Proposal of a new green process for waste valorization and cascade utilization of essential oil plants

In this study, different unit operations for distillation, extraction, capturing and separation of essential oil components from essential oil plants are evaluated, on the example of limonene and carvone from caraway fruits. Hydrodistillation is the standard process for obtaining essential oils and leaves the distillation water (hydrolate) after phase separation of the essential oil and the distilled plant material (pomace) as waste streams. In this study, a process for the valorization of these waste streams, using different techniques, such as traps and pressurized hot water extraction, is developed, reaching high yields, with a plus of 35%, compared to established methods, and reducing the overall global warming potential of the whole process, as well as reducing the cost of goods by around 30%

Process analytical technology for precipitation process integration into biologics manufacturing towards autonomous operation: mAb case study

The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept

Process analytical technology for precipitation process integration into biologics manufacturing towards autonomous operation: mAb Case Study

The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept

Pressurized hot water extraction of 10-deacetylbaccatin III from yew for industrial application

In this study a systematic and model-based approach for a process development focusing on pressurized hot water extraction (PHWE) is investigated, considering potential thermal degradation of high-value compounds. For extraction of 10-deacetylbaccatin III (10-DAB) from yew as a representative test system, water at 120 °C provided the best compromise between extraction yield and thermal degradation. A yield of almost 100% with regard to the overall amount of 10-DAB was reached in only 20 min. Each experiment for model parameter determination was carried out with 1.9 g of plant material at a flowrate of 1 mL/min and an applied pressure of 11 bar. All experimental values are assessed by a physico-chemical (rigorous) extraction model with experimental values and simulation results showing high conformity. In order to demonstrate the usability of the extraction model and model parameter determination a scale-up prediction was calculated. The scale-up experiments were predicted precisely and thus the model validated. The experiments and the simulation results for a column with a volume of 104 mL and a mass of 22 g yew needles were consistent with the milli-scale used for model parameter determination

Enabling total process digital twin in sugar refining through the integration of secondary crystallization influences

Crystallization is the main thermal process resulting in the formation of solid products and, therefore, is widely spread in all kinds of industries, from fine chemicals to foods and drugs. For these high-performance products, a quality by design (QbD) approach is applied to maintain high product purity and steady product parameters. In this QbD-context, especially demanded in the foods and drugs industry, the significance of models to deepen process understanding and moving toward automated operation is steadily rising. To reach these aspired goals, besides major process influences like crystallization temperature, other impacting parameters have to be evaluated and a model describing these influences is sought-after. In this work, the suitability of a population balance-based physico-chemical process model for the production of sugar is investigated. A model overview is given and the resulting model is compared to a statistical DoE scheme. The resulting process model is able to picture the effects of secondary process parameters, alongside temperature or temperature gradients, the influences of seed crystal size and amount, stirrer speed, and additives

Need for a next generation of chromatography models: academic demands for thermodynamic consistency and industrial requirements in everyday project work

Process chromatography modelling for process development, design, and optimization as well as process control has been under development for decades. Still, the discussion of scientific potential and industrial applications needs is open to innovation. The discussion of next-generation modelling approaches starting from Langmuirian to steric mass action and multilayer or thermodynamic consistent real and ideal adsorption theory or colloidal particle adsorption approaches is continued

Towards autonomous process control: digital twin for CHO cell-based antibody manufacturing using a dynamic metabolic model

The development of new biologics is becoming more challenging due to global competition and increased requirements for process understanding and assured quality in regulatory approval. As a result, there is a need for predictive, mechanistic process models. These reduce the resources and time required in process development, generating understanding, expanding the possible operating space, and providing the basis for a digital twin for automated process control. Monoclonal antibodies are an important representative of industrially produced biologics that can be used for a wide range of applications. In this work, the validation of a mechanistic process model with respect to sensitivity, as well as accuracy and precision, is presented. For the investigated process conditions, the concentration of glycine, phenylalanine, tyrosine, and glutamine have been identified as significant influencing factors for product formation via statistical evaluation. Cell growth is, under the investigated process conditions, significantly dependent on the concentration of glucose within the investigated design space. Other significant amino acids were identified. A Monte Carlo simulation was used to simulate the cultivation run with an optimized medium resulting from the sensitivity analysis. The precision of the model was shown to have a 95% confidence interval. The model shown here includes the implementation of cell death in addition to models described in the literature

Quality-by-Design (QbD) process evaluation for phytopharmaceuticals on the example of 10-deacetylbaccatin III from yew

The focus of pharmaceutical product development lies on assuring excellent product quality at the end of a cost-efficient process. The Quality-by-Design (QbD) concept shifts the focus from quality assurance through testing to quality control by process understanding, resulting in very robust processes with high quality product. QbD was originally intended by authorities for biologics, where product quality proven completely by analytics is not desired. Product quality has to be controlled by means of appropriate processes and operations as well. These demands were developed in order to improve patients' safety by optimal drug quality at more efficient manufacturing processes reducing costs for healthcare systems. Furthermore, production of biologics includes feedstock variability and complex multi-step manufacturing processes in batch operation with variable lots – condition, which apply to botanicals as well. The use of rigorous (physico-chemical) process modeling in combination with QbD results in a high degree of process understanding. This offers, contrary to popular prejudices, great benefit for manufacturers with little extra effort during development. The methodical QbD-based approach is pursued to develop a process for extraction and purification of 10-deacetylbaccatin III from yew needles. A short history and key elements of the QbD-based application are introduced. The line of argument for basic process conception is described and initial risk assessment is shown. Typical raw material variation and vaporization are identified as causes of process variability, therefore, the implications to subsequent process steps are pointed out. Finally, influences of load and flow rate on the chromatographic separation of 10-deacetylbaccatin III are shown to exemplify sensitivity of purification design

Climate neutrality concepts for the German chemical-pharmaceutical industry

This paper intends to propose options for climate neutrality concepts by taking non-German international experiences and decisions made into account. Asia-Pacific and Arabic countries do have already same lessons learned by large-scale projects with regard to economic evaluations. Quite a few conceptual studies to generate the climate neutrality of the chemical–pharmaceutical industry in Germany have been published recently. Most of the studies differ even in magnitude but do not refer to or evaluate the other ones. These are all first theoretical feasibility studies. Experimental piloting is not far developed; only few and only stand-alone parts are operated, with no overall concepts. Economic evaluation is missing nearly completely. Economic analysis shows a factor 3 more expensive green technologies. Even if a large optimization potential of about 30% during manufacturing optimization is assumed as significant, cost increases would result. To make green products nevertheless competitive, the approach is to increase the carbon-source cost analogue, e.g., by CO2/ton taxes by around EUR 100, which would lead to about factor 3 higher consumer prices regarding the material amount. Furthermore, some countries would not participate in such increases and would have benefits on the world market. Whether any customs-duties policy could balance that is generally under question. Such increasing costs are not imaginable for any social-political system. Therefore, the only chance to realize consequent climate neutrality is to speed up research on more efficient and economic technologies, including, e.g., reaction intensification technologies such as plasma ionization, catalyst optimization, section coupling to cement, steel and waste combustion branches as well as pinch technology integration and appropriate scheduling. In addition, digital twins and process analytical technologies for consequent process automation would help to decrease costs. All those technologies seem to lead to even less personnel, but who need to be highly educated to deal with complex integrated systems. Research and education/training has to be designed for those scenarios. Germany as a resource-poor country could benefit from its human resources. Germany is and will be an energy importing country