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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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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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”. 

Read the panel discussion here

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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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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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"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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Major Challenges Facing Immunotherapy Developers

  

Dr. Marc Better, Vice President of Product Sciences, Kite Pharma - a Keynote Speaker at this years Cell Therapy Bioprocessing & Commercialization Event, sat down to discuss the current projects he is working on at Kite Pharma, the biggest challenges facing immunotherapy developers, 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...

Podcast | Transcript

What are the biggest challenges facing immunotherapy developers?

Well really, I think the biggest challenge for us is that we are charting new ground. There really isn’t a lot of precedent for bringing this type of product to the market. However, we do know - at least in the early trials we are seeing really exciting results both with our collaborators at the NCI and other institutions. We are building a lot of processes and systems around this to allow us to expand these programs and commercialize products like KTC 19.

Any field that is as innovative and exciting as this is very challenging, but we are very committed to being the best in the area that we can possibly be....[Click here to continue reading] 


Want to hear more from Dr. Better? Join him in Alexandria, VA for Cell Therapy Bioprocessing & Commercialization, September 30 - October 2, 2015 - where Dr. Better will have a keynote address titled "Overcoming Challenges for Engineered Autologous T-Cell Therapy". To see the complete agenda, click here. And register now with the code XB15188BLOG to save $100 off the current rate.

See you in Alexandria!

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