Leachables

are components that can migrate from primary (e.g. storage bag) or secondary containment (e.g. label) under normal process conditions (see bDtBPP). Together with the extractables they belong to the substances that can contaminate culture broth, intermediate or final product. Thereby, leachables are regarded as more dangerous as they can occur under normal process conditions. The sources of leachables are additives, especially antioxidants, which arise during the extrusion in bag manufacture (see film manufacture) or the gamma-sterilization, and leak as water-soluble components from the plastic material. Leachables can disturb cell cultivation, increase protein aggregation and are a risk for patients due to their toxic effect when administered parenterally ^{2, 3, 50, 51}. Therefore, it is important to detect the development of leachables at an early stage. This can be done with specific chemical-analytical methods such as the GC-MS or the LC-MS (gas or liquid chromatography mass spectroscopy), or with general tests such as the determination of TOC (total organic carbon, total amount of organic carbon), the pH value, or the conductivity. In addition, cell culture tests (such as the test with CHO XM 111-10 cells recently suggested by DECHEMA) where the vitality and proliferation of cells after cultivation in incubated medium and water for injection is determined ^{3, 52}. It is very important to not only identify films or bags that do not excrete leachables for cultivations, but also for the storage of starting material and products. At present, bags made from films with an improved composition of additives and that are tested for the absence of leachables are available ⁹. See Aegis5-14 film and Flexsafe S80 film.