Reference standards availability/source

The expiration date is also an important consideration in terms of source and availability of the reference substance. Based on the study design, expiration date and amount of reference standard available, the analyst must determine if a new lot of reference standard will be required at some future date to support on-going stndy sample analyis. If it appears that the standard will be consumed or will expire prior to the completion of the study, the client should be contacted immediately to discuss the need to identify a source for additional material. In some instances, a new... 

Estimating the amount of a metabolite when an authentic reference standard is not available is still a challenge. Yu et al.191 described a procedure that uses the results of an in vitro metabolite identification based on a test compound that produces 14C-labelled metabolites essentially the 14C-labelled metabolites are used to provide a correction factor for the MS response when assaying samples that contain the same metabolite in a study that did not use the 14C-labelled test compound. Flop192 described another novel approach for metabolite quantitation based on the observation that the MS responses for most compounds are very similar to responses from nanospray ESI. Valaskovic et al.193 also reported equimolar MS responses for multiple compounds when the flow rate to the nanospray ESI source was set to about 10 nl/min. It is too soon to know whether these intriguing findings can be readily applied to discovery metabolite identification studies. 

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. 

When the criticality and complexity (Refer to Appendix D) of the computer system requires that standard product source code be made available, the legal department of the pharmaceutical company should negotiate one of the following written agreements with the software developer. 

Of additional benefit to enantioselective POP separations is the quantification of enantiomer compositions in standardized reference materials, available from sources such as the US National Institute of Standards and Technology (NIST) and Environment Canada [105, 106]. Such materials are intended for quality assurance/quality control in sample processing and instrumental analysis of their respective matrices, and enantiomer quantification extends this use to enantioselective studies. 

While compendial standards are available for some monographed article impurities, it may be difficult at times to obtain pure standards of impurities. Manufacturers of pharmaceuticals function as a potential source for obtaining reference standards of impurities, which may be synthesis precursors, process intermediates, or degradation products. The characterization and evaluation of these impurities reference standards should be constant with their intended use. In many cases, analytical procedures are developed and validated, where the response of an impurity is compared to that of the new drug substance itself. Response factor evaluation of impurities at the chosen detection wavelength is necessary to determine if a correction factor is needed (when the responses differ). Potentiometric detection, fluorescence/ chemiluminescence detection, and refractive index detection are some examples of detection modes available for compounds that may not be suitable for UV detection. 

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. 

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). 

In addition to federal regulations, additional state, county, and local regulations may also apply. In no way should the above discussion on governmental regulation be considered inclusive and the reader is referred to other sources, particularly those found in the Code of Federal Regulations available on the Internet, These include 29 CFR 1910,120 Hazardous Waste Operations and Emergency Response (HAZWOPER), Respiratory Standards are found in 29 CFR 1910,134, and 42 CFR 84 is the location of the new NIOSH CBRN standards, and a fisting of NIOSH-approved CBRN equipment,... 

Rubber Company Handbook (Weast, 1987) is one of the more commonly available sources. More complete sources, including some with data for a range of temperatures, are listed in the references at the end of the chapter. Note that many tabulations still represent these energy functions in calories and that it may be necessary to make the conversion to Joules (1 cal = 4.1840J). Because of the definition of the energy of formation, elements in their standard state (carbon as graphite, chlorine as CI2 gas at one bar, bromine as Br2 liquid, etc.) have free energies and enthalpies of formation equal to zero. If needed, the absolute entropies of substances (from which AS may be evaluated) are also available in standard sources. 

Reagents and reference materials Likely will change but should have some documentation on early characterization Continue to screen for optimal reagents Lot no. and history (notebook reference) Evaluate different reagents and identify critical reagents Determine if sufficient quantities are available and their stability for later bioanalytical needs Include C of A for reference materials in assay validation documents Keep records of source and lot no. Use optimized capture/ detection reagents Use characterized reference standard from final manufacturing process with Cof A Record all lot nos. and sources... 

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. 

Measurement of the energy of a y-ray emitted (or absorbed) in a recoilless event registers information only about the immediate chemical environment of the emitting (or absorbing) nucleus. Mdssbauer experiments are performed by comparison of a source and an absorber, and it is usual to utihse a source without hyperfine effects as a reference standard for a series of absorber experiments. This is not the only option available, however. If we use a reference absorber, it is possible to study hyperfine effects in the source. These are produced by the chemical environment in which the excited-state Fe nucleus finds itself when it is generated in the source matrix. The total concentration of the Co parent atoms is very small indeed, and each atom can therefore be considered as an isolated impurity in the source matrix. 

Reference standards from reputable sources (WHO or national standards) should be used, if available otherwise the reference substance(s) for the active ingredients) should be prepared, tested and released as reference material(s) by the producer of the investigational pharmaceutical product, or by the producer of the active ingredients) used in the manufacture of that product... 

Reference Material. In contrast to small molecules where reference standards are well characterized and certified standards are often commercially available from sources such as the U.S. Pharmacopeia, the European Pharmacopoeia, or the World Health Organization (WHO), proteins are often not as rigorously characterized and their purity may vary from supplier to supplier. Variation in posttransla-tional modifications such as glycosylation and deamidation may be present. Thus, the proteins can vary in their potency and immunoreactivity. As the reference compounds are used as standard calibrators, validation sample and QC sample variation of the reference will have a profound impact on the assay performance. Therefore, it is important to clearly document the source of the material and to characterize the proteins as thoroughly as possible. Comparability between lots or sources should be evaluated if possible. If the analyte is not a new drug entity, the innovator company is typically the most reliable source of authentic material. As stated for the reagents, stability of the reference compounds is an issue that has to be ensured. 

All instrumental analytical methods except coulometry (Chapter 15) require calibration standards, which have known concentrations of the analyte present in them. These calibration standards are used to establish the relationship between the analytical signal being measured by the instrument and the concentration of the analyte. Once this relationship is established, unknown samples can be measured and the analyte concentrations determined. Analytical methods should require some sort of reference standard or check standard. This is also a standard of known composition with a known concentration of the analyte. This check standard is not one of the calibration standards and should be from a different lot of material than the calibration standards. It is run as a sample to confirm that the calibration is correct and to assess the accuracy and precision of the analysis. Reference standard materials are available from government and private sources in many countries. Government sources include the National Institute of Standards and Technology (NIST) in the US, the National Research Council of Canada (NRCC), and the Laboratory of the Government Chemist in the UK. 

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