scholarly journals Seed train process intensification strategy offers potential for rapid, cost-effective scale-up of biosimilars manufacturing

2021 ◽  
Vol 20 ◽  
Author(s):  
Rajib Malla ◽  
Dhaval Shah ◽  
Chinmay Gajendragadkar ◽  
Vijayalakshmi Vamanan ◽  
Deepak Singh ◽  
...  
Keyword(s):  
Feeding Strategy ◽  
Scale Up ◽  
Control Process ◽  
Process Intensification ◽  
Cost Effective ◽  
Fold Increase ◽  
Exponential Growth Phase ◽  
Production Scale ◽  
Seed Train ◽  
Process Transfer

A perfusion approach at N-1, where cells stay in the exponential growth phase throughout the entire culture duration, is becoming more common as a strategy for process intensification. This is because the higher cell densities it generates allows manufacturers to skip seed stages and reduce process transfer time through multiple bioreactor sizes, thus providing more cost-effective biologics production in smaller facilities. However, this N-1 perfusion approach requires optimization. In this article, we describe the development and proof-of-concept studies with single-use rocking motion perfusion bioreactors in which we have achieved a ten-fold increase in viable cell count in N-1 seed stage, compared to the fed-batch control process, in just 6–8 days. We also mention in detail how we inoculated a 50 L bioreactor production run using this intensified seed train and show comparable growth kinetics and yield with a control process, also at 50 L scale. Using this intensification approach in the future will help our manufacturing facility, the Biopharma Division of Intas Pharmaceuticals Ltd., reach 4000 L production-scale volumes with fewer process transfer steps, and without changing the feeding strategy or production bioreactors of our biologics’ portfolio.

Scale-up of Process Intensifying Falling Film Microreactors to Pilot Production Scale

2007 ◽  
Vol 5 (1) ◽  
Author(s):  
Bhanu Kiran Vankayala ◽  
Patrick Löb ◽  
Volker Hessel ◽  
Gabriele Menges ◽  
Christian Hofmann ◽  
...  
Keyword(s):  
Sodium Hydroxide Solution ◽  
Ambient Pressure ◽  
Scale Up ◽  
Process Intensification ◽  
Aqueous Sodium Hydroxide ◽  
Liquid Films ◽  
Process Conditions ◽  
Falling Film ◽  
Production Scale ◽  
Future Production

Microstructured reactors with their benefits especially concerning enhanced mass and heat transfer represent a means for process intensification. A broadly used microstructured lab tool in the area of gas/liquid contacting is the Falling Film Microreactor (FFMR) developed by IMM in which liquid films of a few tens of micrometer thickness and interfacial areas of up to 20,000 m2/m3 combined with an effective heat exchange can be obtained. Now the concept of the Falling Film Microreactor has been developed further with regard to increasing throughput in order to reach pilot production level and as a basis for future production scale throughput. Therefore, two different prototypes with a tenfold larger structured surface area have been developed and realized. The feasibility of a corresponding increase of throughput has been demonstrated for the oxidation of an organic compound using oxygen which is closely linked to an industrial relevant reaction and additionally by the absorption of CO2 in an aqueous sodium hydroxide solution. Naturally, process optimisation itself also contributes to the efforts to increase throughput. Therefore, the oxidation reaction has been optimised in both varying process parameters (temperature, flow rates, pressure) and reactor parameters (microchannel width and depth) in the original, standard Falling Film Microreactor. Conducting experiments at 10 bar instead of ambient pressure and using a reaction plate with 1200 µm x 400 µm channels instead of 600 µm x 200 µm channels lead to an increase in conversion. These investigations also encourage exploring more challenging process conditions and thereby following the concept of "novel chemistry."

scholarly journals Nattokinase production: Medium components and feeding strategy studies

2014 ◽  
Vol 20 (4) ◽  
pp. 541-547 ◽  
Author(s):  
Aydin Berenjian ◽  
Raja Mahanama ◽  
John Kavanagh ◽  
Fariba Dehghani ◽  
Younes Ghasemi
Keyword(s):  
Feeding Strategy ◽  
Scale Up ◽  
Fold Increase ◽  
Polynomial Equation ◽  
Fed Batch ◽  
Medium Components ◽  
Bacillus Subtilis Natto ◽  
Order Polynomial ◽  
Composite Face ◽  
Central Composite

In the present study, the effect of nutrients on nattokinase activity during the fermentation of Bacillus subtilis natto was investigated. The highest nattokinase activity of 587 U/mL was obtained in fermenter for a media consisting of yeast extract (6%, w/v), soy peptone (1.2%, w/v) and glycerol (6%, w/v). The second order polynomial equation was fitted to the results by using central composite face design. The polynomial model fitted the experimental data well with R2 = 0.939 and R2(Adj) = 0.861. In addition, contribution of fed-batch glycerol addition on the nattokinase production pathway was further investigated. Maximum nattokinase activity was resulted when 3% (w/v) glycerol was added to the fermentation media during the cell growth phase. Results demonstrate 25 fold increase of nattokinase activity compared to the batch and not optimized culture. This study provides valuable data on the key nutrients and feeding strategy for further investigations and scale up of nattokinase production process.

Scale-up considerations

2001 ◽  
Author(s):  
John B. Noble
Keyword(s):  
Clinical Trials ◽  
Scale Up ◽  
Cost Effective ◽  
Pharmaceutical Products ◽  
Protein Product ◽  
Raw Material ◽  
Production Scale ◽  
Product Demand ◽  
Key Issues ◽  
Market Saturation

Once a potential indication has been found for a given protein product, it is necessary to produce increasing quantities to satisfy the demands of market trial activities. In the majority of cases, this will lead to scale-up of the purification process to meet demand whilst maintaining the safety, efficacy, and quality of the product. The following chapter provides an overview of the key issues that will arise during scale-up and provides the reader with practical advice on process and equipment selection. The text examines the key issues in defining production scale, identifies critical scale-up and development issues on an overall process basis, presents practical tips on scale-up, and concludes with two industrial scale-up case studies. The final choice of purification scale must reflect the most cost-effective solution for the whole of an organization and as such there are a great many influences to be considered. As a result the development process is an iterative exercise in which the production demand and schedule are balanced against available resources. A step-by-step approach to choice of purification scale is developed below: (a) Step 1: define volume of product required and when it is needed. (b) Step 2: develop a preliminary scale-up schedule. (c) Step 3: match scale and production schedule to production resources. Each of these steps will now be developed further. From preliminary product trials it will be possible to develop a schedule of product demand against time which can be used as the building block for step 2. Typically for pharmaceutical products the schedule will included materials for pre-clinical trials, phases I-III clinical trials, and commercial manufacture. During trials a defined quantity of product will be required over a clearly defined period whilst, once a product has been approved, demand will be less well defined and generally increase gradually over time to market saturation. From the schedule developed in step 1 and a knowledge of the approximate process yields, a preliminary assessment of overall raw material throughput can be developed. This can then be broken down and combined with information on product shelf-life to assess the most appropriate production strategy for each stage of a product’s life.

scholarly journals Influence of the octogen quality and production scale on characteristics of granulated plastic bonded explosive

2020 ◽  
Vol 26 (2) ◽  
pp. 183-190
Author(s):  
Hicham Kemmoukhe ◽  
Slavica Terzic ◽  
Mirjana Dimic ◽  
Danica Simic ◽  
Zijah Burzic ◽  
...  
Keyword(s):  
Polymer Coating ◽  
Coating Layer ◽  
Scale Up ◽  
Microscopic Analysis ◽  
Cost Effective ◽  
Production Scale ◽  
Slurry Coating ◽  
Granulometric Analysis ◽  
Aqueous Solvent

The compositions of granulated plastic bonded explosive (PBX), based on octogen (HMX) and Estane polymer were prepared by aqueous/solvent slurry coating tehnique, on a laboratory and industrial scale. Scale-up was done in an environmentally friendly and cost-effective way: with provided recyclage and reuse of the used organic solvent. The quality of the obtained granulated PBX samples was observed trough the following analyses: the quality of polymer coating layer on HMX crystals was examined by microscopic analysis; the phlegmatizer content in PBX samples was determined; granulometric analysis and the tests of sensitivity to friction and impact were carried out. Compressibility of granulated PBX was determined by pressing. Measured detonation velocities of pressed PBX charges were compared. The obtained properties of the examined pressed PBX indicated that it may find application as a promising main explosive charge in cumulative warheads.

scholarly journals 2D-3D integration of hexagonal boron nitride and a high-κ dielectric for ultrafast graphene-based electro-absorption modulators

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hitesh Agarwal ◽  
Bernat Terrés ◽  
Lorenzo Orsini ◽  
Alberto Montanaro ◽  
Vito Sorianello ◽  
...  
Keyword(s):  
Boron Nitride ◽  
Hafnium Oxide ◽  
High Speed ◽  
Hexagonal Boron Nitride ◽  
Temperature Stability ◽  
Cost Effective ◽  
Fold Increase ◽  
Building Blocks ◽  
High Quality ◽  
New Device

AbstractElectro-absorption (EA) waveguide-coupled modulators are essential building blocks for on-chip optical communications. Compared to state-of-the-art silicon (Si) devices, graphene-based EA modulators promise smaller footprints, larger temperature stability, cost-effective integration and high speeds. However, combining high speed and large modulation efficiencies in a single graphene-based device has remained elusive so far. In this work, we overcome this fundamental trade-off by demonstrating the 2D-3D dielectric integration in a high-quality encapsulated graphene device. We integrated hafnium oxide (HfO2) and two-dimensional hexagonal boron nitride (hBN) within the insulating section of a double-layer (DL) graphene EA modulator. This combination of materials allows for a high-quality modulator device with high performances: a ~39 GHz bandwidth (BW) with a three-fold increase in modulation efficiency compared to previously reported high-speed modulators. This 2D-3D dielectric integration paves the way to a plethora of electronic and opto-electronic devices with enhanced performance and stability, while expanding the freedom for new device designs.

scholarly journals Allogeneic human neural stem cells for improved therapeutic delivery to peritoneal ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rachael Mooney ◽  
Wafa Abidi ◽  
Jennifer Batalla-Covello ◽  
Hoi Wa Ngai ◽  
Caitlyn Hyde ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Tracking ◽  
Scale Up ◽  
Cancer Therapeutics ◽  
Cost Effective ◽  
Tumor Stroma ◽  
Clinical Safety ◽  
Peritoneal Cancer ◽  
Human Neural Stem Cells ◽  
Link Type

Abstract Background Immortalized, clonal HB1.F3.CD21 human neural stem/progenitor cells (NSCs), loaded with therapeutic cargo prior to intraperitoneal (IP) injection, have been shown to improve the delivery and efficacy of therapeutic agents in pre-clinical models of stage III ovarian cancer. In previous studies, the distribution and efficacy of the NSC-delivered cargo has been examined; however, the fate of the NSCs has not yet been explored. Methods To monitor NSC tropism, we used an unconventional method of quantifying endocytosed gold nanorods to overcome the weaknesses of existing cell-tracking technologies. Results Here, we report efficient tumor tropism of HB1.F3.CD21 NSCs, showing that they primarily distribute to the tumor stroma surrounding individual tumor foci within 3 h after injection, reaching up to 95% of IP metastases without localizing to healthy tissue. Furthermore, we demonstrate that these NSCs are non-tumorigenic and non-immunogenic within the peritoneal setting. Conclusions Their efficient tropism, combined with their promising clinical safety features and potential for cost-effective scale-up, positions this NSC line as a practical, off-the-shelf platform to improve the delivery of a myriad of peritoneal cancer therapeutics.

scholarly journals Pilot-Scale Production of Chito-Oligosaccharides Using an Innovative Recombinant Chitosanase Preparation Approach

Polymers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 290
Author(s):  
Chih-Yu Cheng ◽  
Chia-Huang Tsai ◽  
Pei-Jyun Liou ◽  
Chi-Hang Wang
Keyword(s):  
Cell Density ◽  
Scale Up ◽  
Cost Effective ◽  
Pilot Scale ◽  
Ionic Concentration ◽  
Dihydrogen Phosphate ◽  
Scale Production ◽  
Sodium Dihydrogen Phosphate ◽  
Selective Precipitation ◽  
Pilot Scale Production

For pilot-scale production of chito-oligosaccharides, it must be cost-effective to prepare designable recombinant chitosanase. Herein, an efficient method for preparing recombinant Bacillus chitosanase from Escherichia coli by elimination of undesirable substances as a precipitate is proposed. After an optimized culture with IPTG (Isopropyl β-d-1-thiogalactopyranoside) induction, the harvested cells were resuspended, disrupted by sonication, divided by selective precipitation, and stored using the same solution conditions. Several factors involved in these procedures, including ion types, ionic concentration, pH, and bacterial cell density, were examined. The optimal conditions were inferred to be pH = 4.5, 300 mM sodium dihydrogen phosphate, and cell density below 1011 cells/mL. Finally, recombinant chitosanase was purified to >70% homogeneity with an activity recovery and enzyme yield of 90% and 106 mg/L, respectively. When 10 L of 5% chitosan was hydrolyzed with 2500 units of chitosanase at ambient temperature for 72 h, hydrolyzed products having molar masses of 833 ± 222 g/mol with multiple degrees of polymerization (chito-dimer to tetramer) were obtained. This work provided an economical and eco-friendly preparation of recombinant chitosanase to scale up the hydrolysis of chitosan towards tailored oligosaccharides in the near future.

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