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Linearity and Calibration Verification FAQs

Q. How often is Calibration Verification required?

A. According to the CLIA regulation provided in 42 CFR 493 section 493.1255: "(b) Perform and document calibration verification procedures: (3) At least once every 6 months and whenever any of the following occur: (i) A complete change of reagents for a procedure is introduced, unless the laboratory can demonstrate that changing reagent lot numbers does not affect the range used to report patient test results, and control values are not adversely affected by reagent lot number changes.(ii) There is a major preventive maintenance or replacement of critical parts that may influence test performance.(iii) Control material reflect an unusual trend or shift, or are outside of the laboratory’s acceptable limits, and other means of assessing and correcting unacceptable control values fail to identify and correct the problem.(iv) The laboratory’s established schedule for verifying the reportable range for patient test results requires more frequent calibration verification. These requirements are located on CDC internet site here.

Q. What is Reportable Range?

A. CLIA ’88 uses the term reportable range. The definition is provided in 42 CFR 493 in section 493.2. “Reportable range means the span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response.” This definition is very similar to the definition of Analytical Measurement Range (AMR) used by CAP. Use of the LGC Maine Standards products meets the requirements for reportable range validation and calibration verification. LGC Maine Standards provides five levels and has multiple product configurations available to maximize the reportable range with no dilutions for many instrument systems available. The CLIA regulations are located on the CDC internet site here and definitions can be found here.

Q. What is new instrument performance validation?

A. CLIA ’88 requires new instrument performance validation. The requirements are specified in 42 CFR 493 in section 493.1253 "Standard: Establishment and verification of performance specifications." For a new unmodified, FDA-cleared or approved test system brought into the lab after April 24, 2003, the standard requires the following: "(b)(1)(i) Demonstrate that it can obtain performance specifications comparable to those established by the manufacturer for the following performance characteristics: a) Accuracy, b) Precision, c) Reportable range of test results for the test system." LGC Maine Standards' VALIDATE® products are excellent for this testing and allow you to maximize your reportable range with no dilutions. The CLIA regulations are located on the CDC internet site here and a link to Section 493.1253 is located here.

Q. What is Analytical Measurement Range (AMR)?

A. The College of American Pathologists (CAP) uses Analytical Measurement Range (AMR) as part of their checklist for their Laboratory Accreditation Program. AMR is used as part of the CAP checklists to satisfy the CLIA ’88 requirements for the term ‘calibration verification’. CAP uses two terms – calibration verification and AMR validation – to identify the two distinct processes required. Definitions from CAP are provided below. Per the article below, AMR must be revalidated at least every six months. From March 2003 CAP Today, “Analytical measurement range validation: The process of confirming that the assay system will correctly recover the concentration or activity of the analyte over the AMR. The materials used for validation must be known to have matrix characteristics appropriate for the method. The matrix of the sample – that is, the environment in which the sample is suspended or dissolved-may influence the measurement of the analyte. In many cases, the method manufacturer will recommend suitable materials. The test specimens must have analyte values that, at a minimum, are near the low, midpoint, and high values of the AMR. Specimen target values can be established by comparison with peer group values for reference materials, by assignment of reference or comparative method values, and by dilution or admixture ratios of one or more specimens with known values. Each laboratory must define limits for accepting or rejecting validation tests of the AMR. The AMR must be revalidated at least every six months, at changes in major system components, and when a complete change in reagents for a procedure is introduced, unless the lab can demonstrate that changing reagent lot numbers does not affect the range used to report patient/client test results. Routine reagent lot changes may not require AMR revalidation if they occur within the six-month interval. The laboratory director should determine what constitutes a major system component change or a "complete" change in reagents that would require revalidation of the AMR. Manufacturers’ instructions should be followed.¹ Calibration verification: The process of confirming that the current calibration settings remain valid for a method. If calibration verification confirms that the current calibration settings are valid, it is not necessary to perform a complete calibration or recalibration of the method. Calibration verification can be accomplished in several ways. If the method manufacturer provides a calibration validation or verification process, it should be followed. Other techniques include (1) assay of the current method calibration materials as unknown specimens and determination that the correct target values are recovered, and (2) assay of matrix-appropriate materials with accurate target values that are specific for the method. Materials for calibration verification must have a matrix appropriate for the clinical specimens assayed by that method and target values appropriate for the measurement system. In general, routine control materials are not suitable for calibration verification, except in situations where the material is specifically designated by the method manufacturer as suitable for verification of the method's calibration process.”¹ 1. Southwick, Karen. Language Barrier Falls With Checklist Change. CAP Today 2003;3."

Q. Our inspection checklist requires Analytical Measurement Range (AMR) validation, can LGC Maine Standards’ products be used for AMR validation?

A. Yes, the use of the LGC Maine Standards products meets the requirements for AMR validation and also for calibration verification. The CAP checklist, and CLIA ’88 regulations, require three points for AMR validation: lowest, midpoint and highest values. “’We [in the committee] prefer at least five,’ says Dr. Ashwood, ‘but CLIA says three,’ so the checklist question specifies three.”¹ LGC Maine Standards provides five levels and has multiple product configurations available to get as close as possible to the lowest and highest values for the many instrument systems available to maximize the AMR with no dilutions. 1. Southwick, Karen. Language Barrier Falls With Checklist Change. CAP Today 2003;3.

Q. Do I have to use the CAP Linearity Survey (LN) in order to meet the CAP requirements for Calibration Verification on the CAP Checklist?

A. No, the CAP does not require mandatory use of the CAP LN Survey materials in order to satisfy the CAP accreditation program. In May of 2006, LGC Maine Standards received written confirmation from the CAP regarding this matter. A copy of this correspondence is available for download here. If laboratory users are interested in the position of the CAP on this matter, please feel free to contact CAP directly via e-mail (accred@cap.org). LGC Maine Standards is confident that its products are uniquely suited to provide for linearity and calibration verification needs in today’s clinical laboratory. Please contact us with any questions you may have on this issue.

Q. My laboratory is inspected by JCAHO. Can I use your VALIDATE® linearity and calibration verification products to meet the requirements for calibration verification?

A. Yes, VALIDATE® linearity and calibration verification products can be used to meet the JCAHO requirements for calibration verification. JCAHO calibration verification requirements are contained in Standard QC.1.170, which went into effect January 1, 2005. These standards can be found on the Joint Commission internet site. Highlights, from the standard QC.1.170, concerning linearity and calibration verification are as follows: 1) Reportable range should be tested during calibration verification, including at least a minimal value, a mid-point value and a maximum value. 2) Calibration verification should be performed at least once every six months and whenever the following occur: a) A complete change of reagents is introduced, unless it is demonstrated that control values are not affected, b) there is major preventive maintenance or replacement of critical parts, c) control results indicate that there may be a problem with the test system, d) there is an environmental change, including instrument relocation, as applicable, and e) there is an instrument replacement.

VALIDATE® Products FAQs

Q. How do I get information about your new products?

A. Send an email to CDx-Marketing@lgcgroup.com, or call 1-800-377-9684. We will need typical contact information, such as institution name, contact name, address, phone, fax, and email. We will send you new product information when it is available.

Q. Where can I find the target values for each level?

A. Typical values, by configuration, can be found in your package insert, or by calling LGC Maine Standards Technical Support. Typical values are intended as a guide only, and are not intended to be used as targets for data analysis. Actual results obtained may vary depending on instrumentation, methodology and assay temperature. Results may also be dependent on the accuracy of the instrument/reagent system calibration. The degree of acceptable nonlinearity is an individual judgment based on methodology, clinical significance and medical decision levels of the test analyte.

Q. I do not have a non-frost-free freezer. How should I store your frozen products?

A. VALIDATE® products that require frozen storage need a non-frost-free freezer capable of maintaining the recommended storage temperatures. These storage conditions are similar to many other frozen controls and calibrators typically stored by a laboratory. Please refer to our technical bulletin for more details on why a non-frost-free freezer is needed and what to do if you do not have access to one.

Q. My frozen product was inadvertently placed in the refrigerator over the weekend. Can I still use the kit?

A. VALIDATE® products are temperature sensitive and require specific storage conditions. LGC Maine Standards can only guarantee the performance of test kits stored in accordance with labeled instructions. We recommend contacting us to purchase replacement kits for any product not stored properly. Storage requirements for VALIDATE® products can be found on the kit box label, bottle labels and the package inserts. Products that are to be stored at 2 to 8°C are packaged in BLUE kit boxes. Products that are to be stored at -10 to -25°C are packaged in WHITE kit boxes. The storage conditions required by the VALIDATE® products are similar to other controls, calibrators and reagents used in clinical laboratories. Please refer to the FAQ regarding non-frost-free freezers above, for the products that require frozen storage.

Q. Can VALIDATE® be stored in different containers?

A. VALIDATE stability studies are performing using the final product formulation and package in the final container/closure system. We cannot guarantee our product performance if it is not stored in its original containers.

Data Analysis FAQs

Q. How do I report a non-numeric result on the data submission form?

A. Enter your results on the data submission form exactly as the instrument system provides. A non-numeric result does not always imply a ‘zero’ recovery. Reporting a non-numeric result as zero (0) on your data submission form can effect your data analysis.

Q. How can I send my data to your data reduction department?

A. For submissions via email, fax or mail, download our Data Submission Form or Data Dilutions Submission Form and save the blank forms on your computer for reuse. When ready to submit data, fill in all information and data where required (instructions for completing the Data Submission Forms). Then, save the file using the "Save as" menu item. Use a unique file name that will identify the product used and the date of testing. Then, send us the completed Data Submission Form(s) by email, fax, or mail. Email your completed Data Submission Form(s) as attachments to: msc.datareduction@lgcgroup.com; Fax your completed Data Submission Form(s) to: 1-207-892-2266 Attn: Data Reduction Department; Mail your completed Data Submission Form(s) to: LGC Maine Standards Attn: Data Reduction Department, 221 US Route 1, Cumberland Foreside, ME 04110

Q. Where can I find a detailed explanation of the Data Reduction Report?

A. You can download a copy of our Data Reduction Report Explanation.

Q. Can you provide guidance on interpreting the results?

A. Prior to interpretation, your laboratory should establish acceptable performance criteria for linearity and calibration verification experiments for each analyte. Interpretation should always include consideration from a ‘clinical use’ perspective for each analyte. Care should be observed when interpreting results that fall outside of the applied limits on the extreme low end of a linearity and calibration verification evaluation. The results are generated solely on the statistical evaluation of the data. Often, the analytical differences are small and do not impact clinical use of the test. Clinical significance of differences needs to be considered in the interpretation of any results.

Q. Can you provide guidance on setting acceptable performance criteria?

A. For each test performed, the laboratory is responsible for establishing performance specifications for calibration verification and for reportable range verification. When setting limits for non-linearity, the error allowed can be based on either analytical goals or clinical goals. Ideally, the amount of error allowed due to non-linearity should be independent of error that results from bias and other analytical error (imprecision). Bias is typically that error that is the result of calibration and the element of accuracy imparted by calibration set points. Imprecision error can be influenced by a number of variables such as system maintenance and sample integrity. The CLIA limits represent the entire error allowed, which includes all three sources of error outlined above. Each lab should establish what portion of the total error budget is allowed for non-linearity. Acceptance criteria should always include consideration from a ‘clinical use’ perspective for each analyte. For example, ask the question: with a "Target" of 4.30 mg/dL for glucose, is a recovered value of 4.5 mg/dL glucose an acceptable value? This type of logic can be applied to the entire reportable range to help set acceptance criteria. The CLIA '88 'criteria for acceptable performance' can be found on the internet in two locations: 1) For routine chemistry, 2) For toxicology.

Q. What should I do if I get results that fall outside of the applied limits?

A. Example: Level 5 is outside of the applied limits for linearity analysis:

Results need to be compared to the acceptance criteria you established for the analyte. Points that fall outside of the applied limits may or may not affect the linear range, depending upon your acceptance criteria. Care should be observed when interpreting results that fall outside of the applied limits on the extreme low or high end of a linearity and calibration verification evaluation. The results shown in our output table are generated solely on the statistical evaluation of the data – clinical significance is not taken into account. Often, at the low or high end of the evaluation, the statistical differences may not impact clinical use of the test. Clinical significance of differences needs to be considered in the interpretation of any result. More information on statistical flags on your data reduction reports is provided in this letter. If the nonlinearity seen is deemed acceptable, or, not clinically significant, you could accept the result and document your reasoning. If the nonlinearity seen is determined to be unacceptable, or, clinically significant, you could proceed with troubleshooting. The initial recommendation for troubleshooting is recalibration of the assay, rerunning of the linearity set for the analyte, and resubmission of data. It may be useful for you to submit method information and receive Peer Group Analysis. Peer Group Analysis allows you to see how your results compare to others running the same VALIDATE® test kit on the same analyzer. We have generated FAQs about results that are outside the limits and consistent with Peer Group and results that are outside the limits and different from the Peer Group.

Q. What should I do if I get results that fall outside of the applied limits, but I am consistent with my Peer Group?

A. Example: Level 5 is outside of the applied limits for linearity analysis, but is consistent with the Peers at that level:

Peer Group Analysis allows you to see how your results compare to others running the same VALIDATE® test kit on the same analyzer. If your results are nonlinear but consistent with your peers, this indicates that the nonlinearity is not limited to your specific analyzer and that the method itself may truly be nonlinear. Any result that falls outside the allowable error limits should be evaluated by the laboratory for clinical significance. If the nonlinearity seen is deemed acceptable, or, not clinically significant, you could accept the result and document your reasoning. If the nonlinearity seen is determined to be unacceptable, or, clinically significant, you could chose to limit the upper end of your range to the mean of the highest level tested that was within the statistical limits (Level 4 in the example above), or, proceed with troubleshooting. In the case of nonlinear results that are consistent with Peers, the recommendation would be to contact your instrument manufacturer for troubleshooting steps.

Q. What should I do if I get results that fall outside of the applied limits and I am different from my Peer Group?

A. Example: Level 4 and Level 5 are outside of the applied limits for linearity analysis, and are different from the Peers at those levels:

Peer Group Analysis allows you to see how your results compare to others running the same VALIDATE® test kit on the same analyzer. If your results are nonlinear and not consistent with your peers, this indicates that the nonlinearity may be limited to your analyzer. Any result that falls outside the allowable error limits should be evaluated by the laboratory for clinical significance. If the nonlinearity seen is deemed acceptable, or, not clinically significant, you could accept the result and document your reasoning. If the nonlinearity seen is determined to be unacceptable, or, clinically significant, you could chose to limit the upper end of your range to the mean of the highest level tested that was within the statistical limits (Level 3 in the example above), or, proceed with troubleshooting. The initial recommendation for troubleshooting in this case would be recalibration of the assay, rerunning of the linearity set for the analyte, and resubmission of data.

Q. When I use the data analysis method described in your product insert, I get different target values than those from your data reduction report. Why?

A. The methods described in the data analysis in our product insert are methods that can easily be done without the use of complicated statistics. Our Data Reduction method uses more complex statistical analysis to calculate target values. Both methods are acceptable methods to analyze the data. One method of analysis in the package insert uses two consecutive levels to calculate the target values. The difference between the chosen consecutive levels is first calculated. Then, this difference is added or subtracted as needed to calculate the five target values based on the chosen levels. The second method in the package insert uses Levels 1 and 5 to calculate the target values. The difference between Level 5 and Level 1 is divided by four to determine the delta for each level. Then, this difference is consecutively added to Level 1 three times to determine the target values for Levels 2 through 4. Our Data Reduction method uses linear regression with specific data points as part of the target value calculation. This method is more complex than the one outlined in the product insert and most likely will not result in exactly the same target values. For a detailed explanation of this process, please refer to the method explained page.

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