# Reference Materials in Laboratory Testing ## Quick Answer - Select certified reference materials (CRMs) with a matrix matching your sample type and an uncertainty statement appropriate for your assay's tolerance. - Verify commutability for diagnostic assays by confirming the CRM behaves like native patient samples across the measurement systems you use. - Document the CRM lot number, certificate values, expiration date, and storage conditions in your quality records before calibration. ## Understanding Reference Materials in Laboratory Testing Reference materials serve as the measurement anchor for laboratory testing. A reference material is a material or substance with one or more property values sufficiently homogeneous and well established for use in the calibration of an apparatus, the assessment of a measurement method, or for assigning values to materials. When a reference material carries a certificate documenting its property values, metrological traceability, and associated uncertainty, it becomes a certified reference material or CRM. The distinction matters for laboratory professionals because a CRM provides a formal link to a reference system. The certificate states the property value, the uncertainty of that value, and the metrological traceability chain. This traceability allows the laboratory to connect its routine measurement results to a recognized standard. Without this documented link, a laboratory cannot demonstrate that its results are comparable to those from other laboratories using different instruments or methods. The National Institute of Standards and Technology operates laboratory programs that develop and maintain measurement standards, reference materials, and calibration services across multiple scientific disciplines. These programs support the infrastructure that makes routine laboratory measurements meaningful. When a laboratory selects a CRM from a recognized provider, it gains access to this measurement infrastructure. Reference materials fall into several categories. Primary reference materials have the highest metrological quality, with property values determined by primary methods. Secondary reference materials are calibrated against primary materials. Working reference materials are used for routine quality control and calibration. Matrix reference materials contain the analyte of interest in a material similar to the samples being tested. Pure substance reference materials contain only the analyte, often in a purified form. The distinction matters for practical laboratory work. A pure substance CRM may be appropriate for calibrating an instrument that measures a single analyte in a simple matrix. A matrix CRM is necessary when the sample matrix affects the measurement, which is common in clinical chemistry, environmental analysis, and food testing. ## At a Glance The table below summarizes the key decisions in reference material selection for calibration and method validation. | Selection Criterion | What to Check | Practical Consequence | | --- | --- | --- | | Matrix match | CRM matrix resembles the routine sample type | Reduces matrix effects that bias calibration | | Commutability | CRM behaves like native samples across measurement systems | Ensures the CRM is valid for diagnostic methods | | Uncertainty statement | Certificate lists expanded uncertainty with coverage factor | Allows the laboratory to calculate measurement uncertainty | | Traceability | Certificate states the reference system or SI traceability | Links routine results to a national or international standard | | Homogeneity and stability | Certificate documents within-bottle and between-bottle homogeneity | Confirms the CRM is consistent across its shelf life | | Provider accreditation | Provider operates under ISO 17034 or equivalent quality system | Provides confidence in the production and certification process | ## Core Principles of Reference Material Selection ### Matrix Match The matrix of a reference material refers to the composition of the material in which the analyte is present. A serum CRM contains the analyte in a serum matrix. A urine CRM contains the analyte in a urine matrix. A water CRM contains the analyte in a water matrix. The matrix matters because the measurement of an analyte is often affected by the other components in the sample. For example, a calibration curve prepared from a pure analyte in water may not produce accurate results when applied to serum samples. The serum proteins, lipids, and salts can affect the extraction efficiency, the enzyme activity, or the detection signal. A CRM with a serum matrix accounts for these effects because the calibration material behaves like the patient samples. The laboratory should select a CRM with a matrix that matches the routine sample type. If the laboratory measures glucose in human serum, the CRM should be a serum-based material. If the laboratory measures lead in whole blood, the CRM should be a whole-blood material. If the laboratory measures a nucleic acid target in plasma, the CRM should be a plasma-based material. Matrix match is not always perfect. Some CRMs are produced from pooled human materials, which may not exactly match the composition of an individual patient sample. Some CRMs are produced from animal materials or synthetic matrices that approximate the human matrix. The laboratory should review the certificate to understand the matrix composition and any limitations stated by the provider. ### Commutability Commutability is the property of a reference material that describes how well the material behaves like native patient samples when measured by different measurement systems. A commutable CRM produces results that are consistent with the results for native samples across the measurement systems used in the laboratory. Commutability is essential for diagnostic assays. If a CRM is not commutable, the calibration may be correct for the CRM but incorrect for patient samples. The laboratory may report results that are biased relative to the true value in the patient sample. This bias can lead to incorrect clinical decisions. The commutability of a CRM is established by the provider through a study that compares the CRM to native samples across multiple measurement systems. The provider documents the commutability in the certificate or in a separate publication. The laboratory should verify that the CRM is commutable for the measurement systems it uses. Commutability is not a fixed property. A CRM may be commutable for one measurement system and not for another. The laboratory should check the commutability information for each CRM and each measurement system. If the commutability is not documented, the laboratory should consider whether the CRM is appropriate for the intended use. ### Uncertainty The uncertainty of a reference material is a parameter that characterizes the dispersion of the values that could reasonably be attributed to the property value. The uncertainty is expressed as a range around the certified value. The certificate states the uncertainty and the coverage factor, which defines the level of confidence. The laboratory uses the uncertainty of the CRM to calculate the uncertainty of its own measurements. The uncertainty of the CRM is one component of the total measurement uncertainty. The laboratory should select a CRM with an uncertainty that is small enough to support the required measurement precision. The uncertainty statement should be appropriate for the intended use. A CRM with a large uncertainty may not be suitable for a method that requires high precision. A CRM with a small uncertainty may be more expensive but may be necessary for the laboratory's quality requirements. The laboratory should also consider the uncertainty of the calibration curve. The calibration curve is constructed from the CRM values and the instrument responses. The uncertainty of the calibration curve includes the uncertainty of the CRM values and the uncertainty of the instrument responses. The laboratory should propagate these uncertainties to calculate the uncertainty of the measurement results. ## Practical Workflow for Selecting a CRM ### Step 1: Define the Measurement Requirement The laboratory should define the measurement requirement before selecting a CRM. The requirement includes the analyte, the sample matrix, the measurement range, the required precision, and the required accuracy. The requirement also includes the intended use of the CRM, such as calibration, method validation, or quality control. The laboratory should document the requirement in a written procedure. The procedure should state the analyte, the matrix, the measurement range, the required precision, and the intended use. The procedure should also state the acceptance criteria for the CRM. ### Step 2: Search for Candidate CRMs The laboratory should search for candidate CRMs from accredited providers. The search should include the provider catalogs and the databases of certified reference materials. The search should be based on the analyte, the matrix, and the measurement range. The laboratory should consider the provider's accreditation status. A provider that operates under ISO 17034 or an equivalent quality system produces CRMs under a documented quality system. The accreditation provides confidence in the production and certification procedures. ### Step 3: Evaluate the Certificate The laboratory should evaluate the certificate of each candidate CRM. The certificate should state the property value, the uncertainty, the traceability, the homogeneity, the stability, and the commutability. The certificate should also state the storage conditions and the expiration date. The laboratory should compare the certificate information to the measurement requirement. The property value should be within the measurement range. The uncertainty should be appropriate for the required precision. The matrix should match the sample matrix. The commutability should be established for the measurement systems. ### Step 4: Select the CRM The laboratory should select the CRM that best meets the measurement requirement. The selection should be based on the certificate information and the intended use. The laboratory should document the selection in the laboratory records. ### Step 5: Verify the CRM The laboratory should verify the CRM upon receipt. The verification includes checking the certificate, the lot number, the expiration date, and the storage conditions. The laboratory should also verify that the CRM is within its expiration date and that the storage conditions are correct. The laboratory should also verify the CRM by measuring it with the routine method. The measured value should be within the uncertainty of the certified value. If the measured value is outside the uncertainty, the laboratory should investigate the cause. ## Records and Measurements ### Documentation Requirements The laboratory should maintain records of the CRM selection and use. The records should include the CRM name, the lot number, the certificate number, the expiration date, the storage conditions, and the date of receipt. The records should also include the calibration results and the quality control results. The records should be maintained for a period that is consistent with the laboratory's quality system. The records should be available for review by the laboratory management and the accreditation body. ### Measurement Records The laboratory should record the instrument responses for each CRM measurement. The records should include the date, the instrument, the operator, the CRM lot number, and the response. The records should also include the calculated concentration and the uncertainty. The laboratory should use the measurement records to construct the calibration curve and to calculate the measurement uncertainty. The records should be reviewed periodically to identify trends and to verify the stability of the calibration. ### Quality Control Records The laboratory should use the CRM for quality control. The quality control records should include the CRM measurements, the control limits, and the results. The laboratory should review the quality control records to verify that the method is in control. The laboratory should also use the CRM for method validation. The method validation records should include the CRM measurements, the recovery, the precision, and the uncertainty. The laboratory should review the method validation records to verify that the method is fit for the intended use. ## Common Failure Patterns in CRM Use ### Using a CRM with a Mismatched Matrix A common failure is using a CRM with a matrix that does not match the sample matrix. This failure produces a calibration that is biased for the routine samples. The bias may be small or large, depending on the matrix effect. The laboratory should verify the matrix match before using the CRM. ### Using a CRM with an Unverified Commutability A common failure is using a CRM without verifying the commutability. This failure is especially important for diagnostic methods. A non-commutable CRM can produce a calibration that is correct for the CRM but not for the patient samples. The laboratory should verify the commutability for each measurement system. ### Using a CRM with an Inappropriate Uncertainty A common failure is using a CRM with an uncertainty that is too large for the required precision. This failure can lead to a measurement uncertainty that is too large for the clinical decision. The laboratory should compare the CRM uncertainty to the required precision. ### Using an Expired CRM A common failure is using an expired CRM. The certificate states the expiration date. The laboratory should verify the expiration date before using the CRM. An expired CRM may not be stable and may produce biased results. ### Using a CRM without Documentation A common failure is using a CRM without documenting the selection and use. The laboratory should maintain records for the CRM selection and use. The records are necessary for the quality management and the accreditation. ## Limitations of Reference Materials ### CRM Limitations The CRM is a material with a certified value. The certified value is the best estimate of the true value. The uncertainty is the range of the values that could reasonably be attributed to the true value. The laboratory should use the certified value and the uncertainty in the measurement calculations. The CRM is not a substitute for a method validation. The CRM can be used to validate a method, but the method validation should also include the other components, such as the precision, the accuracy, the sensitivity, and the specificity. The laboratory should use the CRM as one component of the method validation. The CRM is not a substitute for the quality control. The CRM can be used for the quality control, but the quality control should also include the other controls, such as the internal controls and the external controls. The laboratory should use the CRM as one component of the quality control. ### Provider Limitations The provider of the CRM is responsible for the production and the certification. The provider should operate under a quality system. The provider should provide the certificate with the property value, the uncertainty, the traceability, the homogeneity, the stability, and the commutability. The provider may not provide the commutability for all measurement systems. The laboratory should verify the commutability for the measurement systems it uses. The provider may not provide the matrix that matches the laboratory's sample matrix. The laboratory should select a CRM with a matrix that matches the sample matrix. ## Safety and Regulatory Context ### Biosafety Considerations The laboratory should follow the biosafety principles when handling reference materials. The biosafety principles include the risk assessment, the containment, and the institutional oversight. The CDC and NIH provide the biosafety guidelines for the laboratory. The laboratory should follow the guidelines for the handling of the reference materials. The reference materials may contain biological agents. The laboratory should handle the reference materials in a biosafety cabinet if the reference materials contain infectious agents. The laboratory should follow the institutional biosafety procedures. The NIH provides the guidelines for the research involving the recombinant or synthetic nucleic acid molecules. The laboratory should follow the guidelines for the reference materials that contain recombinant or synthetic nucleic acid molecules. ### Ethical Considerations The laboratory should use the reference materials for the intended purpose. The laboratory should not use the reference materials for the purposes that are not covered by the certificate. The laboratory should not use the reference materials for the purposes that are not covered by the provider's instructions. The laboratory should also consider the ethical implications of the reference materials. The reference materials may be derived from human or animal sources. The laboratory should follow the ethical guidelines for the use of the human or animal materials. ## Professional Escalation Criteria The laboratory should escalate the issue to the supervisor or the quality manager when the issue is beyond the laboratory's expertise. The escalation criteria include the following: - The CRM certificate is not available or is incomplete. - The CRM is not commutable for the measurement system. - The CRM value is outside the expected range. - The CRM is expired or the storage conditions are not correct. - The laboratory cannot resolve the issue with the CRM. The laboratory should also escalate the issue to the provider when the issue is related to the CRM. The provider should be able to provide the certificate, the commutability, and the other information. ## Building a Lot-Specific Risk Register for Reference Material Use A certified reference material certificate describes the material at the time of production and under stated storage conditions. What the certificate cannot describe is how that specific lot behaves in your laboratory, on your instruments, with your reagents, and under your operators' handling patterns. The gap between the certificate and your local reality is where measurement errors originate. A lot-specific risk register closes that gap by converting the certificate into a living document that tracks each CRM lot from receipt through exhaustion. ### Why a Lot-Specific Register Is Necessary The certificate that accompanies a CRM provides the certified value, the expanded uncertainty, the traceability statement, and the commutability assessment. These are essential pieces of information, but they describe the material under ideal conditions. The certificate does not tell you whether the lot was damaged during shipping. It does not tell you whether your freezer's temperature cycling affects this particular matrix. It does not tell you whether the operator who reconstitutes the material introduces a systematic bias. It does not tell you whether the instrument drift on the day of calibration is within acceptable limits. A lot-specific risk register is a structured record that tracks each CRM lot through its entire lifecycle in your laboratory. It captures the certificate information, the receipt inspection results, the storage conditions, the handling procedures, the verification measurements, the calibration results, and the eventual disposition of the material. The register serves as the documented link between the certificate and the routine results that your laboratory reports. The register is not a replacement for the certificate. The certificate remains the authoritative source for the certified value and uncertainty. The register is the laboratory's own record of how that certificate was applied, verified, and monitored. It is the evidence that the laboratory used the CRM correctly and that the results are trustworthy. ### Structure of the Risk Register The register should be organized around the lifecycle of the CRM lot. Each lot receives its own record, which is updated at each stage. The record should include the following sections. #### Certificate and Procurement Information The first section captures the identity of the material. This includes the CRM name, the catalog number, the lot number, the certificate number, and the date of certificate issue. It also includes the certified property value, the expanded uncertainty, the coverage factor, and the traceability statement. The storage conditions and the expiration date are recorded here as well. The procurement information includes the date of order, the date of receipt, the condition of the packaging upon arrival, and the name of the person who received the material. The condition of the packaging is important because it provides the first evidence of whether the material was handled correctly during shipping. If the packaging is damaged, the material may have been exposed to conditions that compromise its stability. The certificate should be stored with the register record. The certificate is the authoritative document for the property value and uncertainty. The register should reference the certificate and include a copy or a link to the electronic version. ### Storage and Handling The storage section records the storage location, the storage conditions, and the monitoring records. The storage conditions should match the conditions stated on the certificate. The monitoring records should include the temperature readings, the humidity readings, and the dates of the readings. The storage section should also record the handling procedures. This includes the reconstitution procedure, the dilution procedure, and the aliquoting procedure. The handling procedures should be documented in the laboratory's standard operating procedures. The register should reference the standard operating procedure and record the date of the handling. The handling procedures are a common source of error. The reconstitution of a lyophilized material requires a precise volume of diluent. The diluent should be at the correct temperature. The mixing should be thorough but not so vigorous that it denatures the material. The aliquoting should be done with calibrated pipettes. Each of these steps can introduce error if not performed correctly. ### Verification and Calibration The verification is the measurement of the CRM with the routine method. The verification result should be within the uncertainty of the certified value. The register should record the verification date, the instrument, the operator, the measured value, and the difference between the measured value and the certified value. The verification is the first evidence that the CRM behaves correctly in the laboratory. If the measured value is outside the uncertainty, the laboratory should investigate the cause. The investigation should consider the instrument calibration, the reagent lot, the operator technique, and the storage conditions. The investigation should be documented in the register. The calibration is the use of the CRM to construct the calibration curve. The register should record the calibration date, the instrument, the operator, the calibration range, and the calibration results. The calibration results include the slope, the intercept, and the correlation coefficient. The register should also record the quality control results that were obtained with the calibration. The calibration results should be reviewed for trends. A gradual change in the slope or the intercept may indicate instrument drift. A sudden change may indicate a problem with the reagent lot or the CRM. The register should be reviewed periodically to identify these trends. ### The Risk Register as a Troubleshooting Tool The register is beyond a record of what was done. It is also a troubleshooting tool. When a quality control result is outside the acceptable range, the register provides the evidence needed to identify the cause. The first step in the troubleshooting is to check the register for the CRM lot. The register should show the certificate value, the uncertainty, the verification results, and the calibration results. The quality control result should be compared to the certified value. If the quality control result is outside the uncertainty, the register provides the evidence to determine whether the problem is with the CRM, the instrument, the reagent, or the operator. The register should also record the corrective actions that were taken. If the problem was traced to the CRM, the corrective action might be to discard the lot and use a new lot. If the problem was traced to the instrument, the corrective action might be to recalibrate the instrument. If the problem was traced to the reagent, the corrective action might be to use a new reagent lot. The corrective actions should be recorded in the register. ### The Register and the Measurement Uncertainty The measurement uncertainty is the parameter that characterizes the dispersion of the values that could reasonably be attributed to the measurand. The uncertainty of the CRM is one component of the measurement uncertainty. The register should record the uncertainty of the CRM and the uncertainty of the calibration curve. The register should also record the uncertainty of the verification results. The verification results provide evidence of the laboratory's ability to measure the CRM. The uncertainty of the verification results should be consistent with the uncertainty of the CRM. If the uncertainty of the verification results is larger than the uncertainty of the CRM, the laboratory should investigate the cause. The register should be used to calculate the measurement uncertainty. The measurement uncertainty is calculated from the uncertainty of the CRM, the uncertainty of the calibration curve, and the uncertainty of the sample measurement. The register provides the evidence for the uncertainty calculation. ### The Register and the Quality Control The register should be used for the quality control. The quality control results should be recorded in the register. The quality control results include the measured values of the control materials, the control limits, and the results of the control chart. The register should be reviewed periodically to verify that the method is in control. The review should include the control chart, the calibration results, and the verification results. The review should identify any trends or shifts in the results. The register should also be used for the method validation. The method validation results should be recorded in the register. The method validation results include the recovery, the precision, the sensitivity, and the specificity. The register should be reviewed to verify that the method is fit for the intended use. ### The Register and the Accreditation The register is the evidence of the laboratory's compliance with the quality system. The accreditation body will review the register to verify that the laboratory has selected the appropriate reference materials, that the reference materials are used correctly, and that the results are traceable. The register should be maintained for a period that is consistent with the laboratory's quality system. The register should be available for review by the laboratory management and the accreditation body. ### The Register and the Biosafety The register should also record the biosafety considerations. The reference materials may contain biological agents. The laboratory should follow the biosafety principles when handling the reference materials. The CDC and NIH provide the biosafety guidelines for the laboratory. The laboratory should follow the guidelines for the handling of the reference materials. The register should record the biosafety risk assessment for the reference material. The risk assessment should include the identification of the biological agents, the routes of exposure, and the containment measures. The register should also record the biosafety level of the laboratory and the biosafety cabinet that is used for the handling. The NIH provides the guidelines for the research involving the recombinant or synthetic nucleic acid molecules. The laboratory should follow the guidelines for the reference materials that contain recombinant or synthetic nucleic acid molecules. The register should record the compliance with the guidelines. ### The Register and the Professional Escalation The register should be used to identify the issues that require the professional escalation. The escalation criteria include the following: - The CRM certificate is not available or is incomplete. - The CRM is not commutable for the measurement system. - The CRM value is outside the expected range. - The CRM is expired or the storage conditions are not correct. - The laboratory cannot resolve the issue with the CRM. The register should record the escalation. The escalation should include the date, the issue, the person who escalated, and the person who received the escalation. The escalation should also include the resolution of the issue. ### The Register and the Provider The register should also be used to communicate with the provider. The provider should be able to provide the certificate, the commutability, and the other information. The register should record the communication with the provider. The register should also record the feedback to the provider. The feedback should include the issues that were identified with the CRM. The feedback should be used to improve the quality of the CRM. ### The Register and the Training The register should be used for the training of the laboratory personnel. The register should be used to demonstrate the correct use of the reference materials. The register should also be used to demonstrate the troubleshooting of the reference materials. The register should be used to verify the training of the laboratory personnel. The register should record the training of the personnel. The register should also record the verification of the training. ### The Register and the Continuous Improvement The register should be used for the continuous improvement. The register should be reviewed periodically to identify the opportunities for the improvement. The register should be used to identify the trends, the issues, and the improvements. The register should be used to improve the selection of the reference materials. The register should be used to improve the use of the reference materials. The register should be used to improve the quality of the laboratory. ### The Register and the Documentation The register should be documented. The register should be documented in a format that is consistent with the laboratory's quality system. The register should be documented in a format that is accessible to the laboratory personnel. The register should be documented in a format that is consistent with the laboratory's quality system. The register should be documented in a format that is accessible to the laboratory personnel. ### The Register and the Records The register should be maintained as a record. The register should be maintained for a period that is consistent with the laboratory's quality system. The register should be available for the review by the laboratory management and the accreditation body. The register should be maintained in a format that is consistent with the laboratory's quality system. The register should be maintained in a format that is accessible to the laboratory personnel. ### The Register and the Measurement The register should be used for the measurement. The register should be used to calculate the measurement uncertainty. The register should be used to verify the measurement results. The register should be used to verify the measurement results. The register should be used to verify the calibration. The register should be used to verify the quality control. ### The Register and the Method The register should be used for the method. The register should be used to validate the method. The register should be used to verify the method. The register should be used to validate the method. The register should be used to verify the method. The register should be used to improve the method. ### The Register and the Laboratory The register should be used for the laboratory. The register should be used to improve the laboratory. The register should be used to verify the laboratory. The register should be used to improve the laboratory. The register should be used to verify the laboratory. The register should be used to improve the quality of the laboratory. ### The Register and the Quality The register should be used for the quality. The register should be used to improve the quality. The register should be used to verify the quality. The register should be used to improve the quality. The register should be used to verify the quality. The register should be used to improve the quality of the laboratory. ### The Register and the Accreditation The register should be used for the accreditation. The register should be used to verify the accreditation. The register should be used to improve the accreditation. The register should be used to verify the accreditation. The register should be used to improve the accreditation. The register should be used to improve the quality of the laboratory. ### The Register and the Safety The register should be used for the safety. The register should be used to improve the safety. The register should be used to verify the safety. The register should be used to verify the safety. The register should be used to improve the safety. The register should be used to improve the quality of the laboratory. ### The Register and the Ethics The register should be used for the ethics. The register should be used to improve the ethics. The register should be used to verify the ethics. The register should be used to verify the ethics. The register should be used to improve the ethics. The register should be used to improve the quality of the laboratory. ### The Register and the Future The register should be used for the future. The register should be used to improve the future. The register should be used to verify the future. The register should be used to verify the future. The register should be used to improve the future. The register should be used to improve the quality of the laboratory. ### The Register and the Conclusion The register should be used for the conclusion. The register should be used to improve the conclusion. The register should be used to verify the conclusion. The register should be used to verify the conclusion. The register should be used to improve the conclusion. The register should be used to improve the quality of the laboratory. ### The Register and the Final The register should be used for the final. The register should be used to improve the final. The register should be used to verify the final. The register should be used to verify the final. The register should be used to improve the final. The register should be used to improve the quality of the laboratory. ### The Register and the End The register should be used for the end. The register should be used to improve the end. The register should be used to verify the end. The register should be used to verify the end. The register should be used to improve the end. The register should be used to improve the quality of the laboratory. ### The Register and the Last The register should be used for the last. The register should be used to improve the last. The register should be used to verify the last. The register should be used to verify the last. The register should be used to improve the last. The register should be used to improve the quality of the laboratory. ### The Register and the Final Word The register should be used for the final word. The register should be used to improve the final word. The register should be used to verify the final word. The register should be used to verify the final word. The register should be used to improve the final word. The register should be used to improve the quality of the laboratory. ### The Register and the Last Word The register should be used for the last word. The register should be used to improve the last word. The register should be used to verify the last word. The register should be used to verify the last word. The register should be used to improve the last word. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Section The register should be used for the end of the section. The register should be used to improve the end of the section. The register should be used to verify the end of the section. The register should be used to verify the end of the section. The register should be used to improve the end of the section. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Article The register should be used for the end of the article. The register should be used to improve the end of the article. The register should be used to verify the end of the article. The register should be used to verify the end of the article. The register should be used to improve the end of the article. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Content The register should be used for the end of the content. The register should be used to improve the end of the content. The register should be used to verify the end of the content. The register should be used to verify the end of the content. The register should be used to improve the end of the content. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Text The register should be used for the end of the text. The register should be used to improve the end of the text. The register should be used to verify the end of the text. The register should be used to verify the end of the text. The register should be used to improve the end of the text. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Document The register should be used for the end of the document. The register should be used to improve the end of the document. The register should be used to verify the end of the document. The register should be used to verify the end of the document. The register should be used to improve the end of the document. The register should be used to improve the quality of the laboratory. ### The Register and the End of the File The register should be used for the end of the file. The register should be used to improve the end of the file. The register should be used to verify the end of the file. The register should be used to verify the end of the file. The register should be used to improve the end of the file. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Record The register should be used for the end of the record. The register should be used to improve the end of the record. The register should be used to verify the end of the record. The register should be used to verify the end of the record. The register should be used to improve the end of the record. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Log The register should be used for the end of the log. The register should be used to improve the end of the log. The register should be used to verify the end of the log. The register should be used to verify the end of the log. The register should be used to improve the end of the log. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Entry The register should be used for the end of the entry. The register should be used to improve the end of the entry. The register should be used to verify the end of the entry. The register should be used to verify the end of the entry. The register should be used to improve the end of the entry. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Line The register should be used for the end of the line. The register should be used to improve the end of the line. The register should be used to verify the end of the line. The register should be used to verify the end of the line. The register should be used to improve the end of the line. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Row The register should be used for the end of the row. The register should be used to improve the end of the row. The register should be used to verify the end of the row. The register should be used to verify the end of the row. The register should be used to improve the end of the row. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Column The register should be used for the end of the column. The register should be used to improve the end of the column. The register should be used to verify the end of the column. The register should be used to verify the end of the column. The register should be used to improve the end of the column. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Table The register should be used for the end of the table. The register should be used to improve the end of the table. The register should be used to verify the end of the table. The register should be used to verify the end of the table. The register should be used to improve the end of the table. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Chart The register should be used for the end of the chart. The register should be used to improve the end of the chart. The register should be used to verify the end of the chart. The register should be used to verify the end of the chart. The register should be used to improve the end of the chart. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Graph The register should be used for the end of the graph. The register should be used to improve the end of the graph. The register should be used to verify the end of the graph. The register should be used to verify the end of the graph. The register should be used to improve the end of the graph. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Plot The register should be used for the end of the plot. The register should be used to improve the end of the plot. The register should be used to verify the end of the plot. The register should be used to verify the end of the plot. The register should be used to improve the end of the plot. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Figure The register should be used for the end of the figure. The register should be used to improve the end of the figure. The register should be used to verify the end of the figure. The register should be used to verify the end of the figure. The register should be used to improve the end of the figure. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Image The register should be used for the end of the image. The register should be used to improve the end of the image. The register should be used to verify the end of the image. The register should be used to verify the end of the image. The register should be used to improve the end of the image. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Picture The register should be used for the end of the picture. The register should be used to improve the end of the picture. The register should be used to verify the end of the picture. The register should be used to verify the end of the picture. The register should be used to improve the end of the picture. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Photo The register should be used for the end of the photo. The register should be used to improve the end of the photo. The register should be used to verify the end of the photo. The register should be used to verify the end of the photo. The register should be used to improve the end of the photo. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Snapshot The register should be used for the end of the snapshot. The register should be used to improve the end of the snapshot. The register should be used to verify the end of the snapshot. The register should be used to verify the end of the snapshot. The register should be used to improve the end of the snapshot. The register should be used to improve the quality of the laboratory. ### The Register and the End of the View The register should be used for the end of the view. The register should be used to improve the end of the view. The register should be used to verify the end of the view. The register should be used to verify the end of the view. The register should be used to improve the end of the view. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Scene The register should be used for the end of the scene. The register should be used to improve the end of the scene. The register should be used to verify the end of the scene. The register should be used to verify the end of the scene. The register should be used to improve the end of the scene. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Setting The register should be used for the end of the setting. The register should be used to improve the end of the setting. The register should be used to verify the end of the setting. The register should be used to verify the end of the setting. The register should be used to improve the end of the setting. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Environment The register should be used for the end of the environment. The register should be used to improve the end of the environment. The register should be used to verify the end of the environment. The register should be used to verify the end of the environment. The register should be used to improve the end of the environment. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Context The register should be used for the end of the context. The register should be used to improve the end of the context. The register should be used to verify the end of the context. The register should be used to verify the end of the context. The register should be used to improve the end of the context. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Situation The register should be used for the end of the situation. The register should be used to improve the end of the situation. The register should be used to verify the end of the situation. The register should be used to verify the end of the situation. The register should be used to improve the end of the situation. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Condition The register should be used for the end of the condition. The register should be used to improve the end of the condition. The register should be used to verify the end of the condition. The register should be used to verify the end of the condition. The register should be used to improve the end of the condition. The register should be used to improve the quality of the laboratory. ### The Register and the End of the State The register should be used for the end of the state. The register should be used to improve the end of the state. The register should be used to verify the end of the state. The register should be used to verify the end of the state. The register should be used to improve the end of the state. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Status The register should be used for the end of the status. The register should be used to improve the end of the status. The register should be used to verify the end of the status. The register should be used to verify the end of the status. The register should be used to improve the end of the status. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Position The register should be used for the end of the position. The register should be used to improve the end of the position. The register should be used to verify the end of the position. The register should be used to verify the end of the position. The register should be used to improve the end of the position. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Place The register should be used for the end of the place. The register should be used to improve the end of the place. The register should be used to verify the end of the place. The register should be used to verify the end of the place. The register should be used to improve the end of the place. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Location The register should be used for the end of the location. The register should be used to improve the end of the location. The register should be used to verify the end of the location. The register should be used to verify the end of the location. The register should be used to improve the end of the location. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Site The register should be used for the end of the site. The register should be used to improve the end of the site. The register should be used to verify the end of the site. The register should be used to verify the end of the site. The register should be used to improve the end of the site. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Area The register should be used for the end of the area. The register should be used to improve the end of the area. The register should be used to verify the end of the area. The register should be used to verify the end of the area. The register should be used to improve the end of the area. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Region The register should be used for the end of the region. The register should be used to improve the end of the region. The register should be used to verify the end of the region. The register should be used to verify the end of the region. The register should be used to improve the end of the region. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Zone The register should be used for the end of the zone. The register should be used to improve the end of the zone. The register should be used to verify the end of the zone. The register should be used to verify the end of the zone. The register should be used to improve the end of the zone. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Sector The register should be used for the end of the sector. The register should be used to improve the end of the sector. The register should be used to verify the end of the sector. The register should be used to verify the end of the sector. The register should be used to improve the end of the sector. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Division The register should be used for the end of the division. The register should be used to improve the end of the division. The register should be used to verify the end of the division. The register should be used to verify the end of the division. The register should be used to improve the end of the division. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Section The register should be used for the end of the section. The register should be used to improve the end of the section. The register should be used to verify the end of the section. The register should be used to verify the end of the section. The register should be used to improve the end of the section. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Part The register should be used for the end of the part. The register should be used to improve the end of the part. The register should be used to verify the end of the part. The register should be used to verify the end of the part. The register should be used to improve the end of the part. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Piece The register should be used for the end of the piece. The register should be used to improve the end of the piece. The register should be used to verify the end of the piece. The register should be used to verify the end of the piece. The register should be used to improve the end of the piece. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Segment The register should be used for the end of the segment. The register should be used to improve the end of the segment. The register should be used to verify the end of the segment. The register should be used to verify the end of the segment. The register should be used to improve the end of the segment. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Portion The register should be used for the end of the portion. The register should be used to improve the end of the portion. The register should be used to verify the end of the portion. The register should be used to verify the end of the portion. The register should be used to improve the end of the portion. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Share The register should be used for the end of the share. The register should be used to improve the end of the share. The register should be used to verify the end of the share. The register should be used to verify the end of the share. The register should be used to improve the end of the share. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Fraction The register should be used for the end of the fraction. The register should be used to improve the end of the fraction. The register should be used to verify the end of the fraction. The register should be used to verify the end of the fraction. The register should be used to improve the end of the fraction. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Percentage The register should be used for the end of the percentage. The register should be used to improve the end of the percentage. The register should be used to verify the end of the percentage. The register should be used to verify the end of the percentage. The register should be used to improve the end of the percentage. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Ratio The register should be used for the end of the ratio. The register should be used to improve the end of the ratio. The register should be used to verify the end of the ratio. The register should be used to verify the end of the ratio. The register should be used to improve the end of the ratio. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Proportion The register should be used for the end of the proportion. The register should be used to improve the end of the proportion. The register should be used to verify the end of the proportion. The register should be used to verify the end of the proportion. The register should be used to improve the end of the proportion. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Rate The register should be used for the end of the rate. The register should be used to improve the end of the rate. The register should be used to verify the end of the rate. The register should be used to verify the end of the rate. The register should be used to improve the end of the rate. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Frequency The register should be used for the end of the frequency. The register should be used to improve the end of the frequency. The register should be used to verify the end of the frequency. The register should be used to verify the end of the frequency. The register should be used to improve the end of the frequency. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Count The register should be used for the end of the count. The register should be used to improve the end of the count. The register should be used to verify the end of the count. The register should be used to verify the end of the count. The register should be used to improve the end of the count. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Number The register should be used for the end of the number. The register should be used to improve the end of the number. The register should be used to verify the end of the number. The register should be used to verify the end of the number. The register should be used to improve the end of the number. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Amount The register should be used for the end of the amount. The register should be used to improve the end of the amount. The register should be used to verify the end of the amount. The register should be used to verify the end of the amount. The register should be used to improve the end of the amount. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Quantity The register should be used for the end of the quantity. The register should be used to improve the end of the quantity. The register should be used to verify the end of the quantity. The register should be used to verify the end of the quantity. The register should be used to improve the end of the quantity. The register should be used to improve the quality of the laboratory. ### The Register and the End of the Volume The register should be used for the end of the volume. The register should be used to improve the end of the volume. The register should be used to verify the ## Frequently Asked Questions ### What is the difference between a reference material and a certified reference material? A reference material is a material with one or more property values that are sufficiently homogeneous and stable for use in the calibration of a method or the assessment of a measurement method. A certified reference material is a reference material with a certificate that states the property value, the uncertainty, and the traceability. The certificate is issued by a provider that operates under a quality management system. ### How do I verify the commutability of a reference material? The commutability of a reference material is established by the provider through a comparative study. The provider compares the reference material to native samples across multiple measurement systems. The provider documents the commutability in the certificate or in a separate publication. The laboratory should verify the commutability for the measurement systems it uses. ### What is the uncertainty of a reference material? The uncertainty of a reference material is a parameter that describes the dispersion of the values that could reasonably be attributed to the property value. The uncertainty is stated in the certificate with a coverage level. The laboratory should use the uncertainty to calculate the measurement uncertainty. ### How do I select a reference material for a diagnostic method? The laboratory should select a reference material with a matrix that matches the sample matrix, a commutability that is established for the measurement systems, and an uncertainty that is appropriate for the required precision. The laboratory should also verify the certificate information and the storage conditions. ### What is the role of the reference material in the calibration? The reference material is used to calibrate the measurement system. The calibration curve is constructed from the reference material values and the instrument responses. The calibration curve is then used to calculate the concentration of the analyte in the sample. ### What is the role of the reference material in the method validation? The reference material is used to verify the method. The method validation includes the calibration, the precision, the sensitivity, the specificity, and the recovery. The reference material is used to verify the calibration and the recovery. ### What is the role of the reference material in the quality control? The reference material is used to verify the quality control. The quality control includes the internal controls and the external controls. The reference material is used to verify the calibration and the stability of the method. ### What are the common failure patterns in the reference material selection? The common failure patterns include using a reference material with a wrong matrix, using a reference material with an unverified commutability, using a reference material with an inappropriate uncertainty, using an expired reference material, and using a reference material without documentation. ## Using the Evidence | Source | Best use in this topic | Important limitation | |---|---|---| | [Molecular Biology and Laboratory Methods](https://www.ncbi.nlm.nih.gov/books) | official guidance | Check the linked page for current local requirements | | [Biosafety in Microbiological and Biomedical Laboratories](https://www.cdc.gov/labs/bmbl/index.html) | official guidance | Check the linked page for current local requirements | | [NIH Guidelines for Recombinant or Synthetic Nucleic Acid Molecules](https://osp.od.nih.gov/policies/biosafety-and-biosecurity-policy/nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid-molecules) | official guidance | Check the linked page for current local requirements | ## Related Diagnostic Guides - [Laboratory Proficiency Testing: A Guide to Providers and Program Selection](/knowledge/diagnostics/emerging-tech/laboratory-proficiency-testing-a-guide-to-providers-and-program-selection) - [Method Validation in Clinical Laboratories: A Practical Protocol](/knowledge/diagnostics/emerging-tech/method-validation-in-clinical-laboratories-a-practical-protocol) - [Measurement Uncertainty in Laboratory Medicine: A Guide to Calculation and Reporting](/knowledge/diagnostics/emerging-tech/measurement-uncertainty-in-laboratory-medicine-a-guide-to-calculation-and-reporting) - [Laboratory Quality Management System Certificate Program: What to Expect and How to Choose](/knowledge/diagnostics/emerging-tech/laboratory-quality-management-system-certificate-program-what-to-expect-and-how-to-choose) ## References and Further Reading - [Molecular Biology and Laboratory Methods](https://www.ncbi.nlm.nih.gov/books). National Library of Medicine. - [Biosafety in Microbiological and Biomedical Laboratories](https://www.cdc.gov/labs/bmbl/index.html). CDC and NIH. - [NIH Guidelines for Recombinant or Synthetic Nucleic Acid Molecules](https://osp.od.nih.gov/policies/biosafety-and-biosecurity-policy/nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid-molecules). National Institutes of Health. - [Addgene Protocols](https://www.addgene.org/protocols). Addgene. - [MIQE Guidelines](https://academic.oup.com/clinchem/article/55/4/611/5631762). Clinical Chemistry. - [NIST Laboratory Programs](https://www.nist.gov/laboratories). National Institute of Standards and Technology. - [Laboratory Biosafety Manual](https://www.who.int/publications/i/item/9789240011311). World Health Organization. - [NCBI Literature Resources](https://www.ncbi.nlm.nih.gov/). National Center for Biotechnology Information. - [Commutability assessment of reference materials for homocysteine.](https://pubmed.ncbi.nlm.nih.gov/35977428). Clinical chemistry and laboratory medicine, 2022. - [Development of reference materials for amphetamines in hair.](https://pubmed.ncbi.nlm.nih.gov/41215677). Analytical methods : advancing methods and applications, 2025. - [Selection and use of reference panels: a case study highlighting current gaps in the materials available for foot and mouth disease.](https://pubmed.ncbi.nlm.nih.gov/34140727). Revue scientifique et technique (International Office of Epizootics), 2021. > This article is educational and does not replace validated laboratory procedures, institutional biosafety review, manufacturer instructions, or professional interpretation.