Reference standard characterization

Uncertainties associated with qualitative analysis and with purity assessment, especially at the reference standards characterization, are subjects of increasing attention of the metrological and the analytical communities [18, 19, 20, 21, 22, 23]. 

Reference Standard. Characterization and structure elucidation data are typically derived from tests conducted on the primary reference standard. Its suitability must be documented by information much more extensive than prescribed in the specifications. In addition to the prescribed analyses—especially levels of impurities—other tests normally conducted include elemental analysis and ultraviolet, infrared, nuclear magnetic resonance, and mass spectrometry, along with reviews of each providing assignments of the important features supporting the structure(s) of the drug substance. Other tests such as... 

Ultraviolet-Visible Spectroscopy Ultraviolet-visible (UV-VIS) molecular absorption spectrophotometry (often called light absorption spectrophotometry or just UV-visible spectrophotometry) is a technique based on measuring the absorption of near-UV or visible radiation (180-770 nm) by molecules in solution.35,36 Reference standard characterization by UV-VIS spectophotometry includes determining the absorption spectra and the molar extinction coefficient. These two spectral characterizations are used as identifiers of reference standards. 

Reference standard Characterization and COA Characterization Characterization and COA Characterization and See Appendix II... 

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

Impurity analysis/identification/synthesis Reference standard characterization Change control documentation Stability protocols... 

Fuller, S. R., and Gamer, W. Y., Test Substance and Analytical Reference Standard Characterization and Accountability In Good Laboratory Practice Standards Applications for Field and Laboratoiy Studies (1992) Willa Y. Gamer, Maureen S. Barge, James P. Ussary, Eds. ACS Professional Reference Book, American Chemical Society, Washington, DC. 

Reference standard characterization, including for active drug, and where feasible for impurities, and degradation products... 

Rhinitis is characterized by nasal stuffiness with partial or full obstmction, and itching of the nose, eyes, palate, or pharynx, sneezing, and rhinorrhoea. If left untreated it can lead to more serious respiratory diseases such as sinusitis or asthma. Although several types of dmgs are available for treatment, nasal spray topical corticosteroids are widely regarded as the reference standard in rhinitis therapy (250). 

Analytical chemistry is a critical component of worker safety, re-entry, and other related studies intended to assess the risk to humans during and subsequent to pesticide applications. The analytical aspect takes on added significance when such studies are intended for submission to the U.S. Environmental Protection Agency and/or other regulatory authorities and are thus required to be conducted according to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Good Laboratory Practice (GLP) Standards, or their equivalent. This presentation will address test, control, and reference substance characterization, use-dilution (tank mix) verification, and specimen (exposure matrix sample) analyses from the perspective of GLP Standards requirements. 

It is largely without debate that the term "reference substance" includes those chemical and biological materials that are used as standards in a study (i.e., those materials used for response comparison purposes, such as analytical reference standards). Normally, one thinks of reference substances as just referring to specimen (sometimes referred to as "matrix samples") analyses, but the characterization of test, control, and reference substances (see... 

Some GLP professionals consider positive control substances (i.e., those materials intended to validate responsiveness of the test system to a chemical or biological challenge) to also be reference substances, as opposed to control substances however, the point is somewhat moot as the FIFRA GLP Standards characterization and handling requirements are exactly the same for both control and reference substances. As with test and control substances, reference substances must be characterized (usually determination of purity and stability) according to the abbreviated GLP Standards (see next section). 

The /3-polymorphic form of anhydrous carbamazepine is official in the USP [3], The USP stipulates that, The X-ray diffraction pattern conforms to that of USP Carbamazepine Reference Standard, similarly determined. No limits have been set in the USP for the other polymorphs of anhydrous carbamazepine. Although several polymorphic forms of anhydrous carbamazepine have been reported, only the a- and /3-forms have been extensively studied and characterized [49]. A comparison of the powder x-ray diffraction patterns of these two forms revealed that the 10.1 A line (peak at 8.80° 26) was unique to a-carbamazepine, and so this line was used for the analysis (Fig. 5). It was possible to detect a-carbamazepine in a mixture where the weight fraction of a-carbamazepine was 0.02 at a signal-to-noise ratio of 2. Much greater sensitivity of this technique has been achieved in other systems. While studying the polymorphism of l,2-dihydro-6-neopentyl-2-oxonicotinic acid, Chao and Vail [50] used x-ray diffractometry to quantify form I in mixtures of forms I and II. They estimated that form I levels as low as 0.5% w/w can be determined by this technique. Similarly the a-inosine content in a mixture consisting of a- and /3-inosine was achieved with a detection limit of 0.4% w/w for a-inosine [51]. 

Cheney et al. (1995) analyzed steroids by coupling an HPLC purification step with GC/MS. The steroids were initially characterized by their HPLC retention times compared with the retention times of tritium-labeled recovery standards. Next, the nemosteroids were characterized by their GC retention times. Finally, they were identified by their unique fragmentation spectra following derivatization with heptafluorobutyric anhydride or methoxyamine hydrochloride. For structmal identification, the mass spectra were compared to appropriate reference standards. This approach is highly specific, and its sensitivity is increased by the use of SIM. The detection limit for measuring allopregnanolone achieved in the 1995 study was 0.63 pmol (0.2 ng) starting from 100-300 mg of brain tissue. 

In thip appendix, a summary of the error propagation equations and objective functions used for standard characterization techniques are presented. These equations are Important for the evaluation of the errors associated with static measurements on the whole polymers and for the subsequent statistical comparison with the SEC estimates (see references 26 and 2J for a more detailed discussion of the equations). Among the models most widely used to correlate measured variables and polymer properties is the truncated power series model... 

The final, purified bulk product is thoroughly characterized and compared to reference standards established by the manufacturer for new molecular entities or available from the United States Pharmacopoeia (USP) or the World Health Organization s National Institute of Biological Standards and Control. Characterization tests of proteins may include biologic potency assays, chromatographic assays, gel... 

A thorough search of the reconstructed ion chromatogram (RIC) was made to determine the mass spectra of all detectable components. The spectra were compared with those of reference standards when available or with the spectra from the mass spectral library. Molecular weights of more abundant constituents are shown in Figure b, many additional minor components were also characterized. A complete list of compounds characterized in this sample by GC-MS is given in Table I. 

The peak with the parent ion of m/e 226 was assigned benzo[ghi]flu granthene. The reference standard was not available, but its retention index was in agreement with that reported (389.6) by Lee et al. (6). The presence of benzo[b,j k]fluoranthenes was also confirmed. They appeared as one broad peak, but the presence of all three was established by their GC retention time in the HPLC subfraction S1-C2C. Benzo[ejpyrene and benzo[a]pyrene were also characterized by MS. PAHs with higher ring systems were not detected in this sample. 

Authentic sample a purified and characterized sample of a related substance. Unlike reference standards, authentic samples may not be of high purity. However, the purity of an authentic sample has to be determined before use. Authentic samples are used in method development to identify related substances in the analysis. In addition, they are used extensively to prepare the spiked samples in method validation. 

Reference Standard. One of the limitations of the external standard method is that a well-characterized reference standard is essential. In addition, each analysis requires accurate weighings of small quantities (e.g., 10 mg) of reference standard. Therefore, weighing error can affect method precision and accuracy. 

The quantitative analysis is only as good as the reference material allows. The reference standard is used as the primary standard against which all determinations are made. Reference standard characteristics should be appropriately determined and documented for each batch. Copies of this documentation must be included with study records and must be available for inspection. The reference standard should be (1) of the highest purity obtainable, (2) independently characterized to establish identity, strength or potency, and purity, (3) in the most stable form, and (4) stored under suitable conditions. 

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 ... 

In case there is a need to perform wavelength accuracy and photometric accuracy measurements for the far-UV region below 240 nm, there are new certified reference standards available from Stama Cell [18]. The wavelength standard is a solution of rare earth oxides solvated in dilute sulfuric acid. The standard exhibits well-characterized absorption bands at 210, 211, 222, 240, and 253 nm (Figure 10.13). The photometric accuracy standard consists of a series... 

To establish safety and to ensure consistency, the complete chemical composition should be provided for every material used in the manufacture of a packaging component. Test results from appropriate qualification and characterization tests should be provided. Adequate information regarding the tests, methods, acceptance criteria, reference standards, and validation information should be also provided. 

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