Biotech Manufacturing Trends from the Bioprocess International 2018 Conference

The Bioprocess International Conference, hosted by the industry-leading publication, Bioprocess International, brings people from across the world in the biotechnology field to share insight, network, and discuss the current and prospects in biologics manufacturing. This years’ conference took place September 4-7 in Boston, Massachusetts and was part of the Boston Biotech week. The conference was split into seven tracks to cover a variety of topics including:

  1. Recovery and purification
  2. Manufacturing strategy
  3. Bioprocessing 4.0
  4. Speed from gene to market
  5. Cell culture and upstream processing
  6. Analytical and quality
  7. Drug product, fill finish, and formulations

In addition to attending the conference, I also presented a poster on the results of the scalability and economics of our ExpressTec platform for protein manufacturing. My presentation featured in-field application results using our platform in substituting other expression platforms like CHO cell cultures as a scalable and cost-effective substitute. To convey our platform capabilities, I focused on a liquid lysozyme solution that can replace hen egg white lysozyme (HEWL) as a primary source of lysis activity. Our platform can easily produce the world’s demand of lysis activity with a product that has a higher concentration of activity per mass while being able to undercut the current cost of HEWL.While at the Bioprocess International Conference, I pursued topics on recovery & purification, manufacturing strategy, and bioprocessing 4.0 sections to help get a better idea of how current industry standards can be applied to our ExpressTec platform. Between these tracks, there were three overarching themes that stood out, describing the forward trend for the biotech industry.

Three Over Arching Trends

1. Evaluation and Implementation of Single-Use Systems

Over the past two decades, single-use systems have been gaining traction as a cost-effective manufacturing strategy as compared to traditional stainless-steel systems. With single-use systems, extrinsic contamination risks can be mitigated through a closed system. However, intrinsic contamination risks increase due to higher usage. Therefore, Sartorius has focused on minimizing the risk associated with particulates and leachables in their single-use systems. They have put their manufacturing in an iso7 cleanroom to minimize particulate contamination during manufacture and have expansively tested sources and sinks for leachables into a database. Levitronix provides pumps that are ideally suited for single/multi-use systems, and that can be used to easily implement product changeover. They accomplish this through a magnetically levitated impeller that has low shear and does not directly contact any other surfaces.The shift towards single-use manufacturing has been influenced mainly by the effects of increasingly high titers achievable in cell culture and optimization of manufacturing logistics. High titers result in smaller bioreactors needed, giving rise to manufacturing facilities that can produce several products using different processes. With single-use systems, processing multiple products in the same facility becomes trivial with almost no time needed for cleaning and changeover. This has led to facilities adopting a ballroom-style facility where unit operations are mobile, and manufacturing can be adapted to any product desired.While single-use is becoming a large part of biopharmaceutical manufacturing, stainless steel systems are still applicable, particularly for processes that demand high volumes of cell culture (>2,000L) and large annual quantities of product. When investing into single-use, you are also investing into the company, and maintaining a good partnership should be a priority. Additionally, there is a significant amount of solid waste produced with single-use systems that needs to be considered. While I did not hear many comments on this, the impression I got was that waste management did not have a large impact on its implementation.

2. Continuous Manufacturing

Continuous manufacturing is superfluous in traditional chemical manufacturing plants and typically sees savings in manufacturing costs and product consistency. Manufacturing continuously in the biotech industry has been difficult due to the batch nature of multiple unit operations in the protein purification pathways, primarily the cell culture and chromatography steps.For all the parts of a manufacturing process, making the buffers can be labor intensive and typically done batch-wise. Asahi Kasei makes inline conditioning systems that can be used to make buffers on demand and continuously. Their systems can titrate a buffer using a feedback system to the appropriate pH and add salt to the desired concentrations. Furthermore, Asahi Kasei recently introduced a reagent tracker that simplifies quality assurance and minimizes risks associated with transcription errors. It can track what reagents went into the buffer to allow tracing back a buffer to its origin. It can also provide information on composition, method, date of manufacture and can include date of expiry for the mixed buffer to streamline and save time during operation.For the upstream manufacturing, Cell perfusion has been a known continuous culture platform that typically uses hollow fiber technology to separate excreted proteins from the cells. Perfusion can obtain higher cell densities and thus have a smaller footprint as compared to batch systems. However, perfusion is only applicable to systems where the product is excreted from the cell which limits its potential usage.The downstream processes have been more challenging to make continuous. Recent developments have been focused on simulated moving bed chromatography. Since 2016, Pall has been working and scaling a system for continuous chromatography called Cadence BIOSMP. Their line of equipment is geared toward simple scale-up from lab to process scale, with their largest Cadence system capable of up to 350L/hr flow rate. Additionally, their system has been designed to incorporate single-use flow paths for the benefits single-use systems provide. Continuous chromatography can result in a fraction of the resin volume needed as compared to batch chromatography while increasing the productivity of the resin. A continuous chromatography step can have multiple benefits that ultimately decreased the overall cost of the step and increased the usage efficiency of the resin to process more mass in less time with fewer materials.At the conference there were a few companies that were introducing new resins that could have a large impact in deciding what the best resin is for use in a specific application. Purolite has developed a new manufacturing technology, called jetting, for producing a tighter particle size distribution. With this new resin, the particle size can be shrunk down to provide a higher surface area for binding without sacrificing flow rate. Thermo Fisher Scientific has a new POROS line of HIC resins that can excel at removal of monoclonal antibody (mAb) aggregates. In a case study, they showed that they could achieve a purity of 99% and yield of 98% from a starting solution that was 90% pure with the impurities being dimer and aggregates of the mAb.

3. Bioprocessing 4.0

Biomanufacturing has gone through multiple phases of innovation. The last one, bioprocessing 3.0, referred to the transformation from manual systems to automated systems. Now we see ourselves in the Bioprocessing 4.0 period which is primarily defined by big data, internet of things, and use of artificial intelligence/machine learning to improve and control processes. This data can be used to more accurately plan and predict for downtime in the process, efficiently utilizing a facility’s investment.Bioprocessing 4.0 implementation requires data collection and creation of a virtual plant, commonly called a “digital twin”. The plant should be able to integrate data for the process to constantly update the model, and at the same time predict the process state. This requires a fair amount of investment into data collection, storage, and data analysis infrastructure, which can be difficult to justify when the benefits are usually intangible. Having this data infrastructure provides insight into routes of optimization of the process and logistics of a facility. Furthermore, it simplifies automation of the process and provides opportunity for inline quality control that can catch process deviations before they happen and take corrective actions to mitigate that risk.Overall, my key takeaways from this conference are that biopharmaceutical manufacturing is trending towards a single-use ecosystem that is highly flexible and mostly automated. This will allow for high optimization of various processes in a single facility that will lead towards more efficient use of time and investment. I found that Ventria Bioscience’s ExpressTec could fill a very useful niche since our processes span two fields: food chemicals and pharmaceutical chemicals.Our upstream process can utilize insights and improvements from food to efficiently produce and extract protein, while skirting the costs associated will cell culture production. Furthermore, infrastructure and designs for large scale food systems exist and lend the benefits of large and continuous production of protein extracts. Meanwhile, our downstream processes can follow the benefits of single-use and continuous manufacturing that is being commonly implemented in current biomanufacturing processes. I am excited to see how the field continues to evolve to create drug products that are more available, specific, and cost effective for the consumers.

About the Author

Brandon Tomás, Process Engineer at Ventria Bioscience. Brandon has his B.S. in Chemical Engineering and Biochemistry from the University of Kansas with 4 years of protein purification experience from laboratory to manufacturing scale. His work focuses on developing new manufacturing processes for proteins expressed and scaling the processes to a manufacturing level.