Day two of the 12th annual Bioprocess International (BPI) Conference & Exposition featured a full day of exhibitions and continued high-level technical discussions and presentations that attendees have come to expect from the show. The day began on a high note with keynote speakers giving insight into the next generation of manufacturing. Valuable conversations continued during exhibit hours with the curtain rising on the BPI Theater. Of course, there were technical sessions throughout the day, as well. Some of the highlights from the second day of BPI 2015 are below.
Bioprocessing manufacturing facilities were the topic of the day during the keynote addresses, as representatives from Amgen and Genzyme, a Sanofi company, built on the keynotes presented on day one. Both day two speakers opened the door on technologies and trends to provide a peak on what the future may hold for the industry.
The future is now was the theme of the first presentation, given by Kimball Hall, Vice President Manufacturing, Amgen Singapore Manufacturing Pte. Ltd. Her address was on Amgen’s Next-generation Biomanufacturing Facility, which was four years in the making and is scheduled to open its doors in 2017. In changing the manner in which Amgen conducts bioprocessing manufacturing, the company is also re-shaping the entire industry, according to Hall.
“Whereas in the past, the focus was on high margins and capacity, today biomanufacturing is centered on cost, speed, and operation flexibility,” she explained.
Hall shared the thoughts of one of Tuesday’s keynote speakers, David J. Pollard, PhD, Executive Director, BioProcess Development, Merck & Co., Inc., when she spoke of a modular method for facility design.
“In a conventional facility design, capacity becomes a consideration in Phase II. That is not the case with a modular design as it allows facilities to expand or contract as the market demands. Additionally, the modular format is agnostic to a country or location,” she explained.
In addition to a modular format, the Amgen Singapore facility incorporates other design elements that have proven to create benefits in construction time, operations, and environmental footprint. Among those elements mentioned by Hall were integration of single-use technologies (95% of the equipment is single use), incorporating connected processing, and real-time and remote monitoring.
Hall explained that the disruptive approach taken by Amgen has cut the construction time of the Singapore facility in half and capital costs are one quarter that of a conventional facility. Operating expenses will be lowered by a third, as well, according to Hall. The end result will be an approximately 60% reduction in protein development cost.
“One of the first questions I’m asked about is the environmental impact of the facility. I am happy to say that it will use less water for heating, cooling, and cleaning. Because it is a smaller facility, it will have a lower air quality classification, and emissions will be lower due to reduced energy usage and Singapore’s cleaner energy,” explained Hall.
All told, the new facility in Singapore is expected to have an 80% reduction in energy and water use.
In the second keynote, Konstantin Konstantinov, PhD, Vice President, Technology Development for Genzyme asked What is the Future of Continuous Processing – What is the Time Frame for Implementing Fully Continuous Processing in Commercial Production? He spoke of changes in upstream and downstream processes that will help create a “dominant design” in the next 5-10 years that will help shape bioprocessing.
“The commercialization of innovation will lead to a dominant design where almost any protein can be developed using a universal platform. It will take a lot of courage and focus to accomplish this dominant design,” offered Dr. Konstantinov.
The dominant design outlined by Dr. Konstantinov is an end-to-end continuous integrated upstream and downstream principle. While there has been promising results in a pilot facility, Dr. Konstantinov noted, “Success is impossible without a high-performance cell line.”
Thankfully, Dr. Konstantinov believes there is tremendous opportunity to improve cell lines. Success will be determined by three factors – stable productivity over a long period of time, stable quality over a long period of time, and low cell specific perfusion rate.
While upstream processing improvements are one step, Dr. Konstantinov expects “a lot of changes” in the downstream. He noted developments in equipment, and spoke of a large scale continuous purification system with a very broad capacity range currently in a laboratory at Genzyme’s Framingham, Massachusetts, campus.
Despite all the progress, Dr. Konstantinov noted that the industry is entering a “very interesting stage.” New technologies still need to be developed to fill a few gaps, including cell retention devices and viral inactivation.
He also suggested the industry broaden its approach to the integration of continuous processing. “Why stop at drug substance? We should also look at drug product because continuous manufacturing can bring advantages there, as well.”
Technical Session Highlights
In his session entitled High-throughput Process Development to Accelerate Speed to the Clinic for Antibodies, Gregory A. Barker, Ph.D., Sr. Engineer, Biologics Process Development, Bristol-Myers Squibb spoke of High-throughput Process Development (HTPD) and how it allows scientists to examine 300,000 compounds per day so it only takes a few weeks to screen millions of substances. Before HTPD, Bayer researchers could take several months to develop special activity assays.
The goal of using HTPD, a computer-based serial-testing method that incorporates robotic systems, is to determine whether a substance reacts biochemically with the target, according to Dr. Barker. During the HTPD process, robots fill millions of reaction vessels with the assays.
“For example, a specific vessel may hold only 50 nanoliters of fluid with the vessels aligned on a plate that holds 1,536 wells. This would allow for 1,536 biochemical or cell-based assays to be performed simultaneously on a single microliter plate. In fact, thousands of these are often used in a single HTPD run,” said Dr. Barker.
As Dr. Barker explained, key benefits of HTPD for chromatography unit operations include:
- A platform for rapid execution of experiments using sparingly small amounts of material to enable investigation of a broad range of process conditions
- Fundamental data that may be used for scale-up via statistical modeling and process simulate
- Systematic and highly reproducible execution of complex DOEs to survey the knowledge space and enable multivariate understanding
Specific methods of HTPD for chromatography were detailed, such as:
2. Batch uptake curves
3. Batch chromatography
Dr. Barker described several HTPD methods that are used to augment FIH process development packages, including protein solubility, Protein A optimization and Sartobind Q membrane optimization. The comparison between common data sets enables adaptation of the platform and modification to process ranges.
In summarizing his remarks, Dr. Barker said that HTPD methods are well-defined and are producing data aligned with literature values. The data alone enables a broader PD knowledge space. Empirical models built directly from batch chromatography data enable a first level of prediction for large scale chromatography and rapid FIH timelines. One thing he noted was that a comparison of HTPD campaigns across different proteins reflected both commonalities and differences. As a result, the next steps will be to explore the drivers of commonalities and differences based on structural motifs.
One of the more distinguished posters at BPI 2015 was presented by MedImmune and was entitled The Final Push? Expelling mAb Drug Product from Pre-Filled Syringe Configurations for Sub-Visible-Particle Testing. The poster proposed that a partial expulsion of drug products in pre-filled syringe (PFS) configurations would more accurately reflect protein behavior.
The poster showed that completely expelling a PFS generates a significant surge of sub-visible particle (SVP) counts, stemming from the silicone oil (SiO) scraped from the syringe barrel and forced through the needle. Conclusions drawn from the experiment and published were that completely expelling a PFS results in SVP counts as much as 50x greater than if PFS was partially expelled. Particles in the surge are SiO droplets scraped off the barrel during the expulsion process and introduced into the liquid upon complete expel. Other conclusions drawn are that partially expelling a PFS is robust with respect to expel volume. Removing the product through the stopper is an orthogonal method of sampling without introducing the high artificial SiO background. The final conclusion was that product stability should be monitored by partial expel during the drug development process, as it best isolates the protein behavior.
Roche Custom Biotech made three announcements, two on products and a third on partnership, at BPI 2015.
The two new production introductions were:
Cedex Bio HT, a highly reliable metabolite and substrate analyzer for cell culture analysis. It offers unique photometric technology that delivers high data accuracy, as well as a cost-saving expandable menu.
Tools for In Vitro Glycoengineering that can be used after proteins have been harvested. The tools increase productivity and can be used in early stage development.
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