts GLP and non- GLP studies similarly will enable you to find new efficiencies by choosing non-GLP services for some of your drug interaction studies. When in doubt, seek technical assistance to help you decide – the result may be significant savings.
A few definitions
In vitro non-clinical laboratory study:
A test article is applied to tissue or tissue-derived material (such as subcellular fractions) in a test tube, plate, etc.
– Examples: enzyme induction studies in cultured human hepatocytes, enzyme inhibition studies with human liver microsomes or recombinant enzymes, and reaction phenotyping (enzyme mapping) with human hepatocytes, human liver microsomes and recombinant enzymes
Ex vivo non-clinical laboratory study:
A test article is administered to a laboratory animal in vivo, after which organs or tissues are removed and analysed in vitro for enzyme induction, etc.
– Examples: enzyme induction studies in mice, rats, dogs or monkeys, often conducted as part of a 14-day toxicity study.
Any food additive, colour additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed or water that is administered to the test system in the course of a non-clinical laboratory study for the purpose of establishing a basis for comparison with the test article.
-Note: Positive and negative controls used to show that the test system is responsive under the actual conditions of the assay may not necessarily be categorised as control articles per GLP regulations.
Any material derived from a test system for examination or analysis.
– Example: microsomes isolated from cultured hepatocytes treated with a test or control article.
Additional definitions and requirements for GLP Studies
Organisation and personnel
– Specific responsibilities are assigned as per GLP regulations for non-clinical studies to:
Quality assurance unit (QAU)
These responsibilities are outlined in SOPs. The study director, facility management and archivist roles are equally applied to non-GLP studies.
– Any corrective actions taken to protocols or SOPs and any GLP deviations must be documented.
– One study director is responsible for the conduct of each GLP-compliant or non-GLP study and acts as the study’s single point of control.
– The quality assurance unit (QAU) monitors GLP studies, reporting to management and the study director. The QAU does not monitor all non-GLP studies or records; however, the QAU does perform facility and process-based inspections of all facility operations to ensure that no deviations were made without proper documentation and authorisation. The QAU also maintains copies of all GLP-compliant and non-GLP audited protocols and a master schedule sheet (MSS) of all GLP-compliant and non-GLP audited studies conducted at the facility.
– As per GLP regulations, adequate facilities must be provided for each study.
– Adequate, procedure-specific laboratory areas contain:
Test article and control article receipt and storage
Test article and control article storage
Sterile and aseptic procedures
– On-site facility archives should be maintained, but specimen archives are not required. At the close of a study, specimens may be shipped to the sponsor or another, designated storage location. Or, they may be disposed of at the sponsor’s request. These procedures are the same for both GLP-compliant and non-GLP studies.
Standard operating procedures
– SOPs covering laboratory operations as listed in the GLP regulations are maintained. These procedures cover both in vitro and ex vivo studies.
– Additional SOPs cover experimental methods and procedures appropriate for specific studies (ie drug metabolism and drug interaction studies).
– Management must approve all new and revised SOPs.
– An archive is maintained for all historical versions of SOPs.
– Hard copies are available in laboratories and electronic SOPs are available at all workstations. With a few exceptions, the same SOPs support the conduct of both GLP-compliant and non-GLP studies.
– Study personnel may use the same laboratories and equipment for all contracted studies. Thus maintenance, calibration, testing and record keeping can be equally applied to all studies in order to maintain the equipment in proper regulatory compliance.
– Appropriate equipment is maintained for in vitro and ex vivo study procedures.
– A Department of Maintenance & Metrology is recommended. They inspect, clean and maintain equipment. These activities are documented in equipment SOPs.
– Verification and calibration may be conducted in-house by study personnel or maintenance and metrology personnel, or these tasks may be performed by equipment vendors or specialised contractors as necessary.
– Where applicable all equipment use is documented in instrument logbooks. Records of equipment inspection, maintenance, testing, calibration and standardisation are archived and retained.
Test and control articles
– Full characterisation of test and control articles is not required for non-GLP studies.
– Test and control articles are assigned internal tracking numbers. Information on test article receipt and distribution are stored in a central location and are archived as facility records. Copies are maintained in the study records.
– Retention of test and control article samples is not required, as in-life study segments (dosing to observation) typically last less than four weeks. Test and control articles remaining after the study’s end should be returned or destroyed, as per the sponsor’s request.
– Test dosing solutions are analysed for concentration and stability for GLP-compliant studies; this analysis is not required for non-GLP studies. A sponsor may provide information on the stability of test solutions; however, if the stability is unknown or has not been characterised, a fresh solution is prepared daily.
Protocol and study conduct
– Contract studies are conducted according to the applicable GLP regulations and the protocol.
– Preprinted forms with selected data may be used, but these must be verified prior to the conduct of any study. The same documentation requirements are applied to both GLP-compliant and non-GLP studies.
– A final report summarising study methods and results, including applicable components listed in the GLP regulations and study protocol must be prepared.
– In a GLP-compliant study report, a compliance statement stipulating the regulations followed in the conduct of the study and any GLP deviations that occurred is included. Protocol deviations are reported for both GLP-compliant and non-GLP studies.
– Corrections or changes to a final report for both GLP compliant and non-GLP studies are only made through amendment as described in the GLP regulations, with prior approval from the sponsor.
– Alternatives to preparing a complete final report for a non-GLP study can be offered, such as a data summary or other simplified version, according to the sponsor’s requirements.
Records storage, retrieval and retention
– All study records must be maintained in a facility archive. Records are indexed and stored either at the test facility or transferred to an offsite commercial archive facility.
– Records from GLP-compliant studies should be stored in fire-resistant cabinets within a restricted access archive room. Access to the archives is controlled, and all access to the archive room and archived records is documented and logged.
– Records from non-GLP studies may be stored in the same archive room with controlled access (as GLP studies), but they may not necessarily be stored in fire-resistant cabinets.
– GLP studies require record retention from the time the sponsor applies for a permit or submits required documents to the FDA. Sponsors may request a specific retention period for study records at the test facility or may request that records be transferred to them after a designated period of time. Otherwise, standard record retention policies based on the specific SOP or default time periods are followed.
Electronic record and electronic signatures
– Instruments, software and networked environments generate electronic records and signatures. Relevant FDA 21 CFR Part 11 regulations are applied differently in a GLP-compliant versus a non-GLP study.
– Computerised systems used in GLP-compliant studies must meet all Part 11 requirements including validation and electronic signatures, whereas computerised systems used in non-GLP studies may not be validated or include electronic signatures.
– A computerised system master list identifying all systems and their validation status must be maintained. Individual system SOPs cover the use of electronic signatures and the maintenance of electronic records.
Bioanalytical method validation
– Specific SOPs define how FDA guidelines are applied in bioanalytical methods validation.
– All methods used in GLP-compliant studies must be validated. Methods are tested for accuracy, precision, selectivity, sensitivity, reproducibility and stability.
– Routine sample analyses are conducted using quality controls (QCs) to accept and reject runs for GLP studies, or upon request.
– Non-GLP studies may follow methods that have not been validated. Typically, the same methods validated for GLP-compliant studies are used for non-GLP studies; however, in non-GLP studies, QCs are not necessarily used to accept or reject each batch.
This article originally featured in the DDW Winter 2018/19 Issue
Scott Hickman MBA, Sekisui XenoTech Director of Global Marketing, has managed the customer experience for innovative life science companies for more than 25 years.
Dr Brian Ogilvie, Sekisui XenoTech Vice-President of Scientific Consulting, is an author on numerous posters and publications and an invited speaker at many conferences.
Tim Patterson ASQ CQA, CQM, Sekisui XenoTech Quality Assurance Manager, has more than 20 years of experience working in GMP and GLP regulated environments.
1 U.S. Food and Drug Administration’s Good Laboratory Practice for Nonclinical Laboratory Studies, Title 21, Vol. 1, Part 58.
2 Bjornsson et al. The Conduct of in vitro Drug-Drug Interaction Studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) Perspective, p815- 831, 2003.
3 Tucker, Geoffrey T, Houston, J. Brian and Huang, Shiew-Mei. Optimizing Drug Development: Strategies to Assess Drug Metabolism/Transporter Interaction Potential – Toward a Consensus. Br J Clin Pharmacol. 2001 Jul; 52(1): 107-117.