Reference standards certification

National Institute of Standards and Technology (NIST). The NIST is the source of many of the standards used in chemical and physical analyses in the United States and throughout the world. The standards prepared and distributed by the NIST are used to caUbrate measurement systems and to provide a central basis for uniformity and accuracy of measurement. At present, over 1200 Standard Reference Materials (SRMs) are available and are described by the NIST (15). Included are many steels, nonferrous alloys, high purity metals, primary standards for use in volumetric analysis, microchemical standards, clinical laboratory standards, biological material certified for trace elements, environmental standards, trace element standards, ion-activity standards (for pH and ion-selective electrodes), freezing and melting point standards, colorimetry standards, optical standards, radioactivity standards, particle-size standards, and density standards. Certificates are issued with the standard reference materials showing values for the parameters that have been determined. 

Isotope ratios are given as deviations, in relation to a defined primary standard (zero point). The polyethylene foils CH 7 and NBS 22-oil are commercially available secondary standards, certificated and managed by the International Atomic Energy Agency. However, GC-lRMS systems cannot be calibrated without the aid of alternative peripheries like an elemental analyser (EA) or a dual inlet, owing to the lack of commonly accepted reference materials applicable in GC-IRMS techniques (Fig. 17.11). 

The source and lot number, expiration date, certificates of analyses when available, and/or internally or externally generated evidence of identity and purity should be furnished for each reference standard. 

This information should be included in documentation such as the certificate of analysis (CoA), test article characterization (TAC), and reference standard profile. Certified reference standards can be purchased from appropriate suppliers. If standards are not available, the recommendation is to collect or synthesize enough material, and analyze, certify, and use it as the standard. Following are some considerations ... 

To make sure that all the values used in the measurement equation and all other fixed values used in the measurement are traceable, it is necessary to establish procedures for calibration of the measuring equipment or for controlling fixed values, and for ensuring the calibration, certification or control of all the references used in the measurement. Calibration, together with validated methods, is therefore the key to traceability. In practice, it is recognised that calibrated and certified reference standards are not always available, but it is always necessary to establish sufficient control through the appropriate choice of measurement standards. 

More than 220 producers of CRMs throughout the world produce today 12,000 20,000 materials with dif ferent matrixes, analytes and properties [4]. However, many testing (analytical) laboratories cannot find suitable CRMs in the market and develop in-house reference materials (IHRMs) themselves. Often IHRMs are developed in a laboratory to conserve the corresponding expensive CRMs. For example, a pharmaceutical company Chemagis Ltd. produces 30 active pharmaceutical ingredients steroids, benzodiazepines, antihistamines, hipolipidaemics, blood flow reactants, etc. Only for a few of them Mo-metasone Furoate, Fluticasone Propionate and Dobutamine Hydrochloride are of fi-cial reference standards for assay supplied by US, British and European Pharmacopoeias with prices of about 180 per unit (50 200 mg). Thus, to support its customers Chemagis is forced to develop IHRMs for assay as well as for impurities and related substances of each produced compound. Therefore, certification of such IHRMs that leads to traceable values is very important. 

Reference Standard. If an international reference standard (WHO, NIBSC) or compendial reference standard (USP) is used, the applicant should submit the citation for the standard and a certificate of analysis. If an inhouse working reference standard is used, a description of the preparation, characterization, specifications, and testing and results should he provided. 

Provide the certificates of analysis for drug substance, drug product, and reference standard for the lots where the samples were obtained. 

US Department of Commerce, National Bureau of Standards Certificate of Analysis, Standard Reference Material 1567, Wheat Flour, Washington, D.C., 1978 Standard Reference Material 1568, Rice Flour Standard Reference Material 1570, Spinach Standard Reference Material 1571, Orchard Leaves Standard Reference Material 1573, Tomato Leaves Standard Reference Material 1577, Bovine Liver. 

Active ingredients (reference standards) and their certificate of analysis... 

The testing and qualification of reference standards should continue such that the necessary documentation (internal and external reports, certificates of analysis, stability reports, supporting raw data) is complete from both a regulatory and scientific standpoint at the time of the NDA filing. 

Reference standards enter the laboratories under adequate control. These procedures typically identify approved sources and specify the documentation (certificates of analysis, qualification reports) that must accompany the reference standard into the laboratory. The accompanying documentation must be available during a GMP inspection. 

The water sample is obtained from the Environmental Laboratory Approval Program. We have used ICP-AES multi-element Reference Standard supplied by E. Merck with Lot. No 0C030033 for standard calibration. These standards have certified data obtained from NIST as third-generation traceability, assuring reasonable accuracy in the estimations (Certificate of Analysis, Certipur - Reference Material 11355 ICP multielement standad IV made from NIST standards reference materials, Lot No. 0C030033. Dr. Harald Untenecker, Central Analytical Laboratory, Merck). An echello-gram showing all the elements is attached. 

Certified Reference Standards (Standard Reference Materials, SRMs) for clinical laboratories are available ffom the NIST and the IRMM. Cholesterol, the first SRM developed by the NIST, was issued in 1967. Today, the lists from the NIST and IRMM are extensive (Table 1-10 and Table 1-11, respectively). Not aU standard reference materials have the properties and the degree of purity specified for a primary standard, but each has been well characterized for certain chemical or physical properties and is issued with a certificate that gives the results of the characterization. These may then be used to characterize other materials. 

Lab notebooks and certificates of analysis for reference standards, clinical and registration batches, etc. 

TABLE 3 Analytical Tests for Certification of Reference Standards... 

The selection materials and samples to be used in the transfer should be described in detail. In general, one does not choose GMP released materials for transfer activities because the result of not meeting the predetermined acceptance criteria could be an out-of-specification (OOS) investigation. The identity and lot numbers of specific batches should be given. If possible, certificates of analysis for all samples, including reference standards, should be supplied. The instrumentation should be... 

Physical-chemical characterization Reference standard characterization Specifications and analytical methods Certificates of analysis... 

Thus the European policies tackling standards, certification and labelling have been quite successful in overcoming the major difficulties in developing standards and have established an efficient certification system. Although in both areas, private systems exist in addition to the European system, the European system has become the point of reference — even for those interested in stricter systems. 

Selection of a reference standard for most analytical methods is a straightforward task, involving acquisition of the relevant analyte in a state of known composition and purity. However, some analytes are not available in pure form, and structurally similar analogs (e.g. free base) may be used instead. Standard materials should be of a known purity, and the source, lot number, expiration date and certification of identity should be recorded (FDA, 2001). 

N.S. with another project. Since their main business is to prepare certified reference standard solutions for their customers, their laboratory workers spend much time running tests on these solutions to assure their quality. For example, the atomic absorption standard solutions that were earlier suspected by their lab as being contaminated must have a concentration of the indicated metal of 1000 ppm. Their quality assurance laboratory runs quality checks daily on these solutions and the solutions cannot be sold until the laboratory issues the certificate that states that they indeed have the required concentration. In addition, an expiration date must be stamped on the labels of these solutions and so, occasionally, they run tests on solutions that have been manufactured previously but not shipped. 

Purity or potency of the reference-standard compound must be documented. A certificate of analysis should be obtained from the supplier. Whenever possible, a universal concentration or activity unit should be used to provide a constant basis for comparison among studies. 

At a minimum, documentation of the characterization and stability of a standard, such as a certificate of analysis (Co A) and/or a certificate of stability (CoS), is typically available from the suppliers. The certificate should be obtained and recorded. The quantity of reference standard is typically limited in commercial kits designed for research use, and it is not uncommon that the reference material values may differ substantially between lots and manufacturers [16]. Novel biomarkers rarely have established gold standards against which their potency and abundance can be calibrated. A comparison of available sources can be useful, and when validating an assay for advanced applications it is desirable to plan ahead to obtain and reserve a sufficient supply of the same reference material. The example in Fig. 6.5 compares three reference standard curves, each prepared from a concentrated stock solution from a commercial supplier, an in-house reference standard, and a commercial kit, respectively. The instrument responses (optical density, OD) were highest with the standard from the commercial stock, the lowest with the kit, while the in-house reference standard response was intermediate. In this case, either the same commercial stock or the in-house reference standard can be used throughout the clinical study. 

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