Upstream processing, biopharmaceuticals

This chapter aims to overview the manufacturing process of therapeutic proteins. It concerns itself with two major themes (1) sources of biopharmaceuticals and (2) upstream processing. The additional elements of biopharmaceutical manufacturing, i.e. downstream processing and product analysis, are discussed in Chapters 6 and 7 respectively. 

The upstream processing element of the manufacture of a batch of biopharmaceutical product begins with the removal of a single ampoule of the working cell bank. This vial is used to inoculate a small volume of sterile media, with subsequent incubation under appropriate conditions. This describes the growth of laboratory-scale starter cultures of the producer cell line. This starter culture is, in turn, used to inoculate a production-scale starter culture that is used to inoculate the production-scale bioreactor (Figure 5.7). The media composition and fermentation conditions required to... 

Overall, therefore, the routine manufacture of a biopharmaceutical product is initiated by large-scale culture of its producing cell line (upstream processing). Subsequent to this, the product is recovered, purified and formulated into final product format. These latter operations are collectively termed downstream processing and are described in Chapter 6. 

The upstream processing element of the manufacture of a batch of biopharmaceutical product begins with the removal of a single ampoule of the working cell bank. This vial is used to inoculate a small volume of sterile growth medium, with subsequent incubation under... 

The MS techniques described previously for characterization of the final recombinant protein product can be applied at all stages during process development. MS might be used upstream to define clone selection, processing format, and purification steps, and downstream to characterize the final product, ascertain lotto-lot reproducibility, determine stability, and define the formulation of biopharmaceutical molecules. Presented here are some examples found either in the literature or from our own experience in which MS has been found to be a useful or necessary tool. Potential limitations of MS methods are discussed, and when appropriate, other analytical methods are mentioned that can be alternatives to MS and are also efficient tools for biopharmaceutical development. 

Down-scaling of the suspension cultures to microtiter plates was successfully established for testing culture supplementations [43]. This allows efficient and rapid medium optimization, and also opens the possibility of automating the upstream development. In combination, the overall direct transformation, clonal growth without any crossing steps, and the technical abihty to speed the process development will minimize the time-to-market for biopharmaceuticals produced in moss. 

---