How Certified Reference Materials Help Labs Meet Regulatory Requirements

by | Clinical, Food, Molecular, Pharmaceutical, Water | 1 comment

Publish Date: July 26, 2018

As regulatory standards continue to increase, additional responsibility is being placed on laboratories to ensure the quality and safety of finished products. Now more than ever, traceability is a major concern. Laboratories are required to provide evidence that the reference materials being used for method validation and process controls are fit-for-purpose, homogenous, and stable. Certified reference materials (CRMs) are designed to meet these stringent standards.

What Is a CRM?

ISO 17034 defines a reference material as material that is “sufficiently homogenous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process. Properties can be quantitative or qualitative (e.g., identity of substances or species).” A CRM is different than a reference material in that it is accompanied by a certificate, has metrological traceability, and each property value has an uncertainty value assigned to it. Once property values are assigned to a CRM, the values are “stored” by the CRM and then transferred when the CRM itself is transported from one location to another.

To become a CRM producer, the producer’s methods must meet the requirements of ISO 17034:2016 General Requirements for the Competence of Material Producers. To receive ISO 17034:2016 accreditation, the producer must demonstrate that they are competent to supply CRM.

ISO 17025 has now been updated to its newest version, ISO 17025:2017.  Section A.3.1 of ISO 17025:2017 discusses demonstrating metrological traceability.  It states that “Laboratories are responsible for establishing metrological traceability in accordance with this document. Calibration results from laboratories conforming to this document provide metrological traceability. Certified values of certified reference materials from reference material producers conforming to ISO 17034 provide metrological traceability.”

Advantages and Uses

As technology improves over time, the ability and need to measure more precisely and accurately increases. This drives the need for better reference materials to be used in testing and calibration. CRMs provide metrological traceability and known uncertainty for the property values of the material. CRMs can ensure reliable measurements for users. Traceability is provided via a certificate that documents the property values, the uncertainty, and the authoritative issuing body.

Users of CRMs are responsible for determining if the CRM is appropriate for their intended use. The user must follow all labeling instructions provided by the CRM producer. This includes handling and storage, shelf life, and instructions for use. Failure to follow all CRM labeling could invalidate testing results for the user.

ISO 17025 Section states that “The laboratory shall validate non-standard methods, laboratory-developed methods and standard methods used outside their intended scope or otherwise modified. The validation shall be as extensive as is necessary to meet the needs of the given application or field of application. Including calibration or evaluation of bias and precision using reference standards or reference materials.”  Section 7.7.1 states that “The laboratory shall have a procedure for monitoring the validity of results. Including the use of reference materials or quality control materials.”

Common Uses of CRMs Include:

  • Method validation. A laboratory or factory may need to validate the methods or equipment used for measuring or detecting a substance. A CRM may be used to validate the measurement method or the ability to detect a substance.
  • Method verification. A laboratory may need to check the process at any time to ensure the process is continuing to measure and detect as initially validated. For example, a CRM can be used to check a process and determine if a nonconformance has occurred and troubleshooting is necessary.
  • Calibration. CRMs that are a pure substance can be utilized for calibration of equipment, which is intended to detect or measure that substance, or the CRM can be used as an independent check of the calibration.
  • Method monitoring or process control. CRMs can be used continuously to provide evidence that processes are stable and continue to measure and detect as required.
  • Training. A laboratory may use CRMs to train and/or evaluate operators by using a substance that has a known identity and property values.

CRM in Microbiology

Detection and control of microorganisms in food processing applications may require the use of CRMs. There are currently a limited number of options for microbiological CRMs. When choosing a microbiological CRM producer, one should look for the following attributes:

  • Stability and shelf life. Make sure the CRM meets the laboratory’s specific needs.
  • Handling and storage requirements. Consider the ease-of-use and preparation time for all available options.
  • Traceability. Using a microorganism with known property values allows it to be distinguished from other strains of the same species that may be found in the user’s laboratory or products.

Obtaining CRM

A number of CRM databases are available that can assist in finding a CRM to meet  a laboratory’s unique needs. The AOAC Technical Division on Reference Materials (TDRM) has an established database to assist users in finding CRMs. In addition, TDRM offers a Reference Material/Method Matching list. Anyone can submit the reference material methods to be considered for inclusion on the AOAC website. AOAC has a documented process for reviewing and recommending publications.

Other databases available for finding CRMs include the COMAR International database for CRM, the Virtual Institute for Reference Materials (VIRM), and European Reference Materials (ERM).

If CRMs are not available, laboratories must determine if another reference material is available that will meet their testing needs. In Policy on Reference Material Traceability for Life Sciences Testing Laboratories, A2LA outlines four categories of reference materials as alternatives if CRMs are not available.

Other options include a proficiency testing program, which allows one to compare results against results from other laboratories. Care must be taken when utilizing a proficiency program as there may be method bias from the different laboratories. In addition, material used in other laboratories may not be homogenous or stable.

Spiking is another option to consider for method validation if CRMs are not available. Spiking involves taking an actual sample and injecting a known amount of the material to be measured or identified. This method does not provide traceability but can demonstrate a laboratory’s ability to measure or detect a given substance.

In-house reference materials may also be considered if sufficient testing has been conducted to show the material is homogenous and stable.

Key Takeaways

CRMs have become increasingly important to the laboratory’s evidence of compliance to new FDA regulation. In addition, many accrediting bodies require companies to use CRMs in their processes to provide traceability. The use of CRMs plays an integral role in meeting traceability requirements for regulatory standards.

If your laboratory uses CRMs, visit our website to find the strains you need for QC in easy-to-use qualitative and quantitative formats.

Read Next – What Auditors are Looking for in Food Microbiology Labs


Written by Tina Sobania

Tina Sobania, M.S., is the Director of Corporate Quality at Microbiologics where she leads the Quality Systems and Technical Support departments. Tina has over 20 years of medical device quality system and regulatory experience. She earned her bachelor’s degree in manufacturing engineering from St. Cloud State University and holds a Master of Science from the University of St. Thomas.

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1 Comment

  1. Raffaella Giardino

    Thank you very much, a very thorough and helpful article, with all the references, exactly what I was looking for!


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