Related substances critical

Critical Related Substances. Critical related substances are those that may exist at significant levels in the drug product. Authentic samples of these critical related... 

As we have seen, carcinogenesis is a prolonged multi-stage process which usually occurs over many years. Because of its complexity there are, in principle, many critical steps at which food-related substances or metabolic processes may interact with the sequence of events so as to accelerate, delay or even reverse it. Diet-related anti-carcinogenesis can usefully be classified into ... 

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. 

Due to the presence of the internal standard, it is critical to ensure that the analyte peak be separated from the internal standard peak. A minimum of baseline separation (resolution >1.5) of these two peaks is required to give reliable quantitation. In addition, to quantitate the responses of internal standard accurately, the internal standard should be baseline resolved from any significant related substances and should have a peak height or area similar to that of the standard peak. 

System Suitability Tests. The appropriate system suitability tests should be defined before method validation (e.g., precision, resolution of critical related substances, tailing, detector sensitivity). These system suitability tests should be performed in each method validation experiments. System suitability results from the method validation experiment can be used to determine the appropriate system suitability acceptance criteria. 

Authentic samples of critical related substances to show that all known related substances are resolved from each other. 

Typically, a stressed sample of about 10 to 20% degradation is used to demonstrate the resolution among degradation products. A 10 to 20% degraded sample is used because it has a sufficiently high concentration level of critical related substance. Therefore, these related substances can be detected easily. In addition, 10 to 20% degradation is not too excessive, and the related substance profile should be close to that of a typical stability sample. 

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%)... 

Including other critical samples (Process Related Substances)... 

It is unrealistic to envision that a single method can be developed for the determination of the API and related substances in both drug substance and drug product and, at the same time, be optimized to support all phases of pharmaceutical development. Instead, the development of a test method should be conducted in the context of a critical examination of what the method will be used to measure and the method validated to demonstrate that these criteria have been met. For early-phase methods, regulatory guidelines are unspecific, whereas, for late-phase methods, regulatory expectations provide a comprehensive set of performance goals that a method should achieve. 

Critical quality attributes may include items, such as potency, the nature and quantity of product-related substances, product-related impurities, and process-related impurities. Such attributes can be assessed by multiple analytical procedures, each yielding different results. In the course of product development, it is not tmusual for the analytical technology to evolve in parallel with the product. Therefore, it is important to confirm that data generated during development correlate with those generated at the time the marketing application is filed. 

Another example of control of crystal habit and size of cefinatilen hydrochloride hydrate (3, Scheme 24.2) with a habit modifier, an impurity, has been reported recently. It has been demonstrated that concentration of a related substance, a diphenyl methyl substitution at the N3 position in the triazole (4) (formed during deprotection of trityl and diphenyl methyl group (5) with AICI3 and anisole in methylene chloride at elevated temperature) is critical for formation of the particular crystal habit. 

Why are the critical temperature and pressure for H2O so much higher than those for H2S, a related substance (Table 11.6) ... 

Trend analyses Stability monitoring Retrospective validation Supply chain traceability of active substances Critical in-process controls and finished product results Deviations or non-conformities and the effectiveness of the subsequent corrective and preventive actions Quality-related returns, complaints and recalls Qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc. 

Cumulative exposure from structurally related substances with critical hazardous properties (e.g., similar endocrine disrupting property such as antiandrogenic or estrogen-like effect)... 

With chlorobenzene and bromobenzene, which show no change of temperature or of volume when mixed together, and have the same critical pressure, and with methyl and ethyl alcohol, which have widely different critical pressures, the differences D -D, are certainly within the limits of experimental error in the other cases the differences are very small, and it may probably be concluded that the actual boiling points of mixtures of closely related substances may be calculated with very considerable accuracy from the... 

Although cobalt ions are found in both the (II) and (III) oxidation states, the most important biological compound of cobalt is vitamin B12 or cobalamin where the Co(III) form is present (256) (Fig. 6.10). Cobalamin or related substances are important biological compounds that are involved in a great variety of activities, particularly in bacteria. Vitamin B12 is also necessary in the nutrition of humans and probably of most animal and plant species. It is of critical importance in the reactions by which residues from carbohydrates, fats and proteins, are used to produce energy in living cells. Pernicious anemia is a severe disease in elderly people. This disease is usually accompanied in mammals by the increased excretion of methylmalonic acid in the urine. Today it is effectively controlled by a 100 /ig injection of vitamin B,2. 

A Zisman plot of a wood adhesive with varying concentrations of aqueous acetic acid is shown in Figure 13.3. Comparing the data obtained with the acetic acid solutions to the data obtained with the solutions of the dissolved wood-related substances, considerable discrepancies between the apparent critical surface tension arrived at with the mixed solutions compared with the critical surface tension arrived at with the pure probe liquid have been observed (not shown in Figure 13.3) (4). 

The final crystallization or precipitation step of API manufacturing is the stage at which the physicochemical properties of an API are determined and the last stage at which related substances (impurities) can be removed or reduced to acceptable limits. The crystalline form and PSD of an API are often critical to the formulation, dissolution, absorption and bioavailability of a drug. Bioavailability is the fraction of a drug dose that reaches systemic circulation (blood plasma) upon human dosing (USFDA). By definition, any drug is 100% bioavailable when administered by injection. 

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