A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of antibody production processes. Additionally, increasing demands on product quality result in higher complexity of processes and analytics, thereby increasing the costs for product work-up. Concentration and composition of impurities are critical for efficient process development. These impurities can show significant variations, which primarily depend on culture conditions. They have a major impact on the work-up strategy and costs. The resulting "bottleneck" in downstream processing requires new optimization, technology and development approaches. These include the optimization and adaptation of existing unit operations respective to the new separation task, the assessment of alternative separation technologies and the search for new methods in process development. This review presents an overview of existing methods for process optimization and integration and indicates new approaches for future developments.
Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?
Liquid chromatographic methods cover the broadest range of applications imaginable today. Nowhere is this more evident and relevant than in the life sciences, where identification of target substances relevant in disease mechanisms is performed down to the femtomole level. On the other hand, purification of therapeutic drugs on a multi-ton scale is performed by process LC. The complexity and abundance range of biological systems in combination with the extreme purity requirements for drug manufacturing are the challenges that can be mastered today by chromatography, after more than a century of research and development. However, significant improvement is still required for a better understanding of the scientific fundamentals of the underlying phenomena and exploiting those for an enhanced quality of live.
The production of chirality with maximum economy is one of the most challenging tasks of today's pharmaceutical industry. Apart from the use of inherent chirality (starting material from the chiral pool, e.g., amino acid derivatives, carbohydrates), the creation of chiral centers via biocatalysis or asymmetric synthesis is commonly used. Another way to obtain pure enantiomers is the separation of racemates via kinetic resolution through preferred crystallization or preparative chromatography on chiral stationary phases. This paper emphasizes this last method, explains the possibilities of this technique, especially in its application form as simulated moving bed (SMB) chromatography, and shows its benefits and limitations. Therefore, comparisons to classical batch elution chromatographic processes as well as other unit operations (such as crystallization, etc.) must take cost calculations into account. In this paper, a theoretical comparison of optimized SMB and batch elution processes by simulation studies based on rigorous process models is presented for the separation of two different binary mixtures. These examples are chosen to demonstrate the different effects which dominate the applications in large-scale isomer separations and production-scale enantiomer separation. The first example is a fructose/glucose separation with linear isotherms. The model parameters are measured by Nicoud. The second characteristic example is an enantioseparation. The corresponding isotherms are of the modified Langmuir type. The performance of each separation process is quantified by three characteristic objective functions: productivity, dilution, and solvent requirement. Last, the specific separation costs or the total costs of separation are calculated as an objective function to lay emphasis on the economy of the separation, including product recovery and solvent recycling. The comparison of these objective functions, which are determined for batch and SMB processes, leads finally to certain rules of consideration to decide what kind of process (either batch elution or SMB) is preferable as a function of the physical properties of the given binary mixture and the separation task.
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