Continuous countercurrent chromatography has been established in industrial operations for over six decades and in fine chemical and pharmaceutical industry since the 1990s. In biotechnological processing, the area where chromatography plays a criticaland often multipleroles, implementation is lacking for various reasons. Options are shown to correct this and make continuous countercurrent chromatography a technologically and economically viable option in GMP-regulated processing. Current approaches, with the exception of MCSGP (multicolumn countercurrent solvent gradient purification), just operate a manifold of 2–6 columns in a sequential but batchwise scheduling. Modifications were made to reduce equipment complexity in GMP-regulated manufacturing and to exploit benefits of countercurrent operation for adsorbent and buffer reduction. A solution with only one column and a minimum of valves, pumps, and buffer vessels was developed. The approach also describes integration of two or more chromatography steps in continuous production, both GMP- and biocompatible.

Process development and design in a strictly regulated environment need effi cient methods to generate product quality as early as possible, and to prove the reproducibility and reliability of process operation at the production scale afterwards. For pharmaceuticals, regulatory authorities like US Food and Drug Administration ( FDA ) and European Medicines Agency (EMA) have demanded Quality by Design ( QbD ) approaches in order to fi le information -based decisions. This chapter describes the state -of -the -art of QbD by statistical design of experiments. and actual developments to improve the predictive power and accuracy in combination with a reduction of later efforts by physicochemical -based process modeling. The benefi ts are pointed out exemplifi ed by an examplea typical hydrophobic interaction chromatography step in monoclonal antibody ( mAb ) downstream processing.A model has to be generated that is suffi ciently predictive within a given process operation parameter range with a known suffi cient accuracy. Therefore, a physicochemical -based mathematical process model is derived including nonidealities like fl uid dynamics by axial dispersion, mass transfer kinetics by fi lm and pore diffusion, and multicomponent equilibrium phase by interferences.The model parameters are determined experimentally at the laboratory scale (about a few milliliters) in order to gain an acceptable experimental error of lower then ± 5%. The model ' s accuracy is defi ned with the aid of Monte -Carlo simulations, which are described in detail. Afterwards, the model is validated at the laboratory scale and production scale with a set of different operation parameters to determine the predictive range and accuracy. Finally, some parameter studies are described in order to illustrate the method, discuss benefi ts, and point out limitations.

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Hydrophobic interaction and ion exchange chromatography are basic steps in purification of fermentative biopharmaceuticals. An optimization by statistical design of experiments requires a huge amount of feed. An alternative approach is the combination of model parameter determination using small scale experimental model parameter determination (1‐mL columns) and rigorous process modeling. Applicability for the prediction of the separation of a fermentation mixture of CHO mammalian cell culture is validated and hence IgG is purified from cell culture supernatant. Hydrophobic interaction chromatography directly combined with ion exchange chromatography is optimized. Any direct integration of those two main unit operations in purification processes is a methodological first step towards total process optimization. The potential for cost reduction and overall yield improvement is demonstrated and this leads to the conclusion that single step optimization is a feigned and not a real optimum.

For years, microtechnology is being considered as an emerging technique for chemical engineering tasks to overcome safety issues corresponding to high volumes and gaining higher selectivities and yields in reaction technology. Whereas in reaction technology a broad variety of microstructured equipment is available, in product purification/separation adequate equipment is missing. Research is focused on modular fast and flexible smaller production plants being operated continuously instead of batchwise in order to reduce engineering efforts and time‐to‐process. To cope with these demands, an appropriate definition of modules, which could be easily chosen and combined, is inevitable. In addition, these modules have to be well characterized concerning fluid dynamics and separation performance. This paper focuses on the characterization of available modules/devices. A standard method and analysis of the results concerning manufacturing accuracy and operation range is proposed. Miniplant technology is described as an efficient tool to validate process concepts proposed by process simulation studies. Necessary model parameters are determined for industrial complex mixtures in miniaturized laboratory equipment. Parameters are calculated model based to gain maximal accuracy. State of the art of miniplant technology is described and basic characteristic data are presented.