Preparing for future bioprocessing challenges with the Cellca CHO Expression Platform

Therapeutic protein development and production is a very technically challenging, time consuming and expensive endeavor.

What are some of the challenges? There are numerous critical decisions that must be made with regard to mammalian cell line choice (CHO, NS0, etc.), appropriate gene and marker expression systems, cell culture medium and feed optimization, clone selection and scale-up strategies. Biopharmaceutical developers should be careful to choose options which deliver the following:

• Maximum protein titer
• Scalability (5L – 1000L)
• Long-term Stability
• Cost effectiveness
• Shortened development timelines
• No burdensome IP concerns

Why is it important and critical to understand these challenges? There are considerable economic considerations to be made; one should maximize financial budgets by minimizing expenditures on equipment and technologies required for in-house development and characterization of the therapeutic protein. It’s important to make efficient and productive investments in R&D; technology and process development requires highly trained and expert staff. There are also commercial or market considerations which will affect return on investments; to maximize IP and patent life the therapeutic protein must be developed and commercialized as quickly as possible to gain maximum market share in a highly competitive environment. First to market is paramount for biosimilar developers.

How has the CRO industry responded? “Turn-key” cell line development and bioanalytical testing CROs are currently open for business and accessible for outsourcing nearly all upstream, downstream and biomolecular analytical activities. Sartorius Stedim Biotech offer the most comprehensive, scalable and unique bioprocess portfolio to support Biosimilar development and manufacturing. With Sartorius Stedim Biotechs’ recent acquisition of Cellca (cell line development) and BioOutsource (bioanalytical and biosafety testing), there is now established a fully functional, and integrated CRO uniquely positioned to support clients development programs across the entire product lifecycle.

The result of outsourcing biopharmaceutical development and production to experienced CROs will have major positive implications for shortening the time to commercialization at significantly reduced costs.

To learn more about the industry leading Cellca CLD platform which delivers stable, high titre clones, (95% of projects have delivered titres >3.0g/litre) in a proven scalable fed batch manufacturing process in a cost and time efficient manner please join our talk by Dr. Brian Wendelburg at IBC Cell Line Development & Engineering Conference, San Francisco, 14th June at 1.25pm.

Author Bio:


Dr. Brian Wendelburg received his Ph.D. in Molecular Biophysics from the Institute of Molecular Biophysics at Florida State University. He then completed his postdoctoral training at the University of North Carolina’s Lineberger Comprehensive Cancer Center. His professional career has involved diverse roles in sales and business development activities at leading Biotech companies such as Cepheid, Affymetrix and Miltenyi Biotec where he gained a strong technical background in genomics, proteomics and cell and gene therapy applications. He joined the Sartorius-Stedim Biotech team in the spring of 2016 and is currently Sr. Field Marketing Manager for the BioOutsource and Cellca divisions.

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The Standardization of Single-use Components for Bioprocessing

The focus in the bioprocessing industry is shifting from acceptance of single-use technology to standardization. It is critical that components be included in the standardization discussion. The tubing connector is essential for secure, sterile, leak-free connections between various single-use systems and processes. A user can have the best filter, bag and tubing but this is all pointless if the connector is not reliable, easy-to-use or robust. Improving connector compatibility and interchangeability are great opportunities for standardization, particularly because of complications related to managing inventories.

Inventory Issues

Several inventory issues arise from lack of connector standardization:

• Increased ordering complexity because the user must define which tube set or assembly works with which part of the application. 
• Greater risks of specifying the wrong system or connection, resulting in downtime and last minute adjustments at the end user site.
• Longer lead times because systems suppliers are manufacturing lower volumes of multiple SKUs as opposed to higher volumes of fewer SKUs. This lowers the incentive and likelihood for a manufacturer to stock of these items.
• Increased stocking requirements for end users, including connectors of different genders and other components needed to create make-shift adapters.

Reducing Overhead Costs: Less is More

While overhead cost reductions might be difficult to quantify, they cannot be overlooked. Reduction in SKUs and inventory lowers the cost of managing and maintaining that inventory, which allows capital to be allocated to additional process improvements. One way to help simplify and reduce inventory is to use genderless connectors that enable transitions between tubing of different sizes. Using genderless connections (e.g. CPC’s interchangeable AseptiQuik® G connectors) eliminate the need for reducer fittings elsewhere in the process as the connectors can act as reducers.

Component Standardization

By focusing on the most versatile genderless connectors, component standardization will help bioprocessing companies make the best use of single-use technology. The right connectors will enable end users to:
• Streamline operations with easy-to-use, robust sterile connections
• Eliminate potential ordering mistakes and reduce inventory demands related to gendered connectors • Maintain more flexibility and lessen production bottlenecks with onsite connector assembly 
• Reduce overhead costs, freeing up capital for other projects

Ultimately, standardizing components by incorporating single-use genderless connectors lets end users accomplish more with fewer finished goods, saving time and money, and getting their biopharmaceutical products to market more efficiently. 


Author: Todd Andrews, Global Sales and Business Development Manager, Bioprocessing for CPC – Colder Products Company

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Don’t Miss BPI West!

Last chance to register for BPI West is March 9th. Use the code BPIWEST16BL and save $100- Register now!

The clock is ticking. BPI West is just over a week away! Don't miss out on networking with industry experts, scientists and executives, along with emerging and established technology companies. Your registration will gain you access to:

• 700+ global attendees
• 80+ exhibitors highlighting new products and technologies
• 65+ scientific posters showcasing novel research
• 3 thought-leading keynote presentations
• BPI West Theater Presentations
• And More!

Download the brochure for full program details.

PLUS! We're excited to announce that Michael Egholm, President of Pall Biopharmaceuticals joins the upcoming BPI West event in Oakland on March 14th! Join us as he provides an update on the Significant Technology Advances Enabling Integrated Continuous BioProcessing during Monday's The Future of Continuous Processing pre-conference symposia. Best of all, this session is complimentary to all registered attendees!



Can't make it to all 4 days? We've got you covered with special one-day Exposition Hall & Keynotes passes starting at $150! Click here for more information.

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The General Evolution of the Vaccine Industry

For a sneak peek at the high caliber of content presented at BPI West, we had industry expert Rahul Singhvi, COO of Takeda Vaccines join us for an exclusive interview.

In this interview, Rahul Singhvi, MBA, the Chief Operating Officer at Takeda Vaccines starts by discussing the general evolution of vaccine industry over the years and what the industry looks like today. He mentions that companies in the vaccine space today tend to be very insular - controlling all aspects of the process - but continues on to say that Takeda is proudly taking a partnering approach and goes on to explain what that means and why it is important. On top of that, Rahul continues to discuss what he feels the greatest needs and opportunities are in terms of technological innovation, development and manufacturing solutions. And finally makes some bold predictions on the vaccine industries future, and the key trend and opportunities that you should watch for.

Access the Interview

Interested in learning more? Join us at BPI West - March 14-17 in Oakland, CA. Register before 2/19 with the code BPIWEST16BL and save $300 | To activate your savings, click here.

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Advances in Continuous BioProcessing | Experts from Pall Life Sciences Provide Insights

Pall Biopharmaceuticals' Leader Provides an Update on Significant Technology Advances Enabling Integrated Continuous BioProcessing 

There is a lot of talk about Continuous Bioprocessing, but how does the desire for a continuous bioprocess get turned into reality? On October 29th, 2015 at BPI in Boston Michael Egholm provided Pall Life Sciences' view on building a working GMP end-to-end continuous bioprocess. The activity on the project is fast paced and this will be an update on the latest in continuous processing.

Join the Pall Life Sciences team at BPI West for their session on March 14th as they provide a much needed update on technological advances that are enabling integrated continuous bioprocessing.

Interested in learning more? Register for BPI West now and save $300 - To activate your savings, use the code BPIWEST16BL

Pall Life Sciences provides process, pilot and laboratory filtration, separation, purification and fluid handling devices, systems and services, with single-use systems available for all unit operations from cell culture through final formulation and filling.

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[Interview] K.V. Subramaniam, Chief Executive Officer of Reliance Life Sciences

In this interview, K.V. Subramaniam, MBA, Chief Executive Officer of Reliance Life Sciences, discusses the history of Reliance Life Sciences and their companies evolution over their 13 year history. With K.V.'s extensive knowledge in emerging markets, he discusses what it takes to gain traction in India and other emerging markets... more specifically, he discusses the innovation imperatives for India and other emerging markets; in regards to where he sees needs, and the opportunities for technology and product solutions. On top of that, K.V. discusses how the market itself has changed over the years and what it will look like moving into 2016 and beyond.

Access the Interview 

Interested in learning more? Join us at BPI West - March 14-17 in Oakland, CA. Register before 2/19 with the code BPIWEST16BL and save $300!

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8 Reasons Why You Can't Miss BPI West | Plus! Register by Friday, 1/22 and Save $400

8 Reasons Why You Can't Afford to Miss BPI West:

1. First and only phase-based format event that fosters the collective sharing ideas, strategies and solutions across departments to improve speed, cost and quality at every stage of development
2. Breakdown the barriers and collaborate across stages of development to achieve end-to-end integration
3. Discover the latest breakthroughs on successfully implementing continuous processes and linking them together to achieve fully continuous processing from cell culture through to drug substance
4. Accelerate the design and development of novel drug substances for next generation therapeutics by integrating candidate selection and early development
5. Develop strategies for fast tracking early stage biologics and managing the life cycle of a break through therapy designated product
6. Speed up and streamline the transition into development by utilizing manufacturability assessments, automation, and QbD in late stage discovery and R&D
7. Implement disruptive technologies and achieve operational excellence to drive manufacturing efficiencies and minimize costs
8. Uncover the future of single-use systems and next generation facility design, modelling and management in current and emerging markets

Want to learn more about the event? Download the brochure.

Register by this Friday, January 22nd and receive up to $400 in savings - Use the code BPIWEST16BL to save.

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[Podcast] Biodevelopment Centers; Flexibility, Modular Facilities & the Benefits

Many people think about flexibility in many different ways. One of which, ensure the ability to change very quickly the set-up of pants to adapt the various parts of the manufacturing suites. Flexibility is not only about pushing in or pulling out some new equipment, it’s also about changing completely the way you work in the plant.

In regards to modular facilities, Sébastien Ribault, Ph.D., Director Biotechnology/Life Science, Head of BioDevelopment Center, EMD Millipore mentioned that they have had a number of different experiences, the first of which was modifying an existing Biodevelopment Center. He said, “We divided the building into two parts. We’ve kept 50% stainless steel and we’ve modified the remaining 50% by making fully single-use” and it turns out that during the modification process, “we kept running the plants”. Dr. Ribault continued “We noticed then, that you can run the plants while making modifications in you are using flexible concepts.”

In this podcast interview, Dr. Ribault discusses:

• What it means for your Biodevelopment Center to be flexible
• More experiences relating to modular facilities
• The benefits he has experienced (at the expected level)
• The benefits he has experienced (that were not anticipated)
• The next steps

Listen to the podcast or download the transcript here.

Want to learn more? Then join us for BPI West, March 14-17th in Oakland, CA. Rates increase Friday, 1/22 – register now with the code BPIWEST16BL and save $400!
 

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[Podcast] Disposable Membrane Chromatography Systems for mAb Purification

While around 75% of therapies in the market are based on antibodies and the classical way of purifying them in the bed chromatography approach. This method of purification is only good for a product with a long shelf-life or is in high demand. What about the products with low demand or are only for therapeutic and clinical use?

Siddhartha Shrivastava, Ph.D., Senior Scientist, Downstream Process Development, Patheon says “if the product has got a long shelf-life, a long demand, that makes sense for us to invest in it and create a good infrastructure, a good footprint and bear the high operational and capital expenditure. But, if the product is in the development phase and you need to have some quick lots of drugs so that we can try clinically, that does not make sense. And, by moving to the disposable technology we are also reducing the chances of cross contamination.”

In this podcast interview, Dr. Siddhartha Shrivastava explains:

• The importance of disposable membrane chromatography systems for mAb purification
• Why disposable technology is more appealing compared to conventional technology
• The cost effectiveness of disposable technology
• Large scale testing of disposable membrane chromatography systems

Listen to the podcast or download a transcript here!

Editor’s note: Interested in learning more about the importance of disposable membrane chromatography systems for mAb purification? Then join us for BPI West, March 14-17th in Oakland, CA.

Download the event agenda or visit the event website.

Save $400 - Register with the code BPIWEST16BL

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Leaders from Amgen and Celltheon Set to Keynote BPI West

Specialists from every discipline and stage of development aim to achieve the common goals of optimizing speed, reducing cost, and improving quality from basic research to commercialization. What helps the learning curve is to benchmark best practices from the exclusive experience of the top minds in the biopharmaceutical industry.

The leading experts from Amgen and CellTheon will get together at BPI West in Oakland, CA (March 14-17, 2016) to share their exclusive case studies and new data and evaluate the different approaches that are being utilized to streamline and accelerate development and production across:

- Basic Research & Discovery
- Early Stage Process Development & Pre-Clinical Manufacturing
- Late Stage Process Development & Clinical Manufacturing
- Commercial Manufacturing & Beyond

The following keynotes have been announced:

Amita Goel, MSc. Founder, and CEO, Celltheon will be presenting on Innovative Technologies for the Expression of Next Generation Bio Therapeutics;

Rohini Deshpande, Ph.D. Executive Director, Process and Product Development, Amgen will give a talk on End-to-End Integration;

Ran Zheng, Ph.D., Executive Director, Plant Manager, Amgen is joining BPI West with a presentation called “Unleashing the Power of Innovation to Tackle Biomanufacturing's Greatest Challenges, Fuel Growth and Drive Value Creation.”

To see more speakers and to get the most up-to-date brochure, click here. 

Don’t miss the chance to learn the innovative strategies and technologies and help move the pipeline of next generation drug candidates closer to approval!

Register before Friday, January 22nd and save $400 – Simply use the code BPIWEST16BL, to save. 

Follow @Futurebiopharma

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BPI West Brochure is Now Available for Download | Save $500 Now, Rates Increase Friday

Break down the barriers between departments and stages of development at BPI West - the industry's first and only phase-based format event! 

Download the Brochure Now.

BPI West is one-of-a-kind phase-based format is designed to capitalize on the latest approaches and technologies to help move the pipeline of next generation drug candidates closer to approval. Collectively share ideas, strategies and solutions to improve speed, cost and quality from basic research to commercial manufacturing.

Top 3 Reason Why You Can’t Miss BPI West:

1. Learn how to streamline and accelerate the development to approval process by collaborating at the interfaces of discovery, R&D, process development, and manufacturing
2. Discover the latest tools, technologies, and strategic approaches to increase efficiency, productivity, and cost savings at every stage of development
3. Foster the cross-fertilization of new ideas and perspectives to reach new levels of clinical and commercial success

This new format will bring together experts from every discipline and stage of development to achieve the common goals of optimizing speed, reducing cost, and improving quality from basic research to commercialization. Benchmark best practices, hear exclusive case studies and new data presentations at BPI West in Oakland, CA.

Don't forget! This Friday, December 18th is your last chance to save up to $500! Use the code BPIWEST16BL to save - Register here.

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BPI is Paradise for an Old Technologist

By: Frank Corden

As I was driving in this morning to the Hynes Convention Center, I was thinking about how lucky we are to have an international meeting of this caliber in Boston.  I just love BPI. It’s such a great mix of presentations; the breadth of discussions from the applied science around cell engineering to the underlying business drivers that will carry us into the next decade is amazing.  The organizers successfully execute this daunting task with seeming ease, though I’m sure in the background their little duck feet are paddling away.

Those of you who know me have heard the story of how I became a scientist.  As a kid growing up in the sixties and early seventies, my interests in science and technology were birthed from watching Jacques Cousteau television specials and the race to the moon.  In the years since, I’ve had the pleasure of seeing first hand that those fish on the coral reef are really all those beautiful colors and that NASA used proven technology, kerosene and liquid oxygen (aka Rocket Propellant No. 1) to get our astronauts into space.  Fortunately, my interest in all cool things science hasn’t waned with age and that’s why I love BPI.

Yesterday afternoon, I was sitting in on the presentation “Raising the Bar: Advanced Analytics in Upstream Bioprocess Development.”  Much of the discussion focused on the use of Liquid Chromatography coupled with Tandem Mass Spectroscopy (LC-MS/MS) to identify and quantitate attributes of various cell culture processes.  Without getting overly technical, the technique can be used to map the amino acid sequence of a drug substance as well as the pattern of added sugars (glycosylation) that are bound to an intact monoclonal antibody molecule. 

LC-MS/MS works by very accurately measuring the mass of the peptide fragments created from the proteins in the sample during the sample preparation process.  By accurately measuring the mass, the LC-MS/MS can identify the amino acid composition of each fragment.  This composition and the mix of the fragments, especially unique fragments specific to the proteins of interest, enable the instrumentation to identify with a very high certainty the presence and relative concentration of different proteins in the sample.

In the data shown, the presenter, Chris Yu, demonstrated the practical power of the LC-MS/MS method to characterize drug substance.  Data showed that LC-MS/MS could identify and quantitate host cell proteins and, further, could give positive confirmation of glycosylation patterns.  But what was most interesting to me was a more basic discovery…

As part of the effort to characterize a particular drug substance, the team identified a low percentage of peptides which differed from the expected amino acid composition, often a swap between serine and asparagine.  Initially the thought was that the DNA sequence for a fraction of the cells was different, as a result of either spontaneous mutations or by misincorporation of the DNA sequence during cell engineering.  Surprising neither of these possible errors was the root cause.

It turns out that there is a natural error rate for misincorporation of amino acids into the primary sequence of proteins.  The authors presented data that showed the error rate was in the same range for both mammalian cells and E. coli.  The error rate could also be influenced by the relative availability of the amino acids in the cell culture.  Restrict the availability of the intended amino acid relative to the incorrect amino acid and you get higher substitution.  Provide a plentiful source of the intended amino acid and the error rate decreases.

On reflection, it’s not surprising that some low level error rate should be expected.  After all, these biological processes are driven by chemistry.  You can have a preference for a given binding affinity or reaction path, but it’s just a preference even when it’s a very strong preference.  As an analogy, byproduct production in a chemical reaction is common and even if the reaction is very strongly directed for a particular outcome, in all but the simplest reactions, some byproducts are created.  So, you can view the amino acid substitutions as byproducts. 

Whether the protein with the substitution is functionally different than the desired product is unknown.  What we do know is that the LC-MS/MS can measure the error rate and that process conditions affect the error rate. So if the error rate turns out to be a critical quality attribute (CQA) of the protein that is the drug substance, we can monitor it and control it.  Neither the deeper insight gained about misincorporation nor the understanding of the ability to control the rate of amino acid substitution would have occurred without the applied research of Dr. Yu’s team and the advanced capabilities of the LC-MS/MS instruments. 

Gaining that insight into how biology really works is the 21^st century equivalent of rocket science -  that’s why I love this meeting.

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BPI 2015: Day Two Recap

By: LSPR

Day two of the 12^th 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.

Keynote Addresses

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:

1. Isotherms

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.

Poster Highlight

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.

Product Highlight 

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.

Roche also announced a partnership with Flownamics that features auto sampling technology. Through the technology, multiple bioreactors can be sampled simultaneously to streamline testing and reduce down time to enhance manufacturing efficiencies

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BPI 2015: Data Rules

By: Frank Corden

The explosion of readily available data is everywhere around us.  Silicon Valley is bombarding us and those who would like to sell to us with data to purportedly make our lives easier. Whether it be the articles you see on your news feed or the research you do before buying the next gadget, it seems like the current strategy is to conceive of a potential use for the data and throw it at us to see what sticks.  However, often the data isn’t timely or even useful. 

Take my commute in this morning to Boston. The warning of the traffic congestion came about 5 minutes before I hit the slow down.  Since several of the exits are more than 5 miles apart, there wasn’t time to get off Mass Pike.  But even if the data was timely, it wasn’t actionable.  Once you get to I-90 to head into town, there really isn’t an alternative route to get there.

A major theme of this year’s BioProcessing International Conference (#BPIConf) revolves around making informed decisions with data.  Whether it be on-line monitoring data, laboratory data, or process analytical technology (PAT) based data, data rules.  But what are the rules around data and how do we make it useful? What are the “rules” around using process data in bioprocessing?

I was sitting in the 8:15am presentation Evaluation of Continuous Manufacturing in a Downstream Process.  I guess I wasn’t the only one who headed into town early, the room is pretty full.  It’s great to feel the energy and enthusiasm of the group first thing in the morning.

The introduction to the Recovery and Purification track delivered by Marc Bisschops of Pall Life Sciences was provocative.  He challenged us to move from batch manufacturing to continuous manufacturing.  The benefits are clearly dependent on our ability to balance throughput of the various unit operations as you move through the process. 

Kudo’s to the first presentation, Data Based Comparison of Capture and Polishing Steps in a Continuous Mab Process.  The authors, from the chromatography company ChromaCon compared continuous versus batch approaches with hard data analysis.  By evaluating throughput, cost, and resource requirements, the analysis demonstrated that a change in the manufacturing paradigm from batch to continuous chromatography can have some impressive benefits. 

With a better quality outcome (increase in purity from mid 70% to mid 80%), you can cut chromatography resin usage by one-third.  For the resin selected, the reduction in resin usage translated into $190,000/year.  In the pilot facility studied, the breakeven for the investment in continuous chromatography occurred after the transfer of only two molecules.  Clearly, the dollar savings in a full production facility would be significantly greater. 

The decision to shift from the tried and true manufacturing approaches we use today is a difficult one.  We all realize the risk of getting it wrong is what keeps us up at night.  A delay in the release of a product not only affects our companies but also the patients who depend on these products to keep them healthy, or in some cases alive. 

Hard data to help make a difficult decision; now that’s data that rules.

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BPI 2015: Day One Recap

The 12^th annual Bioprocess International (BPI) Conference & Exposition began with a series of technical sessions, many of which broke new ground. BPI 2015 also proved to be an invaluable forum for scientists and engineers with its poster presentations and product announcements, as well as keynote talks from industry leaders. Here are some highlights of Day 1.

Keynote Addresses

Market leaders from Merck & Co., Novartis Pharma, and the Duke School of Medicine gave compelling and insightful keynote presentations on Tuesday at BPI 2015. And it is fitting that in Boston, one of the keynote speakers noted that there is a “revolution” underway in fighting cancer.

By: LSPR

Innovating mAb Production to Support the Immunotherapy Revolution was given by David J. Pollard, PhD, Executive Director, BioProcess Development, Merck & Co., Inc.  Dr. Pollard began the keynote session by stating it was an “exciting time in immunotherapy” and that a revolution is now underway in cancer treatment. To be successful in this revolution, the industry needs to be agile and flexible so it can quickly adapt to change.

To that point, Dr. Pollard emphasized the importance of there being a “collaboration between suppliers and end users” to help lower costs and increase throughput. “Working as a community we can help create a facility of the future,” he stated.

Such a “facility of the future” will create a tremendous opportunity to lower the cost of manufacturing while also being able to handle increased capacities, according to Dr. Pollard. He explained that a modular approach will be taken to develop these facilities so they can easily be built out as needed.

Dr. Pollard stated this next-generation manufacturing approach will improve acceleration to clinical trials and that technology will be used to de-bottleneck activities. This will create high-throughput workflows using enabled formulations from cell line development, process development (both upstream and downstream), and formulation.

Another challenge during this revolution is to create a bridge from IV to subcutaneous. The goal is to achieve the necessary high concentration of >150 mg/mL while also addressing viscosity issues. Dr. Pollard stated that, while it is early proof of concept, Merck has done research in which novel excipients have been added to meet this challenge. 

Next to speak was Spencer Fisk, Global Head, Biologics Process, R&D, Novartis Pharma, AG who spoke of Innovative Process Development Strategies to Drive the Rapid Clinical Introduction of Emerging Biologics. Fisk challenged the industry go beyond the “heavily walked path” and push boundaries to speed drug development and improve efficacy.

Fisk’s approach to accelerating drug development was for his colleagues to not avoid taking risks. He suggested to “use data to guide us” so scientists and engineers can approach the “edge of the cliff.” Using data, risk levels can be determined and comfort levels established with the end result of more quickly selecting the proper candidate for development.  

Choosing the best candidate requires evaluating all the variables such as the biology and the ability to develop the candidate. Each variable has its own elements. For example, in the case of biology, binding, potency and efficacy need to be assessed. In terms of development there are a number of aspects, including stability, that need to be determined.

Risk factors not only need to be established, they should be classified as critical (red), moderate (yellow), and low (green), suggested Fisk. If the risks are predominantly low, then the candidate should be moved ahead. “Green means go,” stated Fisk. The results will be favorable the majority of the time.

“If we get it right >80% of the time, we have significant time savings. In many cases, the 20% that does not work is simply due to the fact that more time is needed,” said Fisk.

Taking this approach will create a cycle that will benefit the market, as well as society. Once scientists have “walked to the edge” and realized it was not as close as they originally believed they will push the boundaries further, creating a continuum of accelerating drug development, according to Fisk.

The final keynote, Novel Approach to Developing and Producing Human Experimental Vaccines for HIV, was given by Michael Anthony, M.D., Chief Medical Officer, Associate Professor of Pediatrics, Duke Human Vaccine Institute, Duke School of Medicine. Dr. Moody emphasized that because HIV is a unique and challenging virus it poses many challenges. Vaccines that are developed and aim to be effective must deal with an incredible diversity of circulating strains.

“By locating and neutralizing antibodies we can prevent disease but this is not an easy task. Antibodies at a sufficient level can target many strains of HIV1,” said Dr. Moody.

One question posed by Dr. Moody during his session was if information gathered from those patients who are infected can be used to make antibodies. “But it’s not that simple. There are many changes to the immunosystem that we may need to mimic with adjuvants to be successful,” he explained.

Novel adjuvants will need to be developed, according to Dr. Moody. Human trials are in the planning stages but there is no guarantee that the answers will be found. There is a paradox in the bnAb development – mutations develop. As a result, Phase I human testing is required. Within that context, two important elements are needed:

·         Targeting of multiple lineages

·         Multiple immunogens, likely in sequence

“Industry, academia and government will need to come together, as one of these alone cannot muster the resources needed to be successful,” emphasized Dr. Moody.

Technical Session Highlights

New Data on Continuous Manufacture in Downstream Process: In the Recovery and Purification technical track, Michael Bavand, PhD, Chairman and CEO of ChromaCon AG, released new data during his presentation entitled Data Based Comparison of Capture and Polishing Steps in a Continuous Mab Process.

Dr. Bavand spoke of a study conducted in which four resins were compared using batch mode, dynamic flow load, and continuous chromatography. The experiment evaluated five outputs – recovery percentage, high molecular rate (HMW%), productivity, host cell protein, and 0.1M NaOH tolerance. The results revealed:

·         Very little difference in recovery percentage, as all the conditions were > 90%

·         Slight reduction in HMW% in the continuous condition

·         Host cell protein (ng/mg) was equivalent or better in continuous condition

·         All DBC levels were > 90% initially after 100 cycles; resin 4 showed reduction in DBC after first measurement

A model was generated with all the productivity data. Validation cost estimates, lab scale system purchase, GMP system purchase, FTE estimates, and the number of new molecules arriving in a plant annually were all accounted for by the model. The model was used to estimate return on investment across the number of new molecules to come into a pilot plant every 12 months. Using a baseline of two new molecules per year, the initial estimates were that cost savings would be realized after three years.

Dr. Bavand also discussed a second part of the experiment that studied a process using MCSGP with a membrane adsorber to determine if it would have equivalent or better outputs than a cation exchange (CEX) resin step in terms of recovery, productivity, and impurity levels. Through the experiment, a Flow Through MCSGP was demonstrated to have equivalent purity and recovery with significant higher productivity levels than batch mode.

As revealed by the results, higher productivity and large cost savings are possible using a continuous chromatography system for both capture and polishing steps. Additional verification of these processes is needed before they can be implemented into a pilot plant concluded Dr. Bavand.

Poster Highlight

Essential Pharmaceuticals’ poster entitled Novel Lipid Based Supplement Increases Protein Yield in Single Use Bioreactor presented the use of a lipid supplement using various strategies to improve protein yield.

The poster stated that by adding the lipid supplements at the beginning of the culture, the yield in titer antibody protein production increased 30% from CHO cells without increasing proliferation. Further, when the metabolic profile was examined, it was discovered that there were no differences in any of the metabolites.

The poster also stated that the supplement was used as a feed and there were two notable effects: 1) increasing the titer yield by 25% and 2) extending the window for peak protein production from one day to two. These results show that there are windows for further optimization of protein production using lipids. It is possible the use of lipids reduces the energy requirement for new cell formation and, therefore, can be used for protein production. 

Product Highlight 

Pall Life Sciences is showcasing key components of its biopharmaceutical portfolio in its booth (#309). A host of updated and new portfolio products will be on display, with particular emphasis on continuous solutions Pall has available for downstream processing support.

Included in the BPI 2015 booth will be:

• The disruptive Acoustic Wave Separation technology for cell-culture clarification in either fed-batch or perfusion applications
• A preview of Pall’s latest advance in depth filtration: Stax™ Depth Filters with Hyperion Flow technology, for direct mammalian cell harvest with a new filter to remove cells and cellular debris effectively and efficiently
• The award-winning Cadence™ Inline Concentrator single-pass tangential flow filtration system for direct flow-through and in-process volume reduction in an integrated or stand-alone format
• The recently introduced BioSMB^® System for single-use or multicolumn continuous chromatography featuring a disposable flow path with a proprietary integrated valve cassette to service up to 16 columns or devices.

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