Avoiding these problems in GLP labs can save you a warning letter
April 14th, 2011 // 11:02 am @ admin
Excerpted from The Journal of GXP Compliance
There are recurring themes of observations documented in warning letters that relate directly to laboratory and study management. They are:
1. QA fails to do its job
One common finding involves the failure of the quality assurance unit (QAU) to fulfill the require-ments of the GLP regulation. The following example illustrates a common theme found within warning letters:
Failure of quality assurance unit to monitor each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with applicable regulations.
Items used as specifics include lack of validation for laboratory methods, failure of the QAU to perform annual validation reviews as stated in standard operating procedures (SOPs), environmental monitoring not performed according to established schedules, failure to determine whether any deviations from approved protocols or SOPs had the proper authorization and documentation as required by SOPs, and a general lack of ensuring that the stipulated and often implied requirements of the GLP regulation are addressed satisfactorily.
FDA scrutinizes the quality of final reports with regard to statements or assertions that are not supported by facts or data. It is not uncommon for a warning letter to state that final reports failed to include a description of all circumstances that may have affected the quality or integrity of the data [21 CFR § 58.185(a)(9)] (1). Test and control article stability statements must be accompanied by the basis for the conclusion either by stability testing or alternative do-cumentation regarding why the test or control article is stable for the stated period and under established storage conditions. Also overlooked by the QAU is the requirement for each of the individual scientists or other professionals involved in the study to sign and date their reports. Finally, the lack of pharmacokinetic data and analyses and the scientist or other professionals involved in that portion of the study is a QAU responsibility, which will lead to an observation.
The QAU can circumvent problems and prevent issues of these types by creating a pre-study checklist such as the example presented in Table I.
The checklist should include all required elements for the study and will take substantial time to prepare, but it is worth the investment.
Another way to ensure that activities are com-plete is simply by having someone in the QAU that has not developed the report perform an in-depth re-view of the report and list areas where questions or deficiencies exist. Finally, the QAU may contract a third party to perform an audit that includes the entire scope of the study, including test and control articles, facilities and equipment, laboratory and clinical as-pects, and a sampling of the data and reports. The audit should occur early in the process and not be put off until the study is completed to ensure that bad practices do not continue.
2. Equipment management
When equipment is involved in a GLP study, one cannot simply assume that the equipment plugs in and works as expected forever without some type of management. Human intervention is always required, even if it involves only elementary cleaning. These activities must be documented in a procedure and the actions recorded. Otherwise you can expect the following comment from FDA
Failure to adequately inspect, clean, and maintain equipment.
Warning letters include multiple observations of objectionable or absent practices when it comes to ensuring that equipment used in the study operates in a manner that produces accurate and reliable results.
The message here is if equipment is used in a GLP study, read the manual, develop written procedures, establish calibration and maintenance schedules, document daily and periodic activities, and perform reviews to ensure that things are in a state of good repair and control. Develop methods to investigate and remediate problems when deviations in operability occur and train individuals in these procedures
For example, if the temperature of a refrigerator is found to be outside the allowable limit, don’t ignore it. Determine what is in the refrigerator that re-lates to the study, assess its stability, determine the impact on the study, document corrective action and, by all means, document both the out-of-specification temperature and the temperature after remediation. Don’t forget to “tag out†nonconforming equipment as out of service if it fails to perform. Finally, apply these rules across the board. Remember, you are responsible for your own house and the study sites, so make sure that all equipment receives this measure of scrutiny, regardless of its location.
3. Bad laboratory practices
The lab is a world of its own. Often misunderstood in its capabilities, duties, regulatory require-ments, and throughput, the laboratory and the professionals working in it are required to respond to both reasonable and unreasonable or impossible tasks to support the GLP study. It is important to understand that just because an array of equipment fills a room, not all laboratory workers comprehend the criticality of their work in a study.
Numerous citations in FDA warning letters relate to the lack of the use of validated laboratory methods. Without even minimum validation, there is no assurance that the results of an analytical method reflect the true status or concentration of the analyte in the sample submitted for analysis. Methods for per-forming analytical method validation are beyond the scope of this article, but the resources listed in the references section will provide sufficient detail (2,3, 4).
Overlooking the laboratory and the counsel of quality lab workers can lead to a train wreck with the FDA, such as the following example:
The protocol required an analysis for CBC with ajjerential to he performed with regard to the test system, sheep. Instead of conducting this analysis as required by the protocol, you employed a contract facility, [redacted], that was not capable of performing this analysis on sheep Hood and instead attempted to run the test on equipment calibrated for humans, generating results you knew to be invalid. Even though you were aware of this problem, you ad not change to a laboratory capable of running the tests required by the protocol and ad not submit a protocol amendment to eliminate the requirement to conduct these hema-tology analyses.
This observation by FDA is a multi-layer failure that could have been avoided if communication, method validation status, and lab capabilities had been considered. The lesson here is that attention to detail is critical when choosing a contract lab.
It is acknowledged that not all studies can be performed in an in-house laboratory. Methods may re-quire expensive equipment, specialized training, ex-pensive materials, or even specialized environments. It may be a requirement to refer samples. But not all contract labs are created equal. The following are some points to consider:
* Inspect the facility – especially relating to its portion of the study. Ask questions. Ask to see equip-ment maintenance logs, SOPs, contingency plans, storage capabilities, receipt, storage, and traceability procedures for samples.
* Insist on GLP – Ensure that the contract laboratory is capable of operating under the GLP regulations.
* Review quality control – Good labs perform a strict regimen of quality control (QC) that accompanies the assays they perform. There should be a com-prehensive quality control procedure that details how results of quality control samples are interpreted and remedial activities when QC results fall out of specifi-cation. Review this remedial action and ask yourself if you would be satisfied with the documentation, approach, and strategy.
* Prepare a contract – A contract with an out-side lab should not only include the scope of testing, but should also define the means of communication that is required (i.e., problems, remediation, changes in personnel, changes in methodology, and the impact on the study), and the timing, format, and content of interim and final reports.
* Ensure the lab is capable – If the GLP testing includes rodents, primates, or other species, ensure that the laboratory has the proper experience with these animals. Additionally, request that normal limits for clinical pathology, blood, urine, and other sample values be provided.
Even if an in-house lab is used, the points to consider should be applied to an assessment of inter-nal capabilities, practices, and attention to quality It all pays off when the inspector visits.
4. SOPs are non-existent
The following excerpt from a GLP-related warning letter says it all:
The testing facility management failed to establish standard operating procedures (SOPs) adequate to ensure the quality and integrity of the data generated during the course of a study, to limit unauthorized and undocumented procedural deviations, and to establish controls to ensure accountability of SOPs.
While study protocols, contract agreements, professional affiliations, and stacks of impressive resumes are rarely overlooked during a GLP study, SOPs often are overlooked. Again, the details matter.
Even lowly SOPs such as operation of a pH meter are important if pH measurement comes into play in a study. Table III demonstrates a sampling from warning letters regarding the importance of hav-ing a complete suite of SOPs to support the study.
Note that it is not sufficient to have SOPs, but to have effective and directive SOPs that state how something is accomplished or performed. If there is a risk of failure when the task is performed, the procedure should direct the operator in specific steps to take. Every stage of the study where activity is required must be defined in writing that is complete, reviewed, controlled, and approved. The responsibility for this ultimately falls in the study director’s lap. However, it is really driven by the QAU, who must assess the requirements for and provide guidance to the development, training, and use of the procedures related to the study. The take-away here is to assess, develop, and operate under a documented system.
5. Missing data
You must take care of and account for specimens received and used in the GLP study. This requirement involves means of identifying, preserving, handling, and storing clinical and biological samples and the data that result from laboratory studies or clinical examinations. Failure to properly store specimens and data violates 21 CFR 58.51. The following are a few examples taken from warning letters that should have been no-brainers, but occurred:
* Raw study data are archived and maintained on open shelves in an unused restroom.
* There is no individual who is identified as being responsible for maintaining the archived data
* Access to the archive area is based on an honor system since all study personnel are issimi keys to the room
* The study director failed to assure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study
* The animal organs directed for collection in study were not transferred to the archives at the close of the study
* The protocol for study and resulting data were not transferred to the archives at the close of the study
A good GLP study will provide up-front thought to ensure that adequate plans are made to ac-count for the samples and documentation. Fail to do this and a warning letter will appear in your mailbox.
