Batch vs. Continuous, Scale-Up & Scale-Down, Case Studies

Early-stage process development to introduce new molecules or active materials is often performed in a batch mode and a small scale. These process steps typically include synthesis, separation, and purification. However, when the development team explores the commercial viability of the new process technology, the decision of batch vs. continuous operating mode and a combination of scale-down from feasible commercial embodiments and risk-managed scale-up is critical. 

Depending on the process technologies and materials, many factors and potential tradeoffs need to be considered when identifying the most optimal operation mode and scale factor. Examples include a reduced number or right-sizing of experiments and possibly step-skipping, process safety, complexity, product form & quality, production volume, manufacturing cost, investment & physical footprint, production time, location, waste generation, sustainability, and commercialization timeline. 

This session will cover case studies on how the differences in the benefits & risks for these aspects impact the batch vs. continuous, scale-up & scale-down process decision, and methodologies for accelerated process scale-up.

Session Chairs:

• Omid Ebrahimpour, DuPont
• Anastasios Skoulidas, ExxonMobil

Tentative Schedule:

Abstracts:

Development and Scalability Assessment of a Continuous Perfusion Process for mAb Production in CHO

Xiaodan Ji, GlaxoSmithKline; Gabrielle Lomanto, GlaxoSmithKline

Continuous perfusion processing has gained growing interest in the biopharmaceutical industry due to its economic benefit, higher volumetric productivity, facility advantages, and enhanced control of product quality attributes, compared to the batch processes. However, the optimization of the culture performance and scalability of a perfusion process remain challenging due to the process complexity of supporting high cell densities and scaling of perfusion parameters and equipment. Here, we present a case study where an ATF (Alternating Tangential Flow) based high-density perfusion process for mAb production was developed using a 3-L glass stirred tank bioreactor. This process was scaled up to a 50-L single-use bioreactor (SUB) as well as scaled down to Ambr250 SUBs at the same time, to analyze the performance at microscale, bench scale, and large scale simultaneously. Similar process performance with cell growth and productivity profiles were observed across the three scales, with slightly reduced cell viability in 50-L and Ambr250 compared to that in 3-L reactors. The accompanied increase in lactate levels and higher glucose consumption in the 50-L reactor indicated the cells were undergoing hypoxic stress caused by the long ATF residence time. By adjusting the ATF cycle rate in the 50-L reactor to reduce ATF residence time, the cell viability was recovered, and the lactate levels became stabilized. The lactate production and glucose consumption were not elevated in Ambr250 cultures, suggesting different causations for the viability drop in Ambr250. Instead, other factors including higher gassing and antifoam addition as well as semi-continuous bleeding contributed to the reduced viability in Ambr250. Despite the small discrepancies in metabolic profiles, this study confirms the scalability of our process and demonstrates scale-to-scale comparability in the perfusion process. The results also underline the role of ATF cycle rate as an important operating variable during scale up design of a perfusion process.

Practical Guidelines for the Design of Sustainable Technology

Mike Schultz, PTI Global Solutions

We are in the midst of a global crisis with the need to reduce carbon in order to limit global warming to 1.5 deg C above pre-industrial levels, as established in The Paris Agreement.  This drives a need for breakthrough technologies across all industries that can both reduce carbon and create value. We can draw on experience to reduce the time, cost, and risk of technology scaleup, through guidelines and practices that are the key to practical technology scaleup. This increases the chance of success for individual technologies and will enable us as a society to meet these aggressive climate targets.  

Key challenges associated with scaleup and design of a new sustainable technology include: 

·       reducing technology risk 

·       reducing time to market 

·       optimizing/minimizing cost 

·       maximizing value 

These are often competing objectives, and usually reducing time to market and reducing risk win out. Of course, if the capital and operating cost are too high then a new technology will not be successful, so these criteria cannot be ignored.   

This presentation will provide guidelines and best practices for scaleup and design of sustainable technology, with the aim of reducing the time, cost, and risk. Sustainable technologies bring unique scaleup challenges whether due to lack of established kinetic models or data (e.g., bacterial growth kinetics and flux models), new separation challenges (CO2 from air, intracellular bioproducts), new optimization criteria (carbon footprint and other ESG/LCA metrics), and unit operations used in new applications.  

The conceptual process design is established early to drive the scale-up effort, not just inform it. This then enables innovation to be directed to create the greatest value from breakthrough and disruptive ideas and to identify challenges early, fail fast when it is cheaper and quicker, and make sure efforts are focused on solving commercially relevant problems. 

The conceptual process design is developed, and iteratively revised, through a combination of creative process engineering, multi-scale experimental data, and modeling and analysis.  

The key benefits to this approach are: 

•               Prioritization of R&D to de-risk and optimize a new technology. 

•               Identification of cost reduction opportunities throughout the scale-up effort. 

•               Anticipation of process design needs as early as possible.  

This leads to an approach that can reduce risk and optimize economics of the new design, while efficiently managing the time and cost of these efforts. 

In this presentation these concepts will be illustrated with examples from real life projects in sustainable technology areas such as CO2 fermentation to produce alternative dairy proteins, conversion of fatty acids into base oils for lubricants, and green ammonia through electrolysis.  

Process development excellence to scale up: a path towards expedited technology transfer and commercisalization within Biotechnology

Ashkan Tavakoli, Alpha Teknova

Traditional process development may not be the fastest and the most efficient approach for scaling up/down of certain processes, especially in a Contract Manufacturing Organization, where speed of truing new ideas to product is of the essence. In fact, the technologies that have moved the industry for decades are proven to be no longer competitive in the market. While proper Design of Experiments and performing adequate pilot scale studies are very crucial for successful technology transfer and introduction of new processes, expedited process development and process engineering call for risk-based approach and a built-in agility within the processes, equipments and operations to manage the risks associated with change in production scale. The wide portfolio of products with very different distinct requirements (e.g. Animal Origin Free, Endotoxin Free) plays a huge factor in the design of processes and equipment to meet not only what is required today but also what may be in the horizon. Thus, the vision of the business and continuous education and exploration of solutions along with risk mitigation and risk management is what will differentiate how quickly scale up of any product can be taking place. In this presentation, the development and scale up of batch manufacturing of Broth products from small scales of 10-20 Liters to 1200 Liters in a modified geometry is discussed based on a combined strategy of risk mitigation and proper experimentation. Moreover, the scaled-up processes including dispensing, mixing, heating up and cooling down along with the associated hardware were automated for achieving more efficient process controlling and enhanced reproducibility.