Augustine Smith and Nadine Ritter
Abbott Laboratories
High-quality laboratory practices have long been the standard in most academic core facilities. Why, then, is there a significant interest in quality issues related to regulatory compliance among ABRF member facilities? A survey conducted by the GLP Committee in 1994 showed about half the survey respondents have a high or very high interest in information relevant to cGMP (current Good Manufacturing Practice) and GLP (Good Laboratory Practice) compliance, especially information about FDA Guidelines and Points to Consider, process and test method validation protocols, system suitability standards for analytical methods, and instrument calibration.
This workshop presented three perspectives on quality issues in analytical science: the view of an academic facility attempting to follow compliance guidelines, the view of an industry client requiring compliance practices, and the view of the FDA and their expectations for compliance activities.
Nadine M. Ritter, Abbott Laboratories Diagnostics Division, "Compliance Issues in Academic Core Facilities"
Good Laboratory Practices (GLPs) were defined and compared to current Good Manufacturing Practices (cGMPs). Both promote product safety and efficacy, but GLPs focus more on research and drug development and cGMPs on production and testing of clinical materials and products for sale. Both the FDA and the EPA have GLP regulations that govern the entire preclinical trial process. Analytical testing is one part of that process and is frequently contracted to outside laboratories. cGMP regulations are codified in federal law and impose more stringent requirements than GLPs to the testing process and to the physical facility where testing is done. For these reasons, academic facilities can be involved in GLP testing but are less likely to perform cGMP testing, and so this presentation focused on GLPs in academic facilities.
The basic GLP requirements for analytical laboratories include:
* established, controlled standard operating procedures (SOPs) for sample handling, instrument operation, test methods, data handling, and analyst training;
* use of labeled, traceable reagents properly stored and used within expiration dates;
* use of traceable reference standards as testing controls;
* maintenance of controlled, complete laboratory notebooks, including raw data archiving and retrieval systems;
* having calibrated, regularly maintained equipment for every step in sample storage, handling, and testing; and
* documentation of all activities performed in operations related to GLP samples, including personnel qualifications and training records.
A client must tell you when samples are to be handled under GLP conditions, but upon accepting these samples, you become responsible for complying with GLP regulations. Academic facilities are not required to operate all their services under GLP to be considered compliant--laboratory activities can be selectively designated as compliant. For example, there may be a calibrated, monitored freezer for GLP sample storage and a separate logbook specifically for GLP samples. Only certain personnel may be designated to handle and test GLP samples on specific, calibrated instruments following SOPs. There may be special data analysis, archiving, and retrieval systems just for these samples. Under this paradigm, a laboratory may become GLP-compliant section by section, in response to resources and demand.
Regardless of their GLP workload, academic facilities benefit from establishing and following GLPs. Industrial clients who need analytical data to support their product submissions can contract work to an academic facility that is GLP-compliant, increasing the facility's user base. When deciding how best to allocate their resources, many companies use academic facilities for early-phase analytical testing rather than establishing a large in-house facility. GLPs improve data quality during research and development and reduce the likelihood that analyses will have to be repeated later should a product result from early research efforts. GLPs provide confidence in consistent, excellent analytical performance and data integrity. Overall, implementing even some aspects of GLP--such as SOPs, standard controls, and instrument calibration--can benefit the entire facility.
Dave Shubert, AutoImmune, Inc., "The Role of GLPs in Drug Development"
The purpose of regulatory practices is not to create rows of document cabinets filled with SOPs that support laboratory data; they are meant to promote the development of high quality data to support the release of commercial products. Historically, the discovery of poor data records has jeopardized the FDA's confidence in product integrity, so regulations were enacted to define the expectations of agencies like the FDA. Compliance to these regulations is intended to assure data quality and integrity.
Attention to five steps of data acquisition for product analysis can help to focus on the goals of compliance activities: analyses should be planned, performed, monitored, recorded, and reported. Viewing these as distinct activities can greatly enhance a facility's ability to follow GLPs.
Planning: Designate a study protocol and a study director. The protocol will include descriptions of the nature and purpose of the study, sample information, dates, test methods used, justifications, and references. Any modifications to the protocol must be signed and dated. The study director is the party responsible for adhering to compliance activities. Contract laboratories should designate a study director to coordinate efforts with the client's in-house pre-clinical study director.
Performing: Where is the analytical work done? Facilities should be of suitable size, design, and construction for analyses. SOPs should describe all aspects of sample handling (such as receipt, identification, labeling, and storage) and instrument use (such as maintenance, calibration, and monitoring--including freezers, water baths, and incubators). Equipment should be of adequate capacity and suitably located. Personnel should be experienced in the methods they perform and have documented training.
Monitoring: Analysis systems need to be examined by a quality assurance unit, who will review database information, data analysis, and the final report. A statement should be attached to the final report documenting review by this unit.
Recording: This includes documentation, data generation and analysis, and data storage and retrieval. It includes everything from the study protocol, procedures, final reports, audits, personnel qualifications, equipment records, and sample records.
Reporting: A final study report will be delivered to the client, describing the nature and purpose of the study, the protocols used, the samples tested, the results, references to raw data (including computer files), and any applicable literature references. All data should be signed and dated, with corrections included as amendments.
For drug development companies, it is important to clearly define the expected analyses, where these analyses will be performed, and when these analyses will be done during product development. During the early stages, analysis in GLP laboratories is acceptable, but late-stage products will require "lot release methods" performed in cGMP facilities. Companies need to insure that the analytical facilities can meet the expected compliance requirements. A company's decision to have these analyses done in-house or at a contracted laboratory can be difficult; they will have to assess the costs and benefits of having in-house scientists do early testing versus having these tests done by a reputable and reliable outside laboratory. Because of the time required to establish an in-house facility, contract facilities may be able to offer services in a more timely manner.
One advantage of contracted working relationships is the opportunity for the contracted and contracting laboratories to interact during the study. The company will have a vested interest in the integrity of the analytical laboratory's work and will work as a partner with them. Be aware that analytical laboratories are subject to inspection for the part of the study they performed. Even in Phase I studies, an analytical laboratory can be audited by the company and by the regulatory body. For this reason, analytical laboratories should know the regulations, the nature of the sample, how the data will be used, and its own status. If analytical laboratories can be confident about their ability to provide services to support companies' product submissions, contracting companies can have confidence in the analytical laboratories and in their results.
Malcolm Moos, FDA Center for Biologics Evaluation and Research, "Current Issues in Compliance"
When scientists consult the FDA to discuss the early phases of a development project, they are often searching for specific advice on how their project can more readily meet FDA regulations. Unfortunately, the FDA cannot provide a document specific enough for every conceivable project because each project is unique, and the data required for product evaluation varies according to its intended applications and according to the project's circumstances. Appropriate data for one project may be excessive for another, or hardly enough. For these reasons, this presentation focused not on details, which by necessity will vary, but on global issues.
When choosing the appropriate tests and the means for validating them, make sure that you are measuring the appropriate parameter and that the tests are performing as intended. These are the most critical issues. These choices are driven by the biochemical nature of your sample--not by regulations, procedures, or other bureaucratic guidelines. Choose the appropriate tests and standards.
Products exhibit a continuum of complexity. Some products may have simple, chemically definable structures, and the appropriate testing methods for them may be well established and easy to conduct. Other products may be complex cellular materials, biological agents, or tissues. What testing is appropriate for these materials? As always, the frustrating answer is "It depends", but it is the only answer. It depends on the nature of the product, the manufacturing process, the stage of development, and the state of the art in analytical technology. The most important criteria to satisfy in testing will always be what aspects of these products define their safety and efficacy?
Once tests have been chosen, the next critical aspect is use of validated methods with appropriate standards. An excellent example of this is the peptide mapping of recombinant bovine somatotropin by John Dougherty et al. (Analytical Biochemistry (1990) 190, 7-20). This is the benchmark example of the development of an analytical method for testing a biological product. Regardless of the method chosen for testing, appropriate application and validation are critical. The method's sensitivity and dynamic range are important aspects of validation and should be evaluated for each testing method. The ability to separate artifacts from actual data is also vital: what may appear (or not appear) on a stained SDS-PAGE gel may not truly reflect the nature and purity of the sample.
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