Biological testing criteria

If all of the applicable physicochemical and biological test criteria are satisfied, then a plastic container can be used for packaging the pharmacopeial items. Additional testing may be necessary to assure suitability if light or moisture protection is necessary. These validations will be discussed later. 

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

The acceptance criterion for recovery data is 98-102% or 95-105% for drug preparations. In biological samples, the recovery should be 10%, and the range of the investigated concentrations is 20% of the target concentrations. For trace level analysis, the acceptance criteria are 70-120% (for below 1 ppm), 80-120% (for above 100 ppb), and 60-100% (for below 100 ppb) [2]. For impurities, the acceptance criteria are 20% (for impurity levels <0.5%) and 10% (for impurity levels >0.5%) [30], The AOAC (cited in Ref. [11]) described the recovery acceptance criteria at different concentrations, as detailed in Table 2. A statistically valid test, such as a /-test, the Doerffel-test, or the Wilcoxon-test, can be used to prove whether there is no significant difference between the result of accuracy study with the true value [29],... 

Toxicity tests are necessary tools to evaluate the concentration and duration of exposure of a chemical required to produce certain adverse effects. Molecular processes directly affected by the exposure to the chemical agent are the most liable criterions. Nevertheless, these effects are difficult to detect in aquatic toxicology because the processes are generally not well understood [72], Alternatively, other end points which fulfil the necessary requirements, namely the need to be unequivocal, relevant, easy to observe, describe and measure, biologically significant and repeatable, are used. These include measures of mortality, which is frequently employed in the early evaluation of the toxicity of a pollutant in acute toxicity tests. This criterion allows comparison of toxicity exerted by chemical agents with very different mechanisms of action. 

In the WASTOXHAS procedure, ecotoxicity testing of leachate samples obtained at different liquid-to-solid ratios (or at different times of release) aims at measuring effects on species representing various levels of biological organization (see Section 5.4) as a function of dilution rate while controls without leachate are used as reference. In order to express results in a synthetic form, raw data obtained from concentration-response curves are transformed into a summary criterion corresponding to a specific measurement endpoint (e.g., EC5o, ECX, NOEC, LOEC, etc.) for each test (Fig. 3). 

Ideally, toxicity data for the parent compound and all metaboUtes would be known. Typical toxicity data are effect concentrations leading to 50% of a specified maximum effect, EC50. If the toxicity endpoint is lethahty, the endpoint is termed LC50, i.e. lethal concentration for 50% of the test species. Of course also data for chronic endpoints, e.g., no-observed effect concentrations for endpoints hke reproduction, can be used. It is important, however, that data from the same biological species, the same incubation period, and the same endpoint are compared. This criterion limits the apphcability typically to acute toxicity data because there is rarely a full set of chronic toxicity data available. However, in principle, the model is generally apphcable to any endpoint be it chronic or acute, given that there are both a basehne QSAR and some experimental data for the parent compound available. 

It was originally recommended (Matuszewski 2003) that five different batches of blank matrix (biological fluid in their case) should be tested for ME and RE values in order to assure reliable validation of a bioanalytical method. In the later work (Matuszewski 2006) it was further proposed that assay precision and accuracy should be determined in five different lots of a blank matrix (e.g., a biofluid) instead of repeat (n = 5) analyses using a single lot of blank matrix. Then if an isotope-labeled SIS is not available, determination of the slopes of the five calibration curves and their precision, together with use of <3-4 % (CV %) as a criterion, provides a useful guideline for assessment of the presence or otherwise of a significant relative matrix effect. Of course such a procedure is not always possible, especially for environmental samples a recent example of this problem (Stiiber 2004) involved environmental samples (river water). 

The principles examined in Sections 7.8.1 to 7.8.3 could apply for enzyme active sites and other biological receptor structures. In both cases, the availability of good test for correct binding in the receptor is an important criterion in selecting a biological problem for study by the IR-responsive bioprobe approach. In the case of enzymes, such assays are usually straight forward, since an ability to measure conversion of the substrate into the product will allow both and kj to... 

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