System suitability related substances

The monographs of the European Pharmacopoeia describe a so-called test for related substances which is intended to control the level of impurities. Reference substances may be used in this test in order to ensure the system suitability and/or to control the content of related substances. 

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). 

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. 

System suitability calibration standard 2 (for related substances determination)... 

Once the extensive validation experiments are complete, minor changes to the method description may be required. Typically, these involve adding validation data (RRFs for the related substances, LOQs, etc.) but may also include slight changes to the system suitability requirements due to data from multiple laboratories. There should not be fundamental changes that would alter the principles of the methodology or necessitate revalidation unless a portion of the validation failed, suggesting minor method adjustment and reperformance of the required validation experiments. 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

The surface tension of the system can also be changed by grinding with liquid, thus decreasing interfacial tension. This gives rise to a variety of parameters since, by adding suitable chemicals (electrolytes or surface-active agents), one can modify the end-product properties. Conversely, the size of crystals formed from a supersaturated solution of a substance is related to the surface tension (at the solid-liquid interface). Thus, to obtain fine crystals, a suitable detergent is added, and thus, finer crystals are obtained. 

Determination of the amount of substance is thus in direct relation to basic units of the SI system and does not need a RM for comparison. The Faraday constant is one of the fundamental constants (it can be expressed as the product of the electron charge and the Avogadro constant). It enables the attainment of high precision and accuracy and is independent of the atomic weights of the elements in the sample. Its drawback is lower selectivity, a feature common to titration methods. This makes coulometry especially suitable for determination of relatively pure substances used as standards by other (relative) methods. The Faraday constant has been proposed as an ultimate standard in chemistry [3],... 

Beyond requirements related to sanitation, however, manufacturers, processors, packers, and distributors should establish and exercise other appropriate systems of controls throughout their operations, including food safety assurance systems such as Hazard Analysis and Critical Control Points (HACCP), where applicable, to ensure that FCC substances are safe and otherwise suitable for their intended use. These controls, together with the regulations cited above, constitute good manufacturing practices. While the... 

The results of studies conducted on the drug substance should be summarized and related to the anticipated storage conditions and container/closure system, as well as the retest plan to be used by the sponsor. Statements on whether additional studies are ongoing or planned for the future should be included. Also provide a statement regarding the suitability of the methods used (see the section below on specifications and analytical methods). 

The QSAR-partial order ranking system further appears as an appropriate tool to give specific molecules an identity in relation to others and thus constitute as a support tool in the development of less hazardous substitutes to acknowledged harmful substances. In this connection partial order ranking potentially also constitute a rather strong tool to solve inverse QSAR problems, e.g., to develop suitable synthetic pathways for new substances. 

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