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Calibration, Qualification & Validation

Certified Reference Materials for Calibration and Method Validation

Reference materials are substances having homogenous and well-established values of one or more properties. They play a vital role in ensuring accuracy of measurements through method calibration, validation of a measurement method, estimation of measurement uncertainty, or assigning values to materials.

They are a critical component of analytical testing workflows and broader quality assurance schemes. Manufactured under stringent requirements, reference materials differ from other lab reagents in their certification and traceability of the data provided. The world of reference materials is vast and includes Certified Reference Materials (CRMs) and other quality grades of reference materials and concepts like certificates of analysis and metrological traceability.



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Certified Reference Materials are indispensable for the exact titer determination in general and Karl Fischer Titrations. They are also important for the exact calibration of analytical instruments like pH meters, AAS – Atomic Absorption Spectrometers, ICP – Inductively Coupled Plasma Spectroscopy, HPLC – High Performance Liquid Chromatography, LC - Liquid Chromatography, GC- Gas Chromatography and IC – Ion Chromatography.

Reference materials are a critical component of analytical testing workflows and broader quality assurance schemes. They are manufactured under stringent requirements and differ from other laboratory reagents in the certification and traceability of the data provided. From Certified Reference Materials (CRMs) and other quality grades of reference materials to certificates of analysis, metrological traceability, and other concepts, the world of reference materials is vast, and at times, confusing.

Reference materials are classified into five major categories based on their quality grades, from national metrology and other primary standards to Certified Reference Materials (CRMs), Reference Materials (RMs), Analytical Standards, and research grade or research chemicals. The certification and traceability requirements increase from one quality grade to the higher one. The top-level is given standardization by the national governments, whereas specific ISO guidelines provide standardization for CRMs and RMs. These ISO requirements include ISO 17034, ISO/IEC 17025, and ISO Guide 31.

Reference material producers must meet these ISO requirements to manufacture CRMs or RMs. For Certified Reference Materials, a Certificate of Analysis must be provided, and the information contained within is defined by the earlier mentioned ISO guidelines. The quality specifications for the last two levels are outlined by each independent producer rather than by a national government or ISO accreditations specific to CRMs and RMs.

Choosing the Correct Reference Material for your Testing Purpose

National Metrology Standard (e.g. NIST, JRC, NMI Australia)
Compendial Standard (e.g. USP, EP, BP, JP, IP)

  • Issued by an authorized body
  • Considered to provide the highest level of accuracy and traceability

Certified Reference Material (CRM) (ISO 17034, 17025)

  • Considered to provide the highest level of accuracy, uncertainty, and traceability to an SI unit of measurement
  • Manufactured by an accredited Reference Material Producer

Reference Material (RM) (ISO 17034)

  • Fulfilling ISO requirements which are less demanding than for CRMs
  • Manufactured by an accredited Reference Material Producer

Analytical Standard (ISO 9001)

  • Certificate of Analysis available
  • Level of certification varies

Reagent Grade / Research Chemical

  • May come with a Certificate of Analysis
  • Are not characterized for use as reference materials

Figure 2. The Hierarchy of Reference Materials - What Are the Different Types?

Depending on the method requirements or product availability, reference materials are used in three different formats ‒ powder, solution, or matrix. Selection of the right reference material is of critical importance to a laboratory’s testing application, since results are only as accurate as the reference.

 Selection of reference materials based on testing purpose

The qualification and calibration of instruments require the maintenance and establishment of its traceability. The selected reference material helps a laboratory to achieve this. In daily routine system suitability applications, it might be important to qualify a reference material which is practical and easy to use, yet reliable and cost-effective for everyday use. In method validation, the use of highly accurate and precise reference materials is critical to show that the laboratory method is accurate and precise. For identity and screening purposes, important attributes of reference materials include proven authenticity and identity. In applications involving quantitation, assays, or stability assessments stable and accurate reference materials are required.

Table 1.Use for reference materials - type of test

The selection of Fit-for-purpose reference materials can depend on several factors such as regulatory requirements, availability, type of testing application, level of accuracy, and sample matrix.

Table 2.Fit for purpose guidance in standard selection
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