State-of-the-art of process development, scale-up and design for downstream processes is described for complex mixtures in biotechnology. The focus is on fermentation broth and plant-based extracts to derive methodological arguments. Academic and industrial approaches are discussed with an assessment based on some process relevant criteria. Examples of monoclonal antibody, insulin and penicillin production processes are chosen to develop a sound argumentative basis.Demands of total process integration, accuracy and sensitivity of phenomena, resulting e.g. in miniaturization of laboratory experiments and linked with necessary in-depth modeling are developed and implemented. Specific tasks of unit operation are displayed and their integration into an efficient process sequence is demonstrated. Based on that, further research needs are pointed out and corresponding activities are identified. For instance, the transfer of well established methods in chemical engineering like process modeling in combination with laboratory scale experiments and final miniplant validation should be followed consequently also in biotechnology applications. Some drawbacks in academic education and industrial training as well as organizational structures are discussed to help address this issue.

The number of products used as agro-chemicals, food additives, flavors, aromas, pharmaceuticals and nutraceuticals which are made by fermentation or extraction from plants has increased significantly. Despite this growth, initial predictions for a potential product purification process for these complex mixtures remains entirely experimentally based. The present work represents an initial study to demonstrate the benefits of a systematic approach. For process development of chemically well-studied systems model based process design methods are already available. Therefore the proposed approach focuses on a method for the efficient characterization of the physical properties of the key components. Once this is adequately defined, unit operations and their potential to separate the feed components can be modeled. The current state of research is discussed. Based on this evaluation the most efficient method for conceptual process development has been identified and further developed. The resulting methodology consists of model-based cost accounting accompanied by experimental model-parameter determination. The latter is carried out at in miniaturized laboratory-scale measurement cells for each unit operation using the complete original feed. The model-based modelparameter determination from these experiments is accompanied by a comprehensive error analysis. The experimental plan currently includes the determination of thermodynamic equilibrium conditions in the mixture directly from the raw material mixture. Transport kinetics and fluid dynamic parameters are first estimated from known correlations or preexisting knowledge. Later on these parameters are determined exactly in mini-plant experiments. Furthermore, biological and botanical-based guidelines are developed to identify thermodynamically favored basic operations. Finally, the developed approaches are successfully validated using two plant extracts. Firstly, it could be proven that the botanical pre-selection can reduce the experimental plan significantly. Secondly, it was shown that the experimental equilibrium data of the kinetics and fluid dynamics can have a significant impact on the separation costs. Therefore, detailed rigorous modeling approaches have to be chosen instead of short-cut methods in order to make any valid process development conclusions or to further optimize the system.

The market for products made by biotechnology is diverse and has significantly grown in recent years. Despite this growing demand, the first proposal of product purification processes for these complex mixtures remains purely experimentally based and is not methodically targeted. The present work represents an initial study to demonstrate the benefits of a systematic approach. The study focuses on the adaptation of established methods for process development to these so‐called complex mixtures. It also assesses the suitability of these methods for complex mixtures, given the current state of research. Based on the described adaption, the most efficient method for the conceptual process development is identified and is subsequently developed. The resulting methodology consists of model‐based cost accounting with a miniaturized experimental determination of model parameters, accompanied by a comprehensive error analysis. The developed approaches are successfully validated by using a protein mixture.

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