Innovative Technologies, People, and Organizations Drive the Future of Bioprocessing

By  S. Anne Montgomery, Editor in Chief, BioProcess International 

In the 14 years that BioProcess International (BPI) magazine has been around, the biopharmaceutical industry has experienced a dramatic confluence of technologies, analytics, and regulatory initiatives aimed toward accelerating development and commercialization of life-saving biotherapeutics. Although a number of these topics were “on the radar” before the turn of the century, by the time of BPI’s first issue in January of 2003, they were beginning to be discussed in earnest, and references to “disruptive technologies” began to appear in print, online, and conference discussions across development phases.

As revealed in BPI’s article archive the list is impressive and includes, notably
• single-use technologies
• quality-by-design
• process-analytical technologies
• advanced medicines/cell and gene therapies
• antibody–drug conjugates
• biosimilars and biobetters
• immunotherapies
• combination products
• companion diagnostics
• platform analytics and manufacturing technologies
• product life-cycle development
• continuous processing.

We have watched, too, as those innovations spread across the globe into regions not previously considered to be biomanufacturing hubs and as international regulatory agencies sought to harmonize pathways to approval. Different partnering models have emerged with both long- and short-term goals, but many in response to concerns about supply-chain integrity in an era of life-cycle management.

Presenting information and guidance for sorting through these choices of platforms, technologies, and manufacturing models is the continuing work of technical publications and conference presentations. BioProcess International magazine has always benefited from its close collaboration with the Informa conference groups (IIR/IBC) to create separate but compatible content and presentation vehicles. Many of the magazine’s editorial advisors also have served on the conference advisory panels, for example, and industry trends (and the best people to speak and write about them) identified by one group are shared with the other to bring as consistent a message to our readers and event attendees as possible.

Our two annual flagship events — now called BPI West and BPI — pull these interrelated topics together into week-long programs that you don’t want to miss if you need to stay on top of the latest interpretations of these trends. A quick look at the program for the upcoming BPI West (14–17 March 2016 in Oakland, CA) reveals the ongoing impact of the past decade’s advances on the current biopharmaceutical industry. The opening preconference symposia in themselves reflect key areas of attention: innovative approaches and technologies in process development and manufacturing, cell-therapy commercialization, ADC development, and continuous processing. Many elements of those topics were just promising ideas a decade ago, research topics that “might someday” be brought into commercial viability.

Another example is that the Basic Research and Discovery track of this year’s conference is far from the relatively “siloed” research presentations of the past. Speakers here now will stress the needed overlap of development strategies with early risk analysis and process optimization — with their goals (repeating across product classes and development stages) of shortening the times for lead optimization and transition into manufacturing. Enabling technologies incorporate analytical tools that in themselves introduce new questions: How much information is too much? What are we seeing now of contaminants and particulates in marketed products that we didn’t know were there before, and what does that mean for developers of follow-on products? What statistical knowledge for assessing this wealth of data is now required of those entering the industry that was not deemed necessary before?

I urge you to visit the conference site, download the program, and plan to attend sessions that will help you navigate the current and future worlds of biomanufacturing. Network with your peers, among whom are many veterans who helped build our current industry as well as a younger generation who are introducing fresh insights and new ways of implementing technologies and communication tools.

And as you contribute to advancing this new world biomedical approaches, take a look, also, at BPI’s third biennual awards program categories. Our awards are designed to reflect key milestones in the industry, highlight technologies that are making often-disruptive changes in how biopharmaceutical products and modalities are reaching those who desperately need them, and honor companies and people who are building a new world of healthcare options for both regional and global communities.

I have followed the biopharmaceutical industry as an editor since 1988, and I sometimes take a step back and marvel at how far this work has come. Technologies come and go — and some return again, with problems solved and new challenges revealed. Terminology may look the same, but its connotations are sometimes radically different to new generations. As always, communication is key, but exchange of knowledge must be based on shared understanding of terminology and technologies. Plan to join us in March and continue to contribute to these meaningful discussions. Make your mark on the future of biomanufacturing — we need your voice and we want to hear about your experiences.

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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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BioProcess International Conference 2015 - An Overview for Anyone Who Missed It!

by Brandy Sargent

Introduction
While attending this year’s BioProcess International Conference (BPI) in Boston last month, I was excited because it seemed to be a larger turnout then I’d remembered from previous years. BPI recently confirmed that it was in fact the largest attendance in BPI’s twelve-year history. In addition to the larger turnout, the content felt fresher and very relevant to the current challenges and potential solutions facing the industry. BPI provides talks focused on improving the manufacturing process for biopharmaceuticals, enables industry networking opportunities, and the chance to see the latest products and technologies.

Conference Highlights
For me one of the biggest highlights of the conference was the keynote, “Amgen’s Next-Generation Biomanufacturing Facility by Kimball Hall, Vice President Manufacturing, Amgen Singapore Manufacturing Pte. Ltd. In the talk Ms. Hall describes the 200 million dollar next generation manufacturing facility Amgen built in Singapore. The facility was built in less than two years, half the time of a more traditional facility, and is state of the art in terms of innovative technologies. One of the enabling technologies used in the facility is single-use technology. The facility is over 90% single-use, in fact they only need one autoclave. The facility also incorporates continuous processes and relies on the concept of closed system manufacturing.

Ms. Hall describes how they have implemented a closed system approach to allow for a central manufacturing suite where upstream and downstream can be conducted in the same room. They are using smaller, single-use bioreactors coupled with continuous processes in downstream and real time quality analysis to ensure both an efficient process and a closed system. Ms. Hall states that using this manufacturing approach, they have been able to achieve improvements in yield and reduction in cost per gram.

In addition this closed system approach also permits their solution prep area to operate for both media and buffer prep with closed raw material bags, anti-static powder transfer sleeves and connections to 5,000 L single-use mixing vessels ensuring material stays closed within its equipment. To move solutions from the prep room to manufacturing, they have built openings in the walls, which allow solutions to be pumped through this opening into the other room. Material can also be pumped from the central manufacturing suite through an opening in the wall into the final purification room.

Ms. Hall addresses possible environmental impact concerns about the amount of single-use materials by walking through the environmental impact. First, they use less water for heating, cooling and cleaning. The facility overall has a smaller footprint with lower air quality classifications, thus reducing energy consumption and lowering emissions. They have can achieve solid waste reduction due to the smaller reactor size and they are working on recycling the bags and are with a group developing a way to incinerate them for biofuel.

Responding to a question about perceived regulatory risk for this next generation facility, Ms. Hall said that they have met with regulatory bodies along the way, who have been positive but have always said “we’ll have to see on inspection”. They would like it to be licensed as is but have risk mitigation plans in place for how to accommodate any required changes.

One thing that Ms. Hall also makes clear is that the relationships with suppliers have been critical. The suppliers are deeply embedded in this process and she even remarked that there were employees from the supplier companies sitting in her cafeteria during performance lot runs, waiting to help solve any problems that might arise. With the increasing complexity of these technologies, it is key that the relationships with suppliers be strong and that there is trust. Specifications and product details must be shared back and forth so that the best process can be developed and if any problems arise they can be addressed quickly.

As the question and answer session began, one person stood up to ask a question, I’m sorry I didn’t catch her name, but she called the building of this facility “Brave.” Initially it struck me that she used that that term to describe the building of this facility, but upon further reflection I understand why. In building this facility, Amgen has really committed to changing the biomanufacturing paradigm. They have invested incredible amounts of time and resources into a project that has no absolute assurance of regulatory licensing and have shared these details publically as a guide for others. For the industry to evolve it takes a company to embrace new technology and to “go first” to prove that it is feasible and that it can receive approval from the regulatory bodies. The first or firsts must pave the way before others feel comfortable to do it as well. To some in the industry who have been considering this kind of manufacturing platform, but have been waiting to see what will happen, I can see how this move may be considered brave. For a person who has been covering these innovative technologies and was able through Ms. Hall’s talk to see it all put together into one facility, for me it was inspiring.

Another really interesting talk was the keynote on “What is the Future of Continuous Processing – What is the Time Frame for Implementing Fully Continuous Processing in Commercial Production?” by Konstantin Kostantinov, Ph.D., Vice President, Technology Development, Genzyme. Genzyme has long been a proponent and pioneer for continuous processes in biomanufacturing. At the BDP conference earlier this year, there was a wonderful talk given by Dr. Veena Warikoo, Director, Purification Development, Genzyme on their concept of the bioprocessing facility of the future. Please see, “Continuous Bioprocessing – The Biomanufacturing Model of the Future?” for more details.

Other conference highlights this year included:

• Keynote presentations from Merck, Novartis, and the Duke Human Vaccine Institute
• A pre-conference symposium that had an entire track dedicated to Cell Therapy
• Ask the Regulators Open Forum
• Bioprocessing Problem-Solving Moderated Discussions
• Town Hall Forums
• BPI Theater Panel discussions on “Accelerating Biopharmaceutical Development and Manufacturing” and “CMO Panel Discussion on Perspectives and Lessons Learned on Overcoming Challenges with Tech Transfers and Biomanufacturing,”

Different Discussions by Conference Track
There were some overall themes this year that I felt were a continuation of many great discussions that were presented at the BDP Conference earlier this year including continuous processing in both upstream and downstream and implementation of closed systems. This is by no means an exhaustive list, but some highlights of the talks I attended by track include:

Cell Culture

• Perfusion and continuous processes continue to be a hot topic
• Several talks on novel approaches to cell line development including talks on CRISPR/Cas9 technology and how this can be applied to cell line development and production.
• Good discussion surrounding glycolsylation and how to achieve consistentcy. This included discussions around how media is involved in that process and predicting glycosylation profiles using metabolic data.
• Media improvements and using high throughput approaches to process development and media screening.

Recovery and purification

• In downstream, just as in upstream, implementation of continuous processes was a hot topic.
• Several discussions around using new recovery and purification technologies to improve overall efficiency and purification
• Looking at non-chromatographic purification of proteins
• High throughput process development strategies.

Manufacturing strategy

• Facility design incorporating the ballroom suite or central manufacturing suite approach.
• Closed systems as a way to enable more flexible facilities, see “Closed Systems in Biomanufacturing Offer A Variety of Benefits,” for more information.
• Continued process verification (CPV) strategies
• How to utilize facility design, single-use technologies and bioprocess automation in BRIC countries.
• Data collection, data management and bioprocess automation.

Drug Product Manufacturing and Fill-Finish Processing

• Implementing PAT tools and applying QbD
• Streamlining and integrating drug substance and final drug product manufacturing
• New strategies for aseptic filling
• Several talks on particulates and appropriate approaches

Analytical, Formulation and Quality

• Talks on integrating critical quality attribute monitoring and multi-attribute monitoring and control.
• High throughput analytical assays for process development support and quality control
• Many talks on biosimilars and product quality, characterization and comparability.
• Good discussion on supplier relationships and ensuring raw material tracking and control.

I will cover several of these areas in more detail in the coming weeks – stay tuned. In 2016 …

A new BPI West will make its debut March 14-17, 2016 in Oakland, CA and will be the West Coast compliment to BPI in Boston October 4-7, 2016. Register with the code BPIWEST16BL and save $100 off the current rate.


This overview of BPI was contributed by Brandy Sargent, Editor of Cell Culture Dish. View the original post in its entirety here. 

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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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The 4Vs framework and its application in Biopharmaceutical manufacturing

Bioprocessing is an endeavor with some specific challenges associated with it, such as how we might implement single-use technologies or gain regulatory approval for new drugs. It seems to me, however, that it is easy to become so focused on topics such as these that we overlook applying established methods and practices used in a broad array of industries to improve our own. One such framework that could be applied to our sector is an analysis of the 4Vs of volume, variety, variation and visibility. Considering these parameters can help us make decisions about how to best organize biopharmaceutical manufacturing operations.

Volume: The number of doses of a biopharmaceutical to be manufactured varies considerably between drug products. Blockbuster products and products used to manage chronic diseases over long periods of time might be manufactured in large volumes. Due to the specific nature of biopharma drugs the patients that will respond to them can be small and the number of doses required not nearly so many. Orphan drugs for treating relatively rare diseases are a good example of products where the number of doses per year to be manufactured might be very low. Taking this to an extreme, personalized medicines and cell therapies are likely to be required is such small volumes that they are challenging existing industry processing technologies, supply networks and regulatory frameworks in order that they can be successfully commercialized.

Variety: Often linked by an inverse relationship to volume, variety refers to the number of different products an operation must deliver. In the above example of personalized medicine the variety of products to be produced may be very high as the products are in essence customized to the patient receiving them. Less variety tends to imply higher volume production and perhaps less operational complexity. Biopharmaceutical companies often strive to develop platform manufacturing processes capable of delivering a variety of products within their portfolio without adding to this complexity.

Variation: The degree to which demand for the product varies can have a significant impact on operation design. This variation can be more predictable, such as with the seasonal flu vaccines or less predictable, perhaps driven by competitor or regulatory activity. Responding to variations in demand can be a significant challenge for the biopharmaceutical industry where making process changes including process scale-up be a slow process with technical and regulatory challenges. Failure to design operations with sufficient agility to respond to demand fluctuations can result in increased lead times and patients not receiving medicines at the time they are required.

Visibility: Biomanufacturing operations are typically exposed to a high level of internal and external scrutiny due to the regulated nature of the industry. Process visibility is a term often used to describe operations that deliver services in which the customer is typically heavily involved in their design and operation. An example in biologics manufacturing are the use of Contract Manufacturing Organizations (CMOs). Once the decision has been made to outsource production, the management of the relationship between customer and contractor must be given significant attention to ensure successful delivery of drugs to patients and the sponsor must address issues such as relinquishing of some control.

Consideration of the 4Vs can help shape the design of biomanufacturing operations. For instance, high volume-low variety operations are typically more repetitive in nature and may suggest continuous biomanufacturing is an appropriate strategy. Companies requiring a small number of doses of a large number of products will need to design operations that permit a greater level of complexity and more intermittent processes. It is a framework worth reviewing when considering the future design of your companies bioprocessing footprint.

The BioProcess InternationalConference and Exposition to be held on October 26-29, 2015 in Boston will be addressing such topics as personalized medicines, cell therapies, managing supply chains, platform processes, continuous biomanufacturing, contract manufacturing, vaccine production and much more.

Dr Nick Hutchinson 

Join me at #BPIconf

Contact me at nick.hutchinson@parker.com

Dr Nick Hutchinson has a Masters and Doctorate in Biochemical Engineering from University College London, UK where he focused on laboratory tools for rapid bioprocess development and characterization. He then worked at Lonza Biologics in an R&D function investigating novel methods for large-scale antibody purification before moving to an operational role scaling-up and transferring manufacturing processes between Lonza sites in the UK, Spain and USA. Nick now works in Market Development at Parker domnick hunter where his focus is in bringing Parker's strengths in Motion & Control to Bioprocessing. This will enable customers to improve the quality and deliverability of existing and future biopharmaceuticals.

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Single-use technologies enable closed-system bioprocessing

The benefits of single-use technology

Single-use technologies provide a number of benefits over traditional hard-piped equipment and facilities. Five key benefits are described below:

1.    Increased flexibility which allow system changes to be readily implemented during process development, scale-up or while a process is in routine operation.

2.    Reduced risk of contaminations either between batches of the same product or between batches of different products manufactured in the same facility

3.    Reduced or eliminated need for steam-in-place and clean-in-place generating equipment

4.    Shorter facility start-up time

5.    No need for cleaning validation

However, an additional benefit that is attracting an increasing amount of attention is the utilization of single-use technologies to allow closed-system processing.

Why perform closed system processing?

Closed-system processing in single-use technology might be an attractive option for a range of biomanufacturers with different motives. These could include:

·         Cell Therapy manufacturers operating short and simple processes with no method of sterilizing their end-product

·         Vaccine and viral vector manufacturers who find that sterile filtration processes significantly reduce process yields of these large biologics

·         Continuous manufacturers operating processes for many weeks at a time and wanting to avoid a build-up of bioburden within their equipment

·         Any biomanufacturer looking to cut facility running costs by reducing the air handling requirements within processing suites

·         Small-scale, localized, temporary bioproduction facilities manufacturing vaccines close to outbreaks of infectious diseases where local infrastructure is limiting.

Single-use developments allowing for closed-system processing

Pre-irradiated, assembled manifolds and containers are available from a range of suppliers. Operators simply need to install the product-contact consumable and are then ready to start processing.

Single-use bioreactors have been available for some time and are designed, of course, to minimise the risk of microbial ingress. Similarly, single-use mixers and bioprocess containers can be connected to and from with sterile connectors. Sterile disconnectors allow ancillary tubing to be removed while maintaining a sterile boundary around the product. Thermoplastic elastomer tubing can be welded to create flowpaths without compromising sterility and can be sealed to close containers.

The sterilization of product streams and necessary process solutions such as culture media and buffers can be achieved using gamma-irradiated membrane filter capsules. Remember, however, that simply used a sterilizing-grade filter in itself does not guarantee sterility and that validation of the sterile filtration process must be performed to ensure a bioburden-free environment.

For a while, closed-system processing was held back by a lack of suitable technologies for the purification of biologics largely because the need had not been identified or the technology not available. The company I work for has now launched a single-use TFF which avoids the need to clean and store cassettes. At a conference I attended last week Dr James Rusche, Senior VP Research & Development at Repligen described a single-use Protein A chromatography column that had been gamma-irradiated to prevent the build-up of bioburden during continuous harvesting operations.

Of course, because a technology can be gamma-irradiated does not mean it is qualified as sterile, however, if the drivers are there then customers will push vendours to generate this data for all single-use technologies allowing closed-system processing to become a reality for a growing number of processes.

Have your say

Are you driving towards closed system processing? What technology would, if available, make operating in this way more feasible?

Want more on single-use technologies? Meet leading companies in the space at BioProcess International Conference & Exhibition this fall in Boston. Here are the sponsors and exhibitors that will be attending:

Eppendrof
Finesse Solutions, Inc.
GE Healthcare Life Sciences
JSR Life Sciences
Levitronix,
Meissner Filtraion Products
Optek-Danulat Inc.
Qosina
Repligen
Saint-Gobain
SpectrumLabs.com
Pneumatic Scale Angelus
ILC Dover
CPC
Pall Life Sciences
TEK
Nordson Medical
Thermo Fisher Scientific
Beckman Coulter
em-tec Flow Technology (LP)
Kuhner Shaker Inc.
Entegris
WR Grace

Dr Nick Hutchinson

Join me at #BPIconf

Contact me at nick.hutchinson@parker.com

Dr Nick Hutchinson has a Masters and Doctorate in Biochemical Engineering from University College London, UK where he focused on laboratory tools for rapid bioprocess development and characterization. He then worked at Lonza Biologics in an R&D function investigating novel methods for large-scale antibody purification before moving to an operational role scaling-up and transferring manufacturing processes between Lonza sites in the UK, Spain and USA. Nick now works in Market Development at Parker domnick hunter where his focus is in bringing Parker's strengths in Motion & Control to Bioprocessing. This will enable customers to improve the quality and deliverability of existing and future biopharmaceuticals.

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