Thursday, October 8, 2015

Look Who's Attending | Last Chance to Save up to $400

Last Chance to Save up to $400 is This Friday, October 9th
Register Today
Be Sure to use code: D15172BLOG


Connect with hundreds of your colleagues this December in San Diego at the largest and most trusted Antibody Engineering & Therapeutics event to discover, engineer and develop novel and next generation antibody modalities across diverse disease indications. Included with your 4-day registration fee this year is a new 2-day Antibody-Drug Conjugate track that will showcase the latest progress and clinical updates from the most exciting ADC programs in development.

Secure your seat today to attend this year's meeting and access:
• 100+ speaker presentations covering critical scientific and development updates that can accelerate your antibody research, discovery efforts and clinical programs - download the agenda. 
• 50+ exhibitors to keep you on the pulse of evolving technologies
• 100+ scientific posters to give you first-hand updates on unpublished, peer-submitted research projects
• 700+ global antibody researchers for you to connect with onsite to forge successful scientific and business partnerships

A sample of the attending companies:
• Abbvie
• Albert Einstein College of Medicine
• Amgen
• Bayer Healthcare
• Biogen
• Boehringer Ingelheim
• Boston College
• Boston University
• Bramhill Biological Consulting
• Bristol Myers Squibb
• Celgene Corporation
• Covagen AG
• Daiichi Sankyo
• Dana Farber Cancer Institute
• Dartmouth College
• David Geffen School of Medicine at UCLA
• Development Center for Biotechnology
• Eli Lilly & Company
• EnGen Bio
• Esbatech A Novartis Company
• Genentech
• Genesun Biopharmaceutical      
• Genmab BV
• Genomics Inst of Novartis Research
• Genzyme Corporation
• Georgetown University
• GlaxoSmithKline
• Global Biological Standards Institute
• Imaginab
• Immunocore
• ImmunoGen
• Janssen
• Johnson & Johnson
• Jounce Therapeutics
• Kookmin University
• KTH Royal Institute of Technology
• Massachusetts Institute of Technology
• Maxcyte Inc
• MD Anderson Cancer Center
• MedImmune
• Meditope Biosciences
• Memorial Sloan Kettering Cancer Center
• Merck
• Merrimack Pharmaceuticals Inc
• National Cancer Center Hospital East
• National Cancer Institute NIH
• National Institute for Communicable Diseases
• National Research Council Canada
• Novartis
• Novo Nordisk   
• OMT Therapeutics
• Oslo University Hospital, Rikshospi
• Oxford University Kellogg College
• Panorama Research Institute
• Pfizer
• Queen Mary University of London
• Regeneron
• Research Corporation Technologies
• Roche
• Royal Institute of Technology (KTH)
• Sanofi
• Seattle Genetics
• Simon Fraser University
• Stanford University Medical Center
• Stanford University School of Medicine
• Taipei Medical University
• Takeda
• Tel Aviv University
• Teva Pharmaceuticals
• The Rockefeller University
• The Scripps Research Institute
• The University Of Tokyo
• Tokyo University of Pharmacy and Life Sciences• UCL Cancer Institute
• UMass Medical School
• Univ. of Texas MD Anderson Cancer Ct
• University of Cincinnati College of Medicine
• University of Pittsburgh Cancer Institute
• Vaccinex
• Yale School of Medicine and more!

Don't miss out! Join the growing list of attendees at the largest antibody engineering and therapeutics event in the industry! This Friday, October 9th is your last chance to take advantage of the early-bird savings of up to $400. Be sure to use code: D15172BLOG – Register here.

The Antibody & Protein Therapeutics – From Discovery to Production Team

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Monday, October 5, 2015

CGMPs essential for commercialization of cell therapy products

 Cell Therapy Bioprocessing & Commercialization attendees heard from a range of speakers on getting treatments to market

By Leah Kinthaert

Novartis's Knut Niss shared his insights
 FDA biologist Moe Heidaran PhD told attendees on the closing day of Cell Therapy Bioprocessing & Commercialization about the benefit of current good manufacturing processes (CGMPs) in the commercialization of cell therapy treatments.

Heidaran told a rapt crowd: “Efficacy of a product can be readily established if a product can be manufactured consistently with the highest quality.” He explained that, along with CGMPs, “in-depth knowledge of product is needed for high-quality product manufacturing”.

He stressed that quality control is the “most important part of CGMPs”.  “Becoming CGMP compliant is a process,” he said, adding: “It is never too early to plan.” Heidaran told the audience to be stay up to date with the FDA’s ICHQ6B guidance.

Heidaran moved on to focus on process change. He noted: “Process change is inevitable and not all of it is planned.” He said that, for a major process change, the FDA needs an amendment, while minor changes can be documented in an annual report. If unsure, a CMC reviewer could advise if a change was major or minor.

He described the time sensitivity of reporting changes: “Post licensure reporting categories have a time limit of four months if they are PAS, while the timeline for review is six months if they are in the category of CBE or CBE-30.” He told the audience they should refer to ICHQ5E for more information and said there was the potential for either clinical or non-clinical data to be required.

Heidaran affirmed the importance of the FDA’s established controls for cell therapy products, explaining their value in his closing remarks: “Change is inevitable, it’s the most critical part of product improvement. Innovation is coming into the cell therapy market, manufacturing is becoming a huge issue. Controls are not designed to be troublesome or obstructive, but to allow you to recognize challenges you have to meet to have a success strategy for commercialization.”

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How to make a cell therapy product commercially successful

 Cell Therapy Bioprocessing & Commercialization attendees heard from a range of speakers on getting treatments to market

By Leah Kinthaert

Novartis's Knut Niss shared his insights
 “I have been coming here since the beginning of this event, and enjoy being in a room with a group struggling with the same questions and problems,” Novartis senior technical project leader Knut Niss told attendees on day  three of Cell Therapy Bioprocessing & Commercialization 2015.

“Five years ago we were discussing Phase 1, today we have much more advanced discussions; we have moved from discussing Phase 1 to commercialization,” he said.

Having worked with Pfizer, Novartis and Biogen, Niss shared his invaluable insight into building teams at these organizations. “When people think about what success in cell therapy would look like, they answer ‘getting to the market’. For me, success is being successful in the market,” said Niss.

Describing the challenges of having a cell therapy product on the market he said: “Once you are on the market you are out of your controlled environment. [With commercialization] you need to continue to pay attention and follow the standard operating procedures.”

He detailed what some of that uncontrolled environment might entail. “A healthy donor will be very different from the patient,” he said, giving an example of how a donor might take an occasional aspirin while the patient will have potentially taken a great deal of prescribed drugs. “Be prepared for that,” he warned. He continued: “Often you cannot use the patient’s material as a process development tool. Until you hit the clinic (you only have access to) donor material.”

Niss challenged the audience to ask the question “Is this process sustainable in the marketplace?” and advised: “CMC is a critical part of clinical development. It is important that the clinical team understands CMC and vice versa. You want to build the right team; cell therapy is very different from what they usually experience.”

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Friday, October 2, 2015

How Novartis leveraged its size to transition to commercialization

Keith Wonnaccott, Novartis
By Leah Kinthaert

Novartis director of regulatory affairs, gene and cell therapy unit, Keith Wonnaccott PhD explained to a packed room at Cell Therapy Bioprocessing & Commercialization 2015 how his organization was able to leverage their company’s large size to make the transition from an academic to a commercial manufacturing environment.

Wonnaccott described how moving from University of Pennsylvania’s facilities to Novartis’s Morris Plains site was fraught with challenges. “At University of Pennsylvania we have the donor on site, the manufacturers on site, administration on site. There is no site variability or difference in medical staffs. Once we begin to transition to commercial there are many administrative sites, many collection sites,” he told attendees.

To prepare for global development and all that comes with global manufacturing, Novartis applied what Wonnaccott described as the “tech transfer process”.  “With our step-wise tech transfer process, we can transfer all the knowledge needed to perform a given process from the transferring site to the receiving site,” he said.

Wonnaccott explained what the four key goals were needed to enhance the tech-transfer process: enhancing compliance, scalability, wide-scale distribution and process optimization.

He then went on to give reasons why the tech-transfer process was so crucial. “There is more scrutiny given to late-phase clinical trials,” Wonnaccott continued. “With early phase clinical trials you need to worry about safety, but with late-phase trials your concerns become safety and efficacy.”

He added: “University of Pennsylvania has only the US requirements, we wanted to appeal to a global market.” His discussion moved on to the list of different requirements in different countries. The group learned that not only are there different standards in the US and UK, but that the EU has an additional group of standards, and then you can add to that MHLW and ISO standards.

“All these different people are defining standards for you, it’s quite the challenge,” he said.

Wonnaccott then explained how to show comparability, one of the key needs faced with transitioning from an academic to a commercial environment. He joked about the vague answer that the FDA gives when asked “What does it take to show comparability?” (“It depends”) and went on to say “There must be robust product characterization, established assays, process consistency, predefined acceptance criteria and statistical analysis.”

Wonnaccott closed his presentation with an important point: “In the face of regulatory uncertainty, good science will make for successful development. We should do what’s right for patients.”

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Equipment and resources are the key Bottlenecks in cell therapy commercialization

Nick Timmins PhD

In the final session of day two at Cell Therapy Therapy Bioprocessing & Commercialization, Nick Timmins PhD, director of product and process development at the Centre for Commercialization of Regenerative Medicine, told attendees that the key bottlenecks and technology gaps in bioprocessing and commercialization of cell therapies are centered around equipment and resources.

He said that while each had different reasons for occurring and different solutions, each delay and prohibit your outcome. “The ideal pathway would be two parallel lines that increase in profits and production,” he said.

Timmins referred to three main issues in technology that often present themselves; connectivity, automation, and data capture & use. “These major gaps in the process are difficult to implement a solution for and require detailed thought out execution,” he said.
As he continued to explain different scenarios and cases of how bottlenecks and technology gaps have prohibited growth, Timmins concluded his talk with two major takeaways:
One; think beyond a single batch – industrialization, plant and equipment utilization, and theory of constraints.
And two; discriminate between bottlenecks and technology gaps – they are different things with different answers, they also have a different cost vs benefit analysis that needs to be taken into account.

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Thursday, October 1, 2015

Automation should support a 'clear vision for commercial viability' - Brian Hampson

Brian Hampson: automation must support a clear vision for commercially viable manufacturing

By Brian Caine

“Companies must understand that automation should support a clear vision for commercially viable manufacturing and is a tactical approach to support a strategic end,” Brian Hampson ME, vice president of manufacturing development and engineering at PCT, a Caladrius company, told attendees at Cell Therapy Bioprocessing & Commercialization.

Hampson has more than 20 years’ experience in the cell therapy industry and has first-hand experience in the evolution and progress being made within the cell therapy development process. He said that “automation strategies vary with fundamental differences of product”, pointing out several factors need to be considered including:
  • Development by design, as defined by quality – COGS – scale and sustainability
  • Should consider needle-to-needle scope
  • Managing comparability risk
  • Automation must be part of a comprehensive strategy
  • Automation considerations:

He also pointed out the many types of automation to consider:
  • Process automation (closed-loop process control)
  • Task automation 
  • Test automation
  • Factory automation
  • Information:  electronic batch records
  • Execution: manufacturing execution system (MES)

He stressed that “automation must be planned in the context of opportunity and value”. “We all talk about doing everything early, but automation can have a dark side to it,” he said. “You need to be sure what is going on inside the process.”

He warned that automation can also create its own problems, including process black box effect, supply chain risk, complexity, cash and timeline sink, comparability risk and unmitigated automation failure.

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GE Healthcare's Vanek: 'a mature cell therapy market is coming'

Philip G Vanek PhD said cell therapy is moving closer to a mature market

GE Healthcare general manager of cell therapy technologies Philip G Vanek PhD told attendees at Cell Therapy Bioprocessing & Commercialization that industries evolve down similar tracks: discovery, development, manufacturing.

“The biology of CTs has happened, process development and optimization is currently happening, a mature CT market is coming,” he said. However, he stressed the need for bespoke tools, "to design equipment that will be needed in the future”.

He pointed to five key areas that need development:
  1. Connect unit operations – increase the use of closed systems to increase repeatability
  2. Drive towards automation – decrease human interaction and involvement
  3. Contain costs per unit
  4. Manage talent – with scale comes need to more trained staff
  5. Risk management
What areas do you think need focus?

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Poor process is hampering cell therapy commercialization

Attendees queue out of the door to hear a panel discussion on alignment with commercialization
In a panel session on alignment with commercialization, attendees at Cell Therapy Bioprocessing & Commercialization were quite literally queuing out of the door to hear the discussion.

Session chair Robert Preti PhD, president of PCT, a Caladrius Company, posed the question of whether a cell therapy product was the process. “Yes and no,” he said. “It’s actually much more than that. But what does define the product?”

He told attendees that a cell therapy product has to be “transformative, have a robust manufacturing process, have the right business model, optimize COGS, must be scalable, logistically practical, clinic friendly and reimbursable”.  “Ultimately a product has to be deliverable,” he said.

However, he stressed that cell therapy products are difficult to deliver compared with a pill. “The benefit derived must overcome the natural tendency to prescribe what is easier to deliver (ie a pill).”

He said one of the main challenges in creating a commercial future for cell therapy was to change and improve the manufacturing model. “It’s a complicated model, but we know it needs to change.  It’s an enormous challenge.  A manual manufacturing process will fail,” he added.

He challenged the panel to answer how to prioritize improvements to the process “to limit the need to go backwards and repeat trials”. 

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Panel discussion: what is the solution to poor process in cell therapy commercialization

Ann Daus PhD debates the priorities in the commercialization of cell therapies
By Brian Caine
Attendees at Cell Therapy Bioprocessing & Commercialization were quite literally queuing out of the door to hear a panel discussion on how to improve processes in the manufacture of cell therapy products.

Session chair Robert Preti PhD, president of PCT, a Caladrius Company, challenged panelists to prioritize improvements to the process “to limit the need to go backwards and repeat trials”. 

Phillip G Vanek PhD, general manager of cell therapy technologies at GE Healthcare named three priorities in how to industrialize manufacturing workflows. “Firstly we must simplify manufacturing environments,” he said. Secondly, he stressed the need to connect unit operations physically. And finally he talked about the importance of digitization. “We must automate,” he told attendees.

Mark Angelino, vice president of pharmaceutical sciences at Bluebird Bio, said that the industry needs to think differently and is constrained by the process.  “We must understand the process so that you can focus on the product,” he said.

“COGs are important, but margin and value proposition are more important,” he added. 

He said the current state of the cell therapy industry is very similar to biologics from the 1980s.  “Infrastructure always lags behind the science,” Angelino said. “We must be patient to allow technology to catch up with the science curve.”

As the discussion opened up, Angelino questioned what the value proposition was for the patient, asking “What is the correct price point? Pricing is based upon the indication and the effect it has on prolonging life”

Ann Daus PhD, vice president of quality assurance and quality control at PCT said: “The better you can define/characterize your product, the less the process is the product.”

She added: “Since CTs are not currently well characterized, this is the reason the  process is the product, but that should diminish go-forward.”

The discussion moved on to the point of care with Preti asking what was the best place for patients to receive treatments?

He pointed to work by Larry Couture of City of Hope who is looking into creating third-party administration centers. “The best model is not clear at this point as the current infrastructure is set up for academic/clinical administration of product, not commercial,” he added. “Making that transition is a daunting task and it will be necessary to move to an automated system,” he said.

Daus added: “We are talking about individual treatments using existing processes designed to administer treatments to thousands.  Need to change that.  An electronic approach is a must.”

“The factory of the future will look different, but right now, we don’t know what that will be,” Vanek added. “Where is automation in CT development? Its coming but, we aren’t there yet.”

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Wednesday, September 30, 2015

Scott Burger on finding the right strategic partner

By Brian Caine

Advanced Cell & Gene Therapy MD Scott Burger gave attendees of Cell Therapy Bioprocessing & Commercialization a detailed overview of the roles, responsibilities and importance of teaming up with the right strategic partners, CMOs, CROs Suppliers and other contract providers.

“While it takes a village to raise a child, it also takes a village to successfully bring a product to market,” he said.

He also outlined the five historical problems with working with CMOs:
  1. Insufficient cell therapy experience and expertise
  2. Inadequate capacity
  3. Lack of commitment to the project
  4. Differing expectations for roles and responsibilities
  5. Inadequate/ineffective communication between client and CMO
Burger provided examples of differences between a biological and a CT CMO and reinforced the critical need to vet each CMO candidate to ensure their “capabilities, capacity, availability match your needs and expectations”.

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Bluebird Bio aims to "bridge the gap to commercial products"

Bluebird Bio's Mark Angelino addresses attendees
By Brian Caine

“Cell therapy products are happening. They are real,” Bluebird Bio vice president of pharmaceutical sciences Mark Angelino told attendees at Cell Therapy Bioprocessing & Commercialization 2015.

He took delegates through his company’s approach to their commercialization. “Bluebird has and will continue to evolve its manufacturing strategy as it progresses through development,” he said.

He said that the historical challenges such as low titers, low purity, tray-based production systems create scale issues and a reliance on vendor availability and flexibility.

To overcome these, Bluebird has worked at “reducing internal barriers, reducing technological barriers, working closely with vendors as a partner and vendor management”.

Bluebird takes a “total portfolio view,” he said, assessing the needs across programs. This assessment integrates and evaluation of the vendor space, “addressing both requirements and risk mitigation plans”, he added.

“Cell therapy products are happening. They are real,” he said. “There is a genuine development opportunity to bridge these to commercial products that will impact patient’s lives.”

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Cell therapy companies must improve internal process development

By Brian Caine 
Michael Paglia, senior director of technical operations at Bluebird Bio, told attendees at Cell Therapy Bioprocessing & Commercialization that companies need to “better understand the evolution of the process”.

Paglia told a packed session on viral production that there is a “significant need to determine how to improve their internal process development”.

He reviewed a specific case focusing on the downstream process development of a lentiviral vector and how one company offset product loss in their downstream process.

Companies must also have “proven tech-transfer in order to ensure proper reproducibility whether the process is internal or outsourced”, he said.

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"Help me to help you" NIH program director Rosemarie Hunziker tells Cell Therapy attendees

Rosemarie Hunziker
By Brian Caine

NIH program director Rosemarie Hunziker told attendees at Cell Therapy Bioprocessing & Commercialization 2015 that there is a “ton of grant money looking into new therapies”.

She said that companies must be able to articulate and document the product development life cycle in order to access these funds and that different agencies looked at different criteria.

“The grant that works for one agency doesn’t work for another,” she said “We all have different cultures."

Hunziker also stressed that manufacturing platforms “must evolve”. “While discovery is critical if you don't move it into commercialization it will stay in a lab forever," she told delegates in her session called “Show me the money”.

“While discovery is critical if you don't move it into commercialization it will stay in a lab forever" - Rosemarie Hunziker, NIH

In many cases “the financials to produce enough cells cannot be supported economically,” she said “Platforms must become more efficient if cell therapies are going to treat a broad patient-base.”

The industry as a whole agreed that there needs to be an evolution towards therapeutics. “The challenges are quite significant," she said. Overcoming these will allow a shift from "boutique treatments to ones deliverable in a clinic".

The NIH has invested more than US$3bn in the past three years, mainly in research Hunziker said. However, she added that the NIH was moving towards “promoting sciences and engineering grants looking at the key manufacturing roadblocks.”

“Help me to help you,” she said. "When you put the right money in the right place you can have some pretty profound impact"

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Early stage cell therapy funding gap can be filled by ‘venture philanthropies’

Attendees gather ahead of Brock Reeves' presentation at Cell Therapy Bioprocessing & Commercialization 2015

By Ryan Geswell

Brock Reeve, executive director of the Harvard Stem Cell Institute joined the Cell Therapy Bioprocessing & Commercialization today to discuss the commercialization of cell therapies and, more specifically, ways to fund early stage science.

He told a packed session that, because of uncertainty in financial markets, venture capitalists and other financially motivated investors have moved away from cell therapy, leaving a gap in funding. This gap is being filled by venture philanthropy organizations.

The goal of these venture philanthropy organizations is to move things from “the academic world and into the commercial market”, he said. 

He cited the 2014 move by the Cystic Fibrosis Foundation to sell rights to a drug its funding helped develop for $3.3bn, which Reeve said firmly placed venture philanthropy organizations as investment vehicles into the spotlight. 

Since then others have come to light, he said. He discussed how the SMA Foundation was created to accelerate the development of a treatment for SMA, the number one genetic killer of infants and toddlers. The foundation has spent more than US$110m on SMA drug development and serves as a hub for SMA research, investing in a cross-section of activity.

Other investment vehicles have also presented themselves, Reeve said. One has been the emergence of debt as a financing mechanism for medical R&D. Traditionally, medical research “has lagged behind other sectors” in the creation and application of novel financing methods to address market failures, he added.

These unique methods of financing for the sector have presented tremendous opportunity for advancements in research, drug development, and treatment, Reeve concluded. And because of these funding opportunities, many organizations have already hinted at potential cures.

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Plenary Sessions Pave the Way for "Cure Not Treatment"

By: Brian Caine

Cell Therapy Bioprocessing & Commercialization got off to an exciting start as plenary speakers Marc Better PhD, Julie Alllickson PhD and Bruce Levine described the cell therapy landscape and their outlined progress.

More than 200 cell therapy professionals heard Dark Horse Consulting president and event chairperson Anthony Davies set the stage by reviewing the real progress and strides the cell therapy market has made while acknowledging the hard work that the industry is facing.

Marc Better, Phd, Vice President, Product Services at Kite Pharma kicked off the first of three presentations describing the market as "exciting and challenging". He outlined the general challenges faced by Kite Pharma and focused on the solutions it implemented to effectively and successfully engineer autologous T cell therapies.

Julie Allickson, PhD, Director, Regenerative Medicine Clinical Center, Wake Forest Institute for Regenerative Medicine said real commercialization would come as research moved to "cure, not treatment".

She provided attendees with Wake Forest’s approach to determine what process design, development, manufacturing, and technologies will best support their initiatives.

"Academic and industry must come together in order to be successful," she said to create "a manufacturing roadmap for TERM Technologies".

Allickson reinforced the need to create a consortium to develop infrastructure and resources to advance manufacturing and set a standards. She also noted that bio-printing is showing greta results and has a bright future.

Bruce Levine, PhD, Associate Professor in Cancer Gene Therapy, University of Pennsylvania detailed their approach to targeting tumors with CAR-modified T-Cells and reported on the positive short and long term results.

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Closed Systems in Biomanufacturing Offer A Variety of Benefits

A Blog by Brandy Sargent, Editor, Cell Culture

I recently attended IBC’s Biopharmaceutical Development and Production week (BDP) and was pleased to find talks focused on single-use technologies, flexible facilities, closed systems and continuous processing. These subjects are sometimes referred to as “biomanufacturing of the future,” because they represent a change in paradigm from traditional biomanufacturing. While we have covered single-use and continuous bioprocessing extensively on Cell Culture Dish in the past, we have not dedicated much time covering the benefits and opportunities associated with closed systems. This blog will attempt to provide a high-level review of some of the topics associated with closed systems and will provide several outside resources for readers who want to explore the topic in more detail.

Traditional Biopharmaceutical Manufacturing

Traditional biopharmaceutical manufacturing has mainly consisted of fed-batch stainless steel bioreactor runs in a fixed facility with an open system. This paradigm, while serving the biopharmaceutical industry well for many years, has faced increasing pressure as single product 20,000L scale manufacturing has begun to lose ground to smaller volume, multi-product manufacturing. This shift has occurred for several reasons, some include:
  • Increases in productivity have reduced the need for very large scale manufacturing vessels and dedicated facilities.
  • Fewer blockbuster drugs with high volumes have reduced the need for large-scale dedicated facilities.
  • Single-use technologies have enabled the implementation of smaller, more flexible manufacturing.
  • Companies have begun to embrace the idea of more flexible, multi-product facilities that can easily be scaled up or down to meet changing product demand.
As a result of the changing landscape, the traditional biomanufacturing paradigm has been challenged by new models including flexible facilities, single-use systems and continuous processes that can create a more flexible and in many cases more cost effective process. Biomanufacturing of the future incorporates technologies like single-use and models like closed systems and continuous processing to move the industry forward.

Closed and Functionally Closed Systems

There have been several definitions of what makes a closed or functionally closed system in biomanufacturing. All the definitions are similar, but I like the definitions used in the BioPharm International article “Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances.” The article provides the following definitions:
  • Closed system: A process system with equipment designed and operated such that the product is not exposed to the room environment. Materials may be introduced to a closed system, but the addition must be done in such a way to avoid exposure of the product to the room environment (e.g., by 0.2 μm filtration).
  • Functionally closed system: A process system that may be routinely opened (e.g., to install a filter or make a connection), but is returned to a closed state through a sanitization or sterilization step prior to process use. It is the owner’s responsibility to define and validate the sanitization or sterilization process required to return an opened system to a functionally closed system
Benefits of a Closed or Functionally Closed System

Reduced Risk of Contamination
One of the biggest and most easily attained benefits of implementing a closed system, whether in research, pilot or large scale, is in reducing the risk of contamination by viruses or other adventitious agents. Open systems naturally provide more opportunities for contamination because the process is open to the room environment and handling by operators. There are also safety concerns associated with breeches of product containment. Operations like fluid transfer present a much higher risk in an open system where splashing and lost media can occur. A closed system, by design, provides physical barriers to reduce the risk of contamination and contain the product.

This is important because contamination can be extremely costly, not only in product loss, but also facility shut downs, cleaning and validation.

Reduced Process Time
The use of a closed system can reduce operating time. A closed system relies on less operator handling and fewer overall steps. Another time saving factor is that many of the closed system components are plug and play meaning that they come pre-assembled, designed for the job they are intended. This reduces the time it takes to set up and launch a manufacturing system significantly.

If single use technologies are employed as part of the closed system, then more time savings can be achieved. Over the course of several talks, the use of single use technologies were reported to save anywhere from a couple of days to a couple of weeks. These times savings were reported in areas including:
  • Reduced cleaning and validation time
  • Reduced set-up time
  • Reduced time to operate or oversee equipment
Examples of Benefits
One example where there is a benefit to time savings and risk reduction is in media preparation. To enable a closed system, instead of mixing and adding media, one might purchase a pre-filled media bag with a connector that is complimentary to a single use bioreactor. This creates a closed portion of the process and saves operator time of mixing media. This method also reduces risk of contamination because the media isn’t exposed to the room environment and there is reduced risk of spilling and loss of media. Aseptic transfer of large volumes of sterile media and solution can be a big challenge.

Another example was provided in a talk at BDP, titled “Processes of the Future: Single Use, Closed and Continuous for Faster, Cheaper and Safer Manufacturing,” given by Sébastien Ribault, Ph.D., Director Biotechnology/Life Science, Head of BioDevelpment Center, EMD Millipore. BDP. In Dr. Ribault’s facility, his team is operating a closed system in one of their manufacturing areas. The group needed to close the cell seeding process, so instead of banking cells in vials, they banked the cells in bags. They then thawed the bags in a water bath and seeded directly in the lab without laminar flow. This saved them time and they reported similar growth and viability to the process using cells banked in vials.

Adopting a Risk Based Approach to Manufacturing Classifications
One hot topic in the discussion around closed systems is the idea of adopting a risk-based approach when it comes to the manufacturing classifications required with closed systems. If a system is closed, or functionally closed, then a barrier already exists between the product and its environment. Therefore, is there really a need for these operations to be conducted in a Classified environment with extensive gowning and airlocks, or would it be more feasible to conduct these operations in a Controlled Non-Classified (CNC) space? The benefits associated with this type of change in classification would provide many manufacturing benefits.

At BDP, Kenneth Green, Ph.D., Head of Manufacturing Science and Technology, Shire, gave an excellent talk titled, “Pushing the Controlled Non-Classified (CNC) Envelope with the Application of Single-Use Systems for Bioprocessing.” In the talk, Dr. Green discussed the debate around whether a closed system or functionally closed system could be proved to regulators, with satisfaction, so that manufacturing could occur in a controlled non-classified environment.

If so, operating in a Controlled Non Classified (CNC) space would open up many more benefits including:
  • Enabling a truly flexible facility – by reducing the classified area requirements you could also reduce the amount of segregation in a facility and increase flexibility. There are many benefits associated with flexible manufacturing, including:
    • Smaller facilities with a simpler design that can be duplicated in multiple locations
    • Multiple products can be manufactured in the same facility or space
    • Less segregation
    • Equipment can be moved around on skids as needed to meet product demand in multiple production lines.
    • Personnel can also move more easily throughout the facility
  • Reduced operating costs include:
    • Energy savings by reducing the environmental monitoring needed and the air handling requirements
    • Removing or reducing gowning requirements reduce cost of both gown materials and provide time savings for the gowning/de-gowning processes.
The idea of employing a risk-based approach in classification requirements is a very interesting topic that could be a blog entirely on its own; however for the purposes of this article, I am only providing a high level overview. There are a number of excellent articles that cover this topic in more detail including:

Challenges to Implementation of a Closed System

Employee Training
While most of these systems are fairly easy to use, there are some major differences between stainless steel systems and single-use. Employees should be trained in maintaining the closed or functionally closed system, proper use of equipment to prevent breakage or tears and employees need to be comfortable using the tubing and connectors.

Breaking New Ground
Completely closed systems represent relatively new technologies. Ensuring all parts of your system are closed may require a good deal of ingenuity and determination particularly when using components from several suppliers. There may not be an off the shelf component that works for you and you may need to work with suppliers to create systems that work for your process.

One example of this ingenuity and determination appeared in Dr. Veena Warikoo’s talk at BDP. Dr. Warikoo, Director, Purification Development, Genzyme, gave a talk titled “Integrated and Fully Continuous Processing of Recombinant Therapeutic Proteins – From Cell Culture Media to Purified Drug Substance.” In the talk she described how Genzyme developed a closed, continuous model system for manufacturing both mAbs and non-mAbs. They had been using a continuous system upstream but needed to also close the downstream process. There wasn’t an off the shelf solution available at the time, so they partnered with GE Healthcare to develop a functionally closed periodic counter-current chromatography continuous process. She showed a picture of the system they used, then stated that GE Healthcare now offers an off the shelf version in their AKTA system.

Demonstrating to Regulators that Systems are Closed and Adopting Risk Based Approach in Classification for Closed Systems
In order to fully gain all of the benefits mentioned above, the industry must work with regulators to demonstrate that CNC manufacturing space is appropriate. BioPhorum Operations Group (BPOG) is currently working to help interpret regulatory guidance and quality expectations and prepare responses that incorporate a risk based approach.

Is a closed system right for your process? – How to navigate a transition
I was able to speak with Erika Hanley-Onken and John Shyu at Corning Life Sciences about their experiences helping customers’ transition to closed systems. They said that they like to conduct a walk through with customers to understand on a technical level the customer’s current system and how that system will transition into a new closed system. They also work with multiple vendors to create a system designed to meet customer needs and goals. Lastly, they train the company on using the new system and they will work with customers to help validate the new system. When asked what customers are most surprised by when deciding to transition they said “how long it takes, it can take weeks to months to develop the system and test it, but we provide a full quality package and we want to ensure that the customer can achieve full and consistent results.”

First it is important to consider what is the primary goal in moving to a closed system. Some examples below:
  • Designing a new facility and want to incorporate flexible manufacturing principals
  • Quality control concerns and are interested in reducing risk of contamination
  • Process improvements with desire to reduce production time or cost
Design and Implementation of a Closed System
In determining the design and implementation of your closed system it is critical to truly understand your existing process needs, strengths and weaknesses. These factors can be very helpful when working with a vendor or vendors to establish your system. It is also important to understand your current cost of goods and net present value analysis, particularly if cost is a driving factor for change. This will allow you to compare your current system against the proposed system once you have a scale model running.

It is imperative to find a partner that you can work well with. Several talks stressed the keys to a good partnership, and I have included some of them below:
  • It is important for companies to understand their process and share this with supply partners.
  • Choose a supplier you trust and can work with. They have to know what your concerns and goals are so they can build a system that works for you.
  • A supplier should have a quality package and service to help with validating the new system.
Supply partners can be a single vendor who will work to design a process using theirs and complimentary products. A company may also choose a supply partner that has the capability to utilize multiple product vendors to put together a system that is compatible.

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Thursday, September 24, 2015

Exclusive Interview with Dr. Ian Tomlinson of GlaxoSmithKline

As Senior Vice President and Head of Biopharmaceuticals R&D and Head of Biopharmaceuticals R&D and Worldwide Business Development (WWBD) at GlaxoSmithKline, Dr. Tomlinson combines the resources and development expertise of a large pharmaceutical company, with the entrepreneurial spirit of a smaller biotech organization, bringing early research, late-stage biopharm development and manufacturing expertise into one organization. He served as the Chief Scientific Officer and Executive Vice President of Domantis Inc., and Domantis Limited. Dr. Tomlinson co-founded Domantis Limited in 2000.

In this interview, listen to his views on antibody therapeutic development, shaped by his background both in large pharma and smaller biotech.

Ian Tomlinson is one of the scientific advisory board members and organizers of the Antibody Engineering & Therapeutics conference scheduled for December 7-10, 2015 in San Diego.

Download the event agenda now.

Register now with the code D15172BLOG and save $400!

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Wednesday, September 23, 2015

Exclusive Interview with Larry Couture, VP, Center for Applied Technology Development, City of Hope

Dr. Larry Couture, Vice President of Center for Applied Technology Development, City of Hope - a Keynote Speaker at this years Cell Therapy Bioprocessing & Commercialization Event, sat down to discuss the biggest challenges facing regenerative medicine developers, how pharma companies benefit from learning the academic model for translation, regulatory hurdles, and this years meeting. Below you will find a brief teaser from the interview, to access the full interview, follow the links below...

What are the biggest challenges facing regenerative medicine developers?
Well, the field is really beginning to take off. There are now four or five or six clinical trials and probably at least as many academic trials – some of those are academic – that are about to enter the clinic or will be entering the clinic in the next couple of years. 

One of the problems and challenges that are starting to emerge about where this is going to go and what we are going to have to face and some of the issues we are dealing with right now that I think are going to become big are cost of goods, the ability to scale-up some of the manufacturing processes that we are using purity to sell product. Not necessarily trying to achieve 100% per se, but trying to optimize purity and identify how pure these products should be...[Click here to read more]

Want to hear more from Dr. Couture? Join him in Alexandria, VA for Cell Therapy Bioprocessing & Commercialization, September 30 - October 2, 2015 - where he will have a keynote address titled "Development of a Well Characterized Regenerative Medicine Cell Product". Register now with the code XB15188BLOG to save $100 off the current rate.

See you in Alexandria!

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