Using Certified Reference Material To produce Compliant Water Purity Data - Pharmaceutical Technology

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Using Certified Reference Material To produce Compliant Water Purity Data
Pharmacopoeial monographs often prescribe reference material for regulated analytical testing methods; however, there are apparent inconsistencies between the use of these reference materials and the manufacture of the reference solutions that are actually used in the regulated test method. The author discusses the qualifications necessary for providers to competently supply reference solutions for regulated water purity testing under pharmacopoeia guidelines.


Pharmaceutical Technology Europe
Volume 22, Issue 10


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Both the US and European Pharmacopoeias require the use of reference material (RM) in their monographs. Within the European Pharmacopoeia (EP), RM is identified in General Notices 10000 section 1.4 Monographs. It is prescribed in certain monographs and is available from the EP via the European Directorate for Quality of Medicines and Healthcare (EDQM). Within the US Pharmacopeia (USP), RM is described in General Chapter 11 USP Reference Standards. USP Reference Standards are also prescribed in certain monographs under the authority of the US Pharmacopeia Convention (USPC) Board of Trustees following the recommendation of the USP Reference Standards Expert Committee. Specifically, these references require the use of RM in relation to the physical tests and determinations under each of the monographs for water purity when performing tests for conductivity and total organic carbon (TOC). As examples, the EP requires the use of certified reference material (CRM) solutions in both monographs 1927 Water Highly Purified and 20238 Conductivity for system calibration. The USP requires the use of USP References Standards in the monograph USP 643 TOC for calibration and system suitability. The RM cited in these monographs is supplied by both the USP and the EDQM as neat or pure material. The TOC monographs require the use of sucrose and 1,4benzoquinone, while the conductivity monographs reference sodium chloride as a RM.1–6

Accreditation of RM providers

The monographs contain specific instructions regarding the use of neat RM to produce reference solutions, which are used in the actual pharmacopoeia test method. These solutions are internationally referred to as working measurement standards, and are prepared by dissolving a known amount of a chemical substance (in this case the neat RM) into a known volume of solution. Analysis of these solutions on a conductivity or TOC instrument is required to meet certain criteria within the monograph, such as routine system suitability checks and calibration performance.


The author says...
Historically, thirdparty vendors, such as instrument manufacturers, instrument service providers and standards manufacturers, have used RM supplied by each pharmacopoeia to provide reference solutions that comply with the necessary requirements. However, the user should be aware that although it may be convenient to use an instrument and/or service provider for the supply of reference solutions, it is very important to take into consideration not only the provider's capabilities to comply with pharmacopoeia requirements, but also the accreditations possessed. Until now, the requirements of these companies' accreditations to supply these working standards has not been made mandatory.

RM as defined by the EP can be found in section 51200 Reference Standards, which defines RM in the same manner as the International Standards Organization (ISO). ISO Guide 30;1992 Terms and Definitions used in Connection with Reference Material and ISO Guide 99:2007 International Vocabulary of Metrology Basic and General Concepts and Associated Terms both have similar definitions for measurement standards. ISO Guide 30:1992 defines RM as: "Material, sufficiently homogeneous and stable with respect to one or more specific properties, which has been established to be fit for its intended use in a measurement process." CRM is defined in EP and ISO Guide 30 as: "Reference material characterised by a metrologically valid procedure for one or more specific properties accompanied by a certificate that provides the value of the specific property, its associated uncertainty, and a statement of metrological traceability." CRM is accompanied by documentation issued by an authoritative body under an accreditation upon which the provider has been proven competent.

RM, as defined by both the EP and USP, applies only to the neat material supplied and prescribed for use in the pharmacopoeia. There are no instructions in the monographs that specify the preparation of the reference solution. Therefore, the actual performance of the preparation of the reference solution from the RM doesn't contain the traceability needed to assure the quality of the solution used in the test method. As such, the reference solutions supplied — and upon which the calibration and system suitability are performed — are not actually the RM referenced in the monographs. Reference solutions provided by third parties should be produced as CRMs, such that the user is confident of the traceability, homogeneity and stability of the solutions for their testing.7–11


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