4Tune Engineering Ltd.

Engineering, Portugal

4Tune Engineering Ltd.

Engineering, Portugal
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Menezes J.,University of Lisbon | Gouveia F.,4Tune Engineering Ltd. | Felizardo P.,4Tune Engineering Ltd.
European Pharmaceutical Review | Year: 2014

Pharma and BioPharma industries are aware of the impact of production processes on sustainability of business operations. To improve performance, companies have recognised that it is necessary to better understand the drivers of both costs and revenues and the actions that can be put in place to address them. In the past, commercial manufacturing emphasis was on full compliance with initially established product specifications leading to a perception of quality assurance based on testing, and avoiding later changes after regulatory submission. Although final product testing is an important element of quality control, final product quality can be measured but not modified, leading to product rejection or reprocessing activities and underperforming business outcomes, two kinds of waste according to lean manufacturing.


Jose G.E.,4TUNE Engineering Ltd | Folque F.,4TUNE Engineering Ltd | Menezes J.C.,University of Lisbon | Werz S.,Hoffmann-La Roche | And 2 more authors.
Biotechnology Progress | Year: 2011

The yield of monoclonal antibody (Mab) production processes depends on media formulation, inocula quality, and process conditions. As in industrial processes tight cultivation conditions are used, and inocula quality and viable cell densities are controlled to reasonable levels, media formulation and raw materials lot-to-lot variability in quality will have, in those circumstances, the highest impact on process performance. In the particular Mab process studied, two different raw materials were used: a complex carbon and nitrogen source made of specific peptones and defined chemical media containing multiple components. Using different spectroscopy techniques for each of the raw material types, it was concluded that for the complex peptone-based ingredient, near-infrared (NIR) spectroscopy was more capable of capturing lot-to-lot variability. For the chemically defined media containing fluorophores, two-dimensional (2D)-fluorescence spectroscopy was more capable of capturing lot-to-lot variability. Because in Mab cultivation processes both types of raw materials are used, combining the NIR and 2D-fluorescence spectra for each of the media components enabled predictive models for yield to be developed that out-performed any other model involving either one raw material alone, or only one type of spectroscopic tool for both raw materials. For each particular raw material, the capability of each spectroscopy to detect lot-to-lot differences was demonstrated after spectra preprocessing and specific wavelength regions selection. The work described and the findings reported here open up several possibilities that could be used to feed-forward control the process. These include, for example, enabling specific actions to be taken regarding media formulation with particular lots, and all types of predictive control actions aimed at increasing batch-to-batch yield and product quality consistency at harvest. © 2011 American Institute of Chemical Engineers (AIChE).


Hakemeyer C.,Hoffmann-La Roche | Strauss U.,Hoffmann-La Roche | Werz S.,Hoffmann-La Roche | Jose G.E.,4TUNE Engineering Ltd | And 2 more authors.
Talanta | Year: 2012

The application of at-line NIR transmittance spectroscopy on supernatant samples from Chinese Hamster Ovary Cells (CHO) based monoclonal antibody (Mab) cultivation processes spanning several scales from 2.5 L to 1000 L, cell-lines and development years is described. The collected and preprocessed spectra were used to do process state estimation and to obtain several culture parameters. Multivariate process trajectories were computed from NIR spectra acquired at-line. These were used to enhance process understanding across different scales up to industrial scale, assess batch-to-batch variability, and examine the relative importance of different sources of process variability. Many parameters of interest in industrial cell culture, like nutrient or product concentrations can be reliably estimated by NIRS with an accuracy of 15% or better, compared to reference methods General calibrations (scale and cell-line independent) are valid across a range of process conditions and different feed regimes. The proposed approach is therefore applicable throughout process development as well as to existing large-scale validated CHO bioprocesses for continuous improvement. © 2012 Elsevier B.V. All rights reserved.


Hakemeyer C.,Hoffmann-La Roche | Strauss U.,Hoffmann-La Roche | Werz S.,Hoffmann-La Roche | Folque F.,4TUNE Engineering Ltd | Menezes J.C.,IBB Institute for Biotechnology And Bioengineering
Biotechnology Journal | Year: 2013

In biomanufacturing processes, the influence of feedstock components on product yield and quality is considerable and often poorly understood. Here we describe the capabilities of near-infrared spectroscopy (NIRS) and two dimensional (2D)-fluorescence spectroscopy in detecting chemical changes over time in two types of culture media (one basal media and one feed media) used in the production of monoclonal antibodies (mAbs) by Chinese hamster ovary (CHO) cells. Both spectroscopies were able to detect compositional changes in basal media over storage period of 12 weeks. NIRS was more effective in detecting changes in feed medium composition. The impact of storage time in process performance was evaluated by using aged media components in mAb cultivations. The study suggests that basal media aging results in a decrease of the integral of viable cells (IVC) (cell growth over time), while product titer is not significantly affected. Feed media appears to be less sensitive to storage and no correlation between the age of the media and cell culture performance was detected. Results obtained provide a basis on which to further improve cell culture raw material quality assessment using vibrational (e.g. NIRS) and optical (e.g. 2D-fluorescence) spectroscopic methods. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Buziol S.,Hoffmann-La Roche | Roth M.,Hoffmann-La Roche | Jung C.,Hoffmann-La Roche | Felizardo P.,4Tune Engineering Ltd. | And 2 more authors.
AIChE Annual Meeting, Conference Proceedings | Year: 2012

The integration of strengths of different spectroscopic methods such as Near Infrared spectroscopy (NIRS), Mid-Infrared spectroscopy (MIRS), 2-Dimensional Fluorescence Spectroscopy (2DFS) and Dielectric Spectroscopy (DS) allowed monitoring and control of different culture attributes to be readily available (inline) instead of being determined in the laboratory (offline). This is an advantage over analytical laboratory methods, since spectroscopic sensors can enable the intensification of in-process analytics. Moreover, since these spectroscopies are focusing on information of different quality attributes (chemical, physical, physiological) extractable from a biotechnological cultivation process, the combination of those has the potential to enhance the process understanding significantly. An overview of our experience in the integration of above techniques - to establish process knowledge in a reduced number of cultivations for different media, clones and products - will be described.


Gouveia F.F.,4Tune Engineering Ltd | Gouveia F.F.,Copenhagen University | Rahbek J.P.,Lundbeck | Mortensen A.R.,Lundbeck | And 4 more authors.
Analytical and Bioanalytical Chemistry | Year: 2016

Significant improvements can be realized by converting conventional batch processes into continuous ones. The main drivers include reduction of cost and waste, increased safety, and simpler scale-up and tech transfer activities. Re-designing the process layout offers the opportunity to incorporate a set of process analytical technologies (PAT) embraced in the Quality-by-Design (QbD) framework. These tools are used for process state estimation, providing enhanced understanding of the underlying variability in the process impacting quality and yield. This work describes a road map for identifying the best technology to speed-up the development of continuous processes while providing the basis for developing analytical methods for monitoring and controlling the continuous full-scale reaction. The suitability of in-line Raman, FT-infrared (FT-IR), and near-infrared (NIR) spectroscopy for real-time process monitoring was investigated in the production of 1-bromo-2-iodobenzene. The synthesis consists of three consecutive reaction steps including the formation of an unstable diazonium salt intermediate, which is critical to secure high yield and avoid formation of by-products. All spectroscopic methods were able to capture critical information related to the accumulation of the intermediate with very similar accuracy. NIR spectroscopy proved to be satisfactory in terms of performance, ease of installation, full-scale transferability, and stability to very adverse process conditions. As such, in-line NIR was selected to monitor the continuous full-scale production. The quantitative method was developed against theoretical concentration values of the intermediate since representative sampling for off-line reference analysis cannot be achieved. The rapid and reliable analytical system allowed the following: speeding up the design of the continuous process and a better understanding of the manufacturing requirements to ensure optimal yield and avoid unreacted raw materials and by-products in the continuous reactor effluent. [Figure not available: see fulltext.] © 2016 Springer-Verlag Berlin Heidelberg


PubMed | Lundbeck, 4Tune Engineering Ltd and Copenhagen University
Type: Journal Article | Journal: Analytical and bioanalytical chemistry | Year: 2016

Significant improvements can be realized by converting conventional batch processes into continuous ones. The main drivers include reduction of cost and waste, increased safety, and simpler scale-up and tech transfer activities. Re-designing the process layout offers the opportunity to incorporate a set of process analytical technologies (PAT) embraced in the Quality-by-Design (QbD) framework. These tools are used for process state estimation, providing enhanced understanding of the underlying variability in the process impacting quality and yield. This work describes a roadmap for identifying the best technology to speed-up the development of continuous processes while providing the basis for developing analytical methods for monitoring and controlling the continuous full-scale reaction. The suitability of in-line Raman, FT-infrared (FT-IR), and near-infrared (NIR) spectroscopy for real-time process monitoring was investigated in the production of 1-bromo-2-iodobenzene. The synthesis consists of three consecutive reaction steps including the formation of an unstable diazonium salt intermediate, which is critical to secure high yield and avoid formation of by-products. All spectroscopic methods were able to capture critical information related to the accumulation of the intermediate with very similar accuracy. NIR spectroscopy proved to be satisfactory in terms of performance, ease of installation, full-scale transferability, and stability to very adverse process conditions. As such, in-line NIR was selected to monitor the continuous full-scale production. The quantitative method was developed against theoretical concentration values of the intermediate since representative sampling for off-line reference analysis cannot be achieved. The rapid and reliable analytical system allowed the following: speeding up the design of the continuous process and a better understanding of the manufacturing requirements to ensure optimal yield and avoid unreacted raw materials and by-products in the continuous reactor effluent. Graphical Abstract Using PAT to accelerate the transition to continuous API manufacturing.

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