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Manufacturer Certification Program

Introduction

In 1985, the National Cholesterol Education Program (NCEP) began an unprecedented campaign to educate the medical community and the general public about the risk factors for coronary artery disease. To identify people at risk for coronary artery disease, the NCEP recommended initial classification using the medical decision points of 200 and 240 mg/dL (5.17 and 6.21 mmol/L) for total cholesterol (1). Proper classification of a patient's risk based on these medical decision points requires reliable and standardized cholesterol measurements. Therefore, the NCEP also developed recommendations for accuracy and precision (2). Thus, cholesterol became the first, and for many years was the only, clinical analyte for which national performance standards were available. However, evaluating performance in the estimated 100,000 clinical laboratories is daunting. Although protocols for preparing proficiency testing materials that closely mimic fresh patient samples have been developed (3), the use of processed materials for evaluation of accuracy is inherently flawed because of matrix effects that cause processed materials to assay differently than patient samples on some instrument systems (4).

A more practical approach to standardizing cholesterol measurements is to ensure that diagnostic products are properly calibrated by the manufacturers and traceable to the National Reference System for Cholesterol (NRS/CHOL). In 1990, CDC established the Cholesterol Reference Method Laboratory Network (CRMLN) to provide reference services to manufacturers. CRMLN laboratories use the CDC reference methods or designated comparison methods that are closely linked to the CDC reference methods. Because matrix effects complicate the traditional approaches to assessing accuracy, the certification program offered by the CRMLN is based on analysis of fresh samples from patients. CDC believes that working with the manufacturers is the most effective means, with the greatest impact, of standardizing the measurement of lipids and lipoproteins within the clinical laboratory community (5).

Procedure

The comparison procedure is based on the NCCLS (formerly the National Committee for Clinical Laboratory Standards) Evaluation Protocol EP9-A, "Method Comparison and Bias Estimation Using Patient Samples" (6). This protocol requires analyzing a minimum of 40 patient specimens in duplicate by both the test method and reference method; specimens are selected to cover a clinically meaningful range, with values uniformly distributed over this range. Additional information is available from the member laboratories of the CRMLN.

Total Cholesterol

Since 1990, manufacturers have collaborated with the CRMLN to develop and evaluate their diagnostic products for measuring total cholesterol. Manufacturers of complete analytical systems or manufacturers of reagents, calibrators, and reference materials with general application to a number of instruments have participated in the CRMLN certification program. The CRMLN provides the clinical laboratory community a list of the manufacturers that have documented traceability to the NRS/CHOL by performing a direct comparison with the CDC reference method using fresh specimens. These products have demonstrated the ability to provide results of cholesterol tests from patient specimens that have bias from the reference method ≤ 3.0% and a coefficient of variation (CV) ≤ 3.0%.

Traceability of any instrument system or its components to the NRS/CHOL does not in itself ensure accuracy in the hands of the product's eventual user. However, successful completion of the comparison with the reference method shows that the instrument system or product application has been thoroughly evaluated for accuracy and can meet the NCEP recommendations when used according to the manufacturer's directions. The ultimate benefit of the CRMLN's certification program is improved patient care; thus, manufacturers are strongly encouraged to recertify their products.

The CRMLN also provides a recertification protocol for analytical systems that have been previously certified. Only those systems that have not been modified can be recertified using this protocol. If modifications to the instrumentation or reformulations of the reagents or calibrators have been made, then the full certification protocol should be followed.

Total Cholestoral Protocol

HDL Cholesterol

The NCEP issued two reports that emphasized the importance of high-density lipoprotein (HDL) cholesterol in identifying people at risk for coronary heart disease (7,8). CDC's reference method is the recommended national accuracy target for HDL cholesterol measurement (9). Standardization of HDL cholesterol measurements presents the same challenges because of possible matrix effects. With the advent of homogeneous reagents for direct measurement of HDL cholesterol and LDL cholesterol, traceability of diagnostic systems to the accuracy bases becomes even more critical (10). Working with manufacturers is again the most effective way to establish traceability to the accuracy base and to begin to standardize HDL cholesterol results.

The NCEP's Working Group on Lipoprotein Measurement issued performance guidelines for HDL cholesterol (7). HDL cholesterol should be measured with a bias from the reference method ≤ 5%. The methods should perform with a CV ≤ 4% at ≥ 42 mg/dL (1.09mmol/L) and a standard deviation of ≤ 1.7 mg/dL (0.044 mmol/L) at < 42 mg/dL (1.09 mmol/L). In 1994, the CRMLN implemented a program for manufacturers similar to the program already in place for total cholesterol (11). Manufacturers are strongly encouraged to certify their products annually.

No recertification protocol is available at this time for analytical systems that measure HDL cholesterol.

HDL Protocol

LDL Cholesterol

The NCEP's Adult Treatment Panel emphasized the importance of low-density lipoprotein (LDL) cholesterol in identifying people at risk for coronary heart disease (1,7,8). As with total cholesterol and HDL cholesterol, the CRMLN believes that working with manufacturers is the most effective way to establish traceability to the accuracy base and to begin to standardize LDL cholesterol results.

The NCEP's Working Group on Lipoprotein Measurement issued performance guidelines for clinical laboratories (12). Clinical laboratories should measure LDL cholesterol with a bias from the reference method ≤ 4% and perform with a CV ≤ 4%. In 1997, the CRMLN began certifying manufacturers of LDL cholesterol diagnostic products. Four of the CRMLN laboratories perform this service: University of Washington Department of Medicine, the Osaka Medical Center for Health Science and Promotion, Rotterdam University Hospital, and Canadian External Quality Assessment Laboratory.

No recertification protocol is available at this time for analytical systems that measure LDL cholesterol.

LDL Protocol

Sample Stability Protocol

The CRMLN provides, as a service to manufacturers, a sample stability protocol to be used to as a guideline in comparing results from frozen samples versus fresh samples. The CRMLN will not evaluate the data collected from sample stability studies. This protocol is provided as a guideline for manufacturers who would like to save additional aliquots of samples used in CRMLN certification protocols. These samples may be used for reanalysis if changes in calibration are required to meet certification criteria. When new lots of calibrators, materials, or reagents are prepared, these frozen samples can provide an important link to the accuracy base during overlap analyses if a frozen versus fresh comparison has been performed.

Sample Stability Protocol

For More Information

The information in these lists is provided as a service to the clinical laboratory community, especially laboratories that are considering purchase of instruments for analyzing total cholesterol, HDL cholesterol, and LDL cholesterol. For more information about these programs, please contact the CRMLN Program.

Frequently Asked Questions

Certification Protocol Helpful Hints

References

  1. National Institutes of Health. Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Bethesda, MD: National Institutes of Health, 1989. NIH publication no: 89-2925.
  2. National Institutes of Health. Recommendations for improving cholesterol measurement: a report from the Laboratory Standardization Panel of the National Cholesterol Education Program. Bethesda, MD: National Institutes of Health, 1990. NIH publication no: 90-2964.
  3. NCCLS. Preparation and validation of commutable frozen human serum pools as secondary reference materials for cholesterol measurement; Approved guideline. NCCLS document C37-A. Wayne, PA: NCCLS, 1999.
  4. Miller WG. Matrix effects in the measurement and standardization of lipids and lipoproteins. In: Rifai N, Warnick GR, Dominiczak MH, eds. Handbook of Lipoprotein Testing, 2nd edition. Washington, DC: AACC Press, 2000:695-716.
  5. Myers GL, Kimberly MM, Waymack PW, Smith SJ, Cooper GR, Sampson EJ. A reference method laboratory network for cholesterol: A model for standardization and improvement of clinical laboratory measurements. Clin Chem 2000;46:1762-72.
  6. NCCLS. Method comparison and bias estimation using patient samples. Approved guideline. NCCLS document EP9-A. Wayne, PA: NCCLS, 1995.
  7. National Institutes of Health. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Bethesda, MD: National Institutes of Health, 1993. NIH publication no: 93-3095.
  8. National Institutes of Health. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Bethesda, MD: National Institutes of Health, 2001. NIH publication no: 01-3670.
  9. Warnick GR, Wood PD. National Cholesterol Education Program recommendations for measurement of high-density lipoprotein cholesterol: executive summary. Clin Chem 1995;41:1427-33.
  10. Warnick GR, Nauck M, Rifai N. Evolution of methods for measurement of HDL-cholesterol: From ultracentrifugation to homogeneous assays. Clin Chem 2001;47:1579-96.
  11. Kimberly MM, Leary ET, Cole TG, Waymack PW. Selection, validation, standardization, and performance of a designated comparison method for HDL-cholesterol for use in the Cholesterol Reference Method Laboratory Network. Clin Chem 1999;45:1803-12.
  12. Bachorik PS, Ross JW. National Cholesterol Education Program recommendations for measurement of low-density lipoprotein cholesterol: executive summary. Clin Chem 1995;41:1414-20.

Disclaimer
Use of trade names is for identification only and does not constitute endorsement by the CDC or the U.S. Department of Health and Human Services.


 
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