Reproducibility potency

Some Chemical Considerations Relevant to the Mouse Bioassay. Net toxicity, determined by mouse bioassay, has served as a traditional measure of toxin quantity and, despite the development of HPLC and other detection methods for the saxi-toxins, continues to be used. In this assay, as in most others, the molar specific potencies of the various saxitoxins differ, thus, net toxicity of a toxin sample with an undefined mixture of the saxitoxins can provide only a rough approximation of the net molar concentration. Still, to the extent that limits can be placed on variation in toxin composition, the mouse assay can in principle provide useful data on trends in net toxin concentration. However, the somewhat protean chemistry of the saxitoxins makes it difficult to define conditions under which the composition of a mixture of toxins will remain constant thus, attaining a reproducible level of mouse bioassay toxicity is difficult. It is therefore useful to review briefly some of the chemical factors that should be considered when employing the mouse bioassay for the saxitoxins or when interpreting results. Similar concepts will apply to other assays. 

Fig. 37.6. PLS biplot obtained from the pharmacological data in Table 37.9, after log double-centering and analysis by two-block PLS [56]. Circles represent 17 reference neuroleptic compounds, squares denote tests. Areas of circles and squares are proportional to the potencies of the compounds and the sensitivities of the tests, respectively. Reproduced with permission of E.J. Kaijalainen.

Analytical scientists will provide support for many of the activities in a biopharmaceutical company. They are responsible for characterizing the molecules in development, establishing and performing assays that aid in optimization and reproducibility of the purification schemes, and optimizing conditions for fermentation or cell culture to include product yields. Some of the characterization techniques will eventually be used in quality control to establish purity, potency, and identity of the final formulation. The techniques described here should provide the beginning of a palette from which to develop analytical solutions. 

Reproducibility of Manufacturing Processes The aim of GMP is to ensure the manufacture of safe, potent, pure, and effective drug in a consistent manner. The development program exists to evaluate procedures and processes that can be implemented in a large-scale manufacturing environment to ensure the drug product conforms to the intended safety, potency, purity, effectiveness, and consistency on a routine basis. 

Preliminary studies [241, 249, 250] of the cardiovascular and sympatholytic properties of prenylamine demonstrated that coronary blood flow and oxygenation could be increased under experimental conditions (in dogs) and that the drug interacted in complex fashion with sympathetically innervated organs, but the picture presented was someudiat confused because of the many uncontrolled variables and limitations of the actual techniques used. Anti-arrhythmic activity of potency comparable with that of quinidine, plus local anaesthetic properties, were also demonstrated [251] but the same worker was notable to reproduce these effects in intact live animals with any consistency. Large doses of the drug actually provoked cardiac fibrillation in some cases. 

The variation in the mutagenic potency of the control compounds was similar to that of the environmental samples the exception was 1-nitropyrene, for which the reproducibility ranged from 127 to 132%. 

Fig. 7.3 Comparison of mutagenic potencies of chemicals tested in Salmonellal microsome and V79 Chinese hamster systems. Ordinate -log P, Chinese hamster. Abscissa log P, Salmonella-liver microsome test. Correlation, R = 0.74 (reproduced from NAS/NRC. 1982).

Reproducibility dosage strengths, the estimated intermediate precision is 0.9%. The average potency result... 

Figure 1. Loss ofRR during anaesthesia with 209 mM ethanol was significantly delayed from 10 min onwards (p<0.005, by x2 test) with young toads treated with Nux vomica 30 CHprepared with 90% ethanol by sonication as compared to the control. Control (o) treated ( ). n=60 in both the test and the control. (Reproduced, with permission, from Sukul et al. Hydrated ethanol, the effective medium for a homeopathic potency as tested by a new toad model. Indian JLandscape Syst Ecol Stud 1997 20 155)...

Until recently, the polyhedral inclusion body has been used conveniently as the "unit of potency of NPV preparations. Thus, in the United States, the potency of preparations of NPV of Heliothis spp. was expressed in "viral units" (1 VU 109 pib), in "larval equivalents" (lLE 6VU 6x 10 PIB), or simply in billions (10 ) PIB per unit weight or volume of the preparation. The reproducibility of PIB counts, however, is... 

---