Specificity related substances

Capsaicin, an active ingredient in red pepper, is well known for its ability to release and deplete substance P in sensory C fibers. However, this action is not specific for substance P, as neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin also are released. 

Non-specific absolute assay methods, e.g. volumetric titration, can be applied to avoid the establishment of a reference substance. This is only appropriate, however, when the monograph describes a separation test for related substances. This approach is certainly valid for the determination of the content of pharmaceutical raw materials but less acceptable for the assay of content of pharmaceutical preparations where the employment of specific assay methods is recommended (ICH Guideline 1994) to take account of decomposition of the active ingredient during the shelf life of the product and to avoid possible interference from excipients. 

The partition coefficient of a substance between several Immiscible solvent pairs can be combined with retention time data to confirm the identity of a substance when a pure standard is available [706]. Devised by Bowman and Beroza, the substance specific partition coefficient ("p-value") was defined as the fractional amount of substance partitioning into the less polar phase of an equal-volume, two-phase system. Only nanogram quantities of sample are required for the measurement and p-values are often sufficiently characteristic to distinguish between closely related substances. 

Pollutants addressed, which may be a specific compound or a class of related substances. 

For the analysis of OTC residues and its related substances in food and fisheries products, LC-MS/MS is presently the most modern and promising method due to its high sensitivity, reproducibility, and specificity. 

IgE antibodies are very highly specific. In a few cases they will cross react with closely related substances but generally they will not. 

Bioassays of related substances can be quite similar in design. Specific growth factors, for example, stimulate the accelerated growth of specific animal cell lines. Relevant bioassays can be undertaken by incubation of the growth-factor-containing sample with a culture of the relevant sensitive cells and radiolabelled nucleotide precursors. After an appropriate time period, the level of radioactivity incorporated into the DNA of the cells is measured. This is a measure of the bioactivity of the growth factor. 

For biocatalysts, binding is followed by a chemical reaction and release of products. Enzymes were the first catalysts used in biosensors and a large number of these natural proteins are available. Although they remain the most commonly employed, the use of purified enzymes is not always satisfactory and in some situations cell preparations containing the required enzymes in their natural environment may be preferable. This approach reduces specificity but can be used to advantage when the analysis of the range of related substances is required as in the case of pollution monitoring. 

The use of spiked batches (with levels approaching the specification limit) is recommended for the transfer of impurity or related substances methodology. In parallel, the receiving site should also assess the LOD/LOQ (Limit of Detection/Limit of Quantitation) of the method for each of the specified impurities or related substances. This can help to identify whether specificity and sensitivity are issues at the receiving laboratory. 

The successful mechanism for a reaction is a theory that correlates the many facts which have been discovered and is fruitful for the prediction of new experiments (1). One approach to mechanism is the study of stereochemistry which seeks information concerning the geometrical relationships between the reactants at the critical stages in the reaction. Information is gleaned from the examination of the products, if several isomers differing only in configuration may be formed, or from a study of the reactivity of closely related substances whose molecular shapes are varied in a specific manner. Occasionally a stereochemical fact places a considerable restraint upon the allowable mechanistic postulates, but the most effective employment of stereochemistry generally depends upon its detailed correlation with other experimental methods. 

The monograph of levocarbastine has already been revised. The determination of the related substances is performed by means of MEKC using an electrolyte solution composed of sodium dodecyl sulfate as a micelle-forming agent in addition to hydroxypropyl-/ -cyclodextrin in a boric acid buffer of pH 9.0. Due to the very good specificity and robustness the method is able to baseline separate the nine specified and detectable impurities and the drug substance. It is easy to meet the system suitability (Rs>4) the resolution between levocarbastine and impurity D was found to be 6.4 and the content of related substances less than 0.5% (see Figure lA and B). 

When data do not exist for a given toxicological endpoint, or when data are limited, the use of SARs may be considered in the hazard assessment. The potential toxicity of a substance, for which no or limited data are available on a specific toxicological endpoint can, in some cases, be evaluated by read-across from structurally or mechanistically related substances for which experimental data exist. The read-across approach is based on the principle that structurally and/or mechanistically related substances may have similar toxicological properties. 

There are no formal criteria to identify structural alerts for toxicity in general, for a specific endpoint or for read-across to closely related substances. However, for substances where no data for one or more endpoints are available, the assessment at a screening level can be performed using data obtained from closely analogous substance(s) to indicate a potential for toxicity, e.g., if a closely related substance has a potential for inducing a specific toxic effect, the substance for which no data on this specific toxic effect are available may reasonably be expected to exhibit a similar potential for inducing this specific toxic effect. In the case of such knowledge, it should be considered whether these data are adequate for a hazard assessment. 

The acceleration of a reaction by a unique catalyst rather than a family of related substances or materials. The term is commonly used with respect to H+ or OH catalysis (thus, specific acid and specific base catalysis). See General Acid Catalysis General Base Catalysis... 

Case 2. Linearity demonstrated from 50% of the ICH reporting limit to 150% of the shelf life specification of related substance. No significant y-intcrccpt is observed (Figure 3.7). In this case, a high-low calculation is more suitable, as... 

When authentic samples of impurities are not available. A stressed drug product can be analyzed to show separation of the most significant related substances. In addition, the peak homogeneity of the stressed sample should be investigated by PDA or mass spectrometry. Alternatively, one may use an orthogonal procedure to verify the method specificity. The orthogonal... 

Range. Ideally, linearity should be established from 50% of the ICH reporting limit to the nominal concentration of drug substance in the sample solution (for area percent method). If the linearity does not support such a wide range of concentration, determine the linearity from 50% of the ICH reporting level to 150% of the proposed shelf life specifications of the related substance (for the high-low and external standard methods) as a minimum. This will ensure a linear response for related substances at all concentration levels to be detected during stability. 

Intercept/slope ratio. The intercept/slope ratio is used to convert the y-intercept from the response unit (peak area) to the unit of percent related substance. The intercept/slope ratio should be compared to the proposed specifications to determine its significance. For example, if the shelf life specification is 2.0%, an intercept/slope ratio of 0.2% may be considered significant, as 0.2% represents 10% relative to the specification. 

Typically, linearity and accuracy determination covers a wide concentration range (e.g., 50% of the ICH reporting limit to 150% of specification). However, the concentration range for precision will be limited by the availability of sample of different related substance levels. Therefore, to ensure an appropriate method validation range with respect to precision, it is critical to use samples of low and high levels of related substance in precision experiments (e.g., fresh and stressed samples). 

The development report has two main sections, one that addresses the dosage form and one that deals with the bulk drug substance The product development scientist compiles the experimental evidence to demonstrate bioequivalency for the first clinical trial lot through those lots that will be used for launch. The report further includes a description of the current process along with a description of the chemical/phys-ical characteristics, purity, related substances, specifications, and stability of the drug substance. 

Registration. The registration of a chemical substance is the set of data management procedures which enables all information relating to a specific chemical substance to be linked together. The registration procedure is concerned with determining if a potentially new substance is equivalent to a substance already on file or if it is new, in which case the substance is added to the file. 

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