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Monoclonal antibodies are being widely used for the treatment of various diseases. Microparticle formation in high-concentration protein solutions is a major problem during the manufacture of therapeutic monoclonal antibodies, because aggregation leads to fouling of aseptic filters and may lead to an immunogenic reaction in patients. We found that stirring using a traditional bottom-magnetic type stirrer results in extensive and sustained formation of 500-nm diameter protein microparticles arising from shear stress on protein molecules. The antibody solution stirred for only 5 min using this type of stirrer exhibited significant fouling of aseptic filter membranes. In contrast, a top-entering type stirrer did not lead to the formation of microparticles, and the solution did not exhibit membrane fouling even after 30 min of stirring. We conclude that a top-entering type stirrer is more suited for the manufacture of concentrated therapeutic monoclonal antibody solutions.

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Testing is a crucial part of the developnient of highly dependable systems. In this paper we consider testing of an implementation that is intended to satisfy a boolean forniula. I n the literature, specification-based testing has been suggested f o r this purpose. Typically, such methods first hypothesize a fault class and then generate tests. However there is alniost no research that justifies fault classes proposed previously. Moreover specifications amenable to autoiiiutic test generation are not always available to testers in practice. Based 011 these observations, we examine the qq,dicubi/io, of nori-specI~cntiori-based approaches, which need no spec$cation in the form of a boolean forniula to create tests. We conipare a specification-based approach to two non-specificatiori-based approaches, naniely, random testing and conibinatorial testing, which is an emerging technique based on conibinatorial designs. The results of an experiment show that conibinatorial testing is often coniparative to specijcation-based testing and is always niuch superior to random testing.