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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.
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
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.
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.
The author says...
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
Many providers of reference solutions for conductivity and TOC are accredited to ISO guides and standards. The two most common are ISO 9001 Quality Management Systems, which shows that the provider has a quality system programme, and ISO/IEC 17025: General Requirements for Competence of Testing and Calibration Laboratories, which demonstrates that the provider can conduct measurements.
Not all providers possessing the above accreditations, however, are accredited to supply CRMs. ISO Guide 34: General Requirements for the Competence of Reference Material Producer accreditation provides confidence that the provider is technically competent to supply CRM for use in testing that are traceable, homogeneous and stable for the intended use. These three elements are documented in accordance with ISO Guide 31: Reference Material Content of Certificate and Labels and the content of the certificate is established using appropriate statistical procedures identified within ISO Guide 35: General Statistical Principles for Certification.12–16
Only a provider accredited to ISO Guide 34 complies with ISO Guide 31 and 35 through their scope of accreditation, providing confidence that the CRM meets all requirements for use.17,18
As a whole, the international laboratory community is gravitating to ISO/IEC 17025 accreditation, which necessitates the use of CRMs. The technical requirements of ISO/IEC 17025 for a laboratory to use CRMs are referenced in section 5.6 Measurement Traceability (18.104.22.168, 22.214.171.124 and 126.96.36.199) and again in section 5.9 Assuring the Quality of Test Calibration Results (5.9.1). These references within ISO/IEC 17025 would yield a higher level of quality for instrument calibrations.14
Historically, laboratory technical management have not scrutinised the providers of reference solutions used in pharmacopoeia monographs. However, it is very important that the quality of these solutions be questioned and verified beyond the presumptions made solely on the basis of ISO 9001 certification. Justification should be established as to why the laboratory has deemed the reference solutions appropriate for use with a particular monograph.
Utilising CRMs for monograph compliance will address these quality and acceptance concerns. CRMs supplied by an accredited provider under ISO Guide 34 assure laboratories that the technical concerns have been appropriately addressed. The Certificate of Analysis will document the robust determinations for the user and also supply all necessary documentation for any authoritative agencies, such as the FDA or the European Medicines Agency. With ISO Guide 34 accreditation, the technical competence of a CRM provider is assured and no further investigation into the requirements of the reference solution is necessary.
Water purity testing following the EP and USP monographs is critical for the production of pharmaceutical products. The use of a CRM for the reference solution employed to determine regulated water quality ensures that the testing process is controlled and documented in accordance with international standards. Questionable water quality during production can potentially lead to an outofspecification (OOS) condition and subsequent costly investigations regarding the water quality used in a particular product or batch. These investigations can be time consuming, subjective and difficult to support because the water used in production will almost certainly have been consumed. As such, the proper use of a documented CRM reference solution is essential for pharmaceutical companies.
A laboratory performing analyses in accordance with EP or USP monographs should review the accreditation of their reference solutions' provider — as a minimum, accreditation to ISO Guide 34 should be required. Reviewing the scope of the ISO Guide 34 is also recommended to ensure that each reference solution is contained in the provider's scope. Do not confuse accreditation to ISO 9001 and/or ISO/IEC 17025 with ISO Guide 34, because although the provider may have a documented quality system and the ability to measure a reference solution, they may not have the required documented technical competency to manufacture a CRM. Providers that are ISO Guide 34 accredited, on the other hand, and that have conductivity and TOC in their scope of accreditation, will provide independent, reliable and highquality reference solutions that can be used with associated monographs. By appropriately choosing a provider, the user will assure compliance with USP, EP and ISO/IEC 17025.
Jeffrey C. Lowry is Director of Technology at ERA — A Waters Company.
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1. European Pharmacopoeia, General Notices 07/2009:10000 1.4 Monographs, pp. 4761–4764 (EDQM, France, 2009).
2. US Pharmacopeia 32-NF 27, General Chapter USP Reference Standards <11>, pp. 35–58 (USP Convention, USA, 2009).
3. European Pharmacopoeia, 01/2009:1927 Water Highly Purified, pp. 4342–4344 (EDQM, France, 2009).
4. European Pharmacopoeia, 01/2008:20238 Conductivity, pp. 59–60 (EDQM, France, 2009).
5. European Pharmacopoeia, 01/2008:20244 Total Organic Carbon in Water for Pharmaceutical Use, pp. 71 (EDQM, France, 2009).
6. US Pharmacopeia 32-NF 27, General Chapter USP Total Organic Carbon <643>, pp. 239–240 (USP Convention, USA, 2009).
7. US Pharmacopeia 32-NF 27, General Chapter USP Water Conductivity <645>, pp. 240–242 (USP Convention, USA, 2009).
8. European Pharmacopoeia, 01/2008:51200 Reference Standards, pp. 663–666 (EDQM, France, 2009).
9. ISO Guide 30, Terms and Definitions used in Connection with Reference Material (Second edition, 1992).
10. ISO Guide 30, Amd.1:2008 Terms and Definitions used in Connection with Reference Material, Amendment 1 Revision of Definitions for Reference Material and Certified Reference material, (Second edition, 1992; Amendment 1, 2008).
11. ISO/IEC Guide 99, International Vocabulary of Metrology Basic and General Concepts and Associated Terms (VIM) (First edition, 2007).
12. ISO 9001, Quality Management Systems – Requirements (Fourth edition, 2008).
13. ISO 9001, Quality Management Systems – Requirements (Fourth edition corrected version, 2009).
14. ISO/IEC 17025, General Requirements for Competence of Testing and Calibration Laboratories (Second edition, 2005).
15. ISO Guide 34, General Requirements for the Competence of Reference Material Producer (Second edition, 2000).
16. ISO Guide 34, General Requirements for the Competence of Reference Material Producer (Third edition, 2009).
17. ISO Guide 31, Reference Material Content of Certificate and Labels (Second edition, 2000).
18. ISO Guide 35, General Statistical Principles for Certification (Third edition, 2006).