Figure 1: Clinical reference materials for calibration verification testing available from Verichem Laboratories.
In today’s vastly regulated setting, clinical laboratories must now contend with numerous agencies and organizations. As a result, it can be time-consuming, confusing, and even costly for the laboratory to monitor and conform to all regulations necessary to achieve full concord. When one reviews the clinical chemistry department, probably the most demanding section of a clinical laboratory, one regulatory requirement has emerged which has major consequences on the diagnostic systems responsible for testing – the calibration verification of those systems. One cannot afford to misjudge the need for, and the importance of, calibration verification testing. As a point of reference, lack of conducting required calibration verification testing, or performing incorrect or incomplete testing, is frequently reported as one of the top reasons for a laboratory to be cited with a deficiency during inspection. However, it is important to remember the reason for calibration verification is not to saddle the laboratory with inconsequential testing, but to confirm that the diagnostic system in use is reporting accurate patient test results.
To start things off, it is best to review a few of the basic key terms applicable to this discussion. To begin, a calibrator is a solution containing known concentrations of given clinical analytes which are traceable to both domestic and international standards. Calibrators, per the Food & Drug Administration (FDA), are designed to inspect and measure the test system to assure the system is suitable for its intended use and capable of producing valid results. Calibrators may also be referred to as calibration materials, clinical reference materials, clinical reference standards, or standard materials. Next, calibration is the procedure of adjusting a diagnostic instrument with a calibrator to establish a correlation between the instrument’s measured response to a specimen being tested and the actual concentration of the analyte in the specimen. In short, calibration is telling the instrument how to read a level of the component being evaluated. Last, calibration verification is the testing of specific materials with known concentrations of a given component, or components, the same as routine specimens to ensure the clinical instrument system is accurately measuring those specimens throughout the measurable range for that specific component.
To understand why such testing is now required, we need to go back to January of 2003, when the Centers for Disease Control (CDC) and the Centers for Medicare & Medicaid Services (CMS) published amended laboratory regulations to the Clinical Laboratory Improvement Amendments (CLIA) of 1988, which were set to go into effect in April of 2003. These amended regulations included requirements for calibration and calibration verification of nonwaived tests. Nonwaived tests included both moderately and high complexity rated tests and had an immediate impact on the clinical chemistry department of the laboratory where many of these tests are performed. Again, the purpose of this testing was formally initiated to ensure that the diagnostic test system in use is reporting accurate test results throughout the test system’s stated linearity, and the laboratory‘s ascertained reportable range, to help ensure accurate patient test results.
As for the materials which may be used to accomplish this testing, acceptable materials may include calibrators with known values which are traceable to the National Institute of Standards & Technology (NIST); quality control materials with known values which are traceable to NIST; proficiency testing samples with known results; and patient specimens with known values. A minimum of three levels – a low, a mid, and a high – must be used for every analyte being assessed and the materials must be able to effectively span across the linear, or reportable, low-end range through the high-end range of the assay. More often than not, commercially available calibration verification materials are the easiest, fastest, and most cost-effective route for the laboratory to utilize (Figure 1). Once the laboratory obtains an acceptable source of acceptable materials, and testing is performed for a given analyte, all results must be documented. Again, three levels of material for each analyte must be run – low, mid, high – just as if one were running actual patient samples. The accepted number of test samples run must be determined by each laboratory, as CLIA does not state a minimum number or replicates allowed.
Actual test results obtained must be compared to the expected values and the laboratory must document these and determine if the results meet the acceptance criteria established. Data must be plotted as a linear graph by hand, or by computer program. Data reduction services and reporting programs available from outside manufacturers of calibration verification materials are also acceptable. As for the frequency of such testing, current requirements mandate that, at a minimum, calibration verification of a clinical test system must be performed once every six months. However, if the laboratory determines that more frequent verification is required, say quarterly as opposed to twice annually, CLIA has no issue with that. Aside from the minimum, other times for additional testing per CLIA include: if QC results indicate a shift, a trend, or are out of the laboratory’s acceptable range; if any major preventative maintenance procedure is performed on the testing system, or there is a replacement of critical system components; and whenever new lots of reagents are introduced, unless the laboratory can effectively verify that there is no change in results.
In closing, it is clear that calibration verification of clinical systems is here to stay. As discussed, it is important to remember that aside from CLIA compliance, the primary reason behind such testing is to help support overall laboratory quality and ensure that clinical diagnostic systems are reporting accurate clinical test results, which ultimately leads to improved clinical testing and better patient care.
Resources
- CLIA Brochure No. 3: www.cms.hhs.gov/clia.
- CLIA ’88: Section 493.2 – Definitions.
- CLSI Document EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures - A Statistical Approach; Approved Guideline.
- www.cap.org/apps/docs/laboratory_accreditation/audio_conferences/cvl_webinar_presentation.pdf/.
- www.cdc.gov/clia/index.html.
About the Author: Robert Janetschek is a seasoned veteran of the clinical laboratory with over 40 years of relevant experience. Aside from his direct clinical involvement, he has also held marketing, business development, and technical support leadership positions with a number of IVD manufacturers. He is now affiliated with Verichem Laboratories Inc. (Providence, RI), an industry recognized leader within the field of calibration verification testing, as their Director of Business Development. Inquiries can be sent directly to his attention at [email protected].