Range related substances

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. 

Sample Concentration (Method Sensitivity). To maintain linearity at the concentration range of the drug substance, scientists may try to lower the sample concentration to improve peak shape for the drug substance. However, if the sample concentration is too low, it will affect the method sensitivity, and the ability to detect low levels of related substances may not be adequate. 

Reduced Linear Range. Unlike the area percent and high-low methods, which use the response of the drug substance in sample injections for calculation, an external standard method uses a standard curve. Typically, the concentration range of the calibration curve is similar to that of related substances in the sample (e.g., 1 to 5% of the nominal sample concentration). Therefore, this method requires a small linear range. 

Case 1. Linearity demonstrated from 50% of the ICH reporting limit to a nominal concentration of drug substance in the sample solution. In addition, no significant v-in(creep is observed (Figure 3.6). In this case, area percent calculation is suitable because the linearity range covers the responses of related substances and that of the drug substance in the sample solution. Therefore, these responses can be used directly to calculate the area percentage of each related substance. 

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. 

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). 

Other Considerations. Typically, the variations in robustness results are compared to the intermediate precision results to demonstrate that robustness is not affected significantly within normal day-to-day variation. When the related substance results are affected by some critical experimental parameters, a precautionary statement needs to be included in the procedure to ensure that this parameter is tightly controlled between experiments. For example, if percent organic of mobile phase affects the results significantly, the procedure should indicate the acceptable range for percent organic (e.g., 50% organic 2%)... 

The p-values for over 100 pesticides and related substances were established by studying the extraction behavior of those compounds in a wide range of binary solvent systems. Gas chromatography—based on electron-capture detection—was used to obtain the experimental data. As a result of these studies, Beroza and Bowman reported that ... 

As a final check on the accuracy of the statistical model, the observed results for total related substances and peak B obtained during stability testing of 18 different manufacturing and lab scale batches of drug substance were compared to predicted increases (Figs. 11 and 12). The stability studies represented amorphous and crystalline material with water content ranging from 3-8%. Temperatures used for stability studies were 5°C, 25°C, and 35°C. The duration of the studies was from 11 weeks to 10 months. The... 

Some pharmacopoeial specifications for pethidine hydrochloride(14)now include a tic limit test for related substances as a result of the detection by glc of homologs formed by exchange of alkyl groups between the nitrogen atom and ester function of pethidine base(15) some samples contained up to 9% impurity even though their melting points lay within the range for the pure salt. 1-Benzylnorpethidine has also been identified as a contaminant of pethidine pharmaceuticals.(16)... 

Range LOQ to 120% of specification limit of largest impurity or related substance... 

---