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Enabling Progress

Tue, 09/24/2013 - 9:03am
Mike Auerbach, Editor in Chief

According to the definition found at businessdictionary.com an “enabling technology” is ”equipment and/or methodology that, alone or in combination with associated technologies, provides the means to generate giant leaps in performance and capabilities of the user.”
While the pharmaceutical industry’s past has not been chock full of advancements that could be classified as “enabling”, recent developments have pointed the way toward a more technologically advanced future for pharmaceutical manufacturing.
Indeed, as many companies have begun to embrace advanced technologies they are finding little use for older technologies, as new equipment and processes are showing them the way to more efficient, less costly and higher quality manufacturing.
For companies in the biopharmaceutical contract manufacturing segment of the industry this confluence of technology could not have come at a better time. As the biopharm market continues to grow, biopharmaceutical product sponsors and service providers are looking for the best tools and techniques to bring products to market faster and with the best quality.
One such company is Catalent. The company has combined the latest single-use equipment with their own technologies to design and commission a world-class contract manufacturing facility in Madison, Wisconsin for the development of clinical trial materials that are used worldwide.

Background & History
Catalent is a global leader in development solutions, and advanced delivery technologies for drugs, biologics and consumer health products. The company offers numerous technologies at dozens of facilities around the globe (see chart).


 The biologics site in Madison started as a spin-off from the University of Wisconsin-Madison with funding from angel investors and was housed in an old army facility outside Madison. The company’s main focus was developing a process to make pharmaceutical proteins from the milk of transgenic cows as this was viewed, at the time, as a cheap way to manufacture pharmaceutical proteins. It was during this time that the company moved to a larger facility in Middleton, WI.
In 2003, Cardinal Health bought part of the company and then bought the rest of it. Catalent as it operates now was created in April 2007 when The Blackstone Group, a global investment and advisory firm, acquired the Pharmaceutical Technologies and Services segment of Cardinal Health.

Global Technologies & Global Reach
As it takes a long time to get a cow to the stage where it can be milked, the company was also concurrently developing its proprietary GPEx® system to make higher expressing mammalian cell lines. As Gregory Bleck, PhD the company’s Director, R&D Platforms explains, this turned out to be good timing. “At this time, Mad Cow disease was identified, so even though there was very limited risk, all investors wanted to stay away from cows, they didn’t want to deal with any possible connections. We had GPEx® to fall back on.”
In addition to the GPEx® cell line platform the company has also licensed SMARTag™ Technology from Redwood Biosciences which is designed to develop optimized Antibody Drug Conjugates.


Under the global Catalent umbrella, the Madison facility, which is currently set-up to manufacture Phase 1 and Phase II batches for clinical trials, can help a client take a gene and deliver a product to a clinical trials site anywhere in the world. Relying on the global network of Catalent facilities, once the bulk product is released from the Madison facility it is sent to the company’s clinical fill/finish facility in North Carolina and then to one of several clinical packaging facilities in the US or Europe, and then on to the company’s extensive clinical trial distribution network.
Speaking to the capabilities and technologies Catalent has to offer, Bleck offers his views. “We have unique technologies all through Catalent – we do more than manufacturing - we want to offer solutions to our customers to make better products. We are continuously developing our own IP internally and exploring arrangements with other technology companies to access unique offerings that will add value to our customers and enable them to provide better products.”

The Madison, WI Biologics Facility
As Catalent’s facility in Middleton, WI began to fill up it was decided to expand and look for a larger building to house their growing operations.
The facility they selected was a former electronics manufacturing building and was essentially a big, wide-open warehouse. This proved to be good choice as this layout resulted in minimal obstacles in facility design – except for the required support pillars which were integrated into the facility. Michael Jenkins, PhD., the facility’s General Manager explains how the empty facility worked in their favor. “We wanted an open area with good ceiling height. Which is absolutely critical to what we do because bioreactors take up a lot space. We put in the appropriate infrastructure from the start so things would work - and made sure the infrastructure was properly sized for our needs.”
Compared to the site in Middleton the new Madison facility has more than doubled in size. In addition the manufacturing area available to the company has tripled in size, and the capacity for making production material has quadrupled.


For more specifics, the Madison site now boasts bioreactors up to 1,000 liters in size, compare to the 200 liter bioreactors in the old facility. In addition, through a comprehensive Operational Excellence (OpEx) program, Catalent has increased the number of runs per suite by 20% which lets them run multiple products per suite while keeping them completely separated.
As part of the global Catalent network of facilities, the team in Madison was able to leverage the experience of others within the Catalent organization. “One of the great things about being part of Catalent,” says Jenkins, “is that at the end of the day you might think we have a nice manufacturing facility here in Madison with about 100 people, but it’s really backed up by the 8,000 people who have a lot of experience in manufacturing, not necessarily biologics, but they know how to get stuff to market – which is a great thing to have. Catalent pays a lot of attention to this business.”
He continues, “Two years ago we were the largest investment Catalent made in its business. That’s a level of commitment they have to biologics. Think of all of the things going on in Catalent – all of the other divisions - and they have a strong commitment to biologics and also integrating this facility in to the rest of Catalent. It’s a great solution for our customers.”
“A lot of our customers are small companies – less than hundred people or even university researchers trying to get a product to market – and the ability to deal with one company that is reliable and to be able to go from DNA construct to an injectable in a clinic is very powerful.”

The Transition to Single-Use Technologies
For Catalent, the decision to move to single-use technologies in their Madison facility was a defining moment because they decided to abandon all of their stainless steel equipment and jump totally into single-use. “A lot of companies that make the transition to single-use keep their stainless steel equipment on the side – we abandoned all of our stainless steel equipment and you won’t see any stainless steel bioreactors in Madison,” says Jenkins, “we sold all the stainless steel equipment to a competitor. We view this as a positive.”
One of the key benefits to moving to single-use was that team did not have to include any of the infrastructure necessary to support stainless steel equipment such as steam lines, CIP carts, etc. all of that infrastructure is unnecessary. In addition, the construction timeline was significantly compressed.


“The typical timeline for a GMP stainless steel facility is to finish construction in a year and six months for validation” says Jenkins. “We went from the start of construction to ready for GMP production in about a year.Single-use equipment enables that.”
Being a reliable supplier of quality products is of critical importance to Catalent and single-use technologies help them accomplish that goal. Single-use equipment allows them to keep their manufacturing processes in a closed system. The company employs an ‘alcove strategy’ - suites are divided into separate rooms and material is pumped through single-use tubing through a port in the wall from one suite to another. This allows products to be separated from one another and also eliminated product from being wheeled through hallways en route to the next suite.
By separating the process into multiple rooms more efficient production is achieved. Product spends about 18 days in the terminal bioreactor room and then is transferred through the wall from the TFF skid to depth filtration, then to the sterilizing filter and then to a mixing vessel in a plastic bag. Once product is pumped out of the first room cleaning can begin, and what was once a 3 day process with stainless steel equipment, now takes one day.
“It’s a simple process actually,” says Jenkins, “but everything that touches the product will be thrown away at the end – no cross contamination and it’s a completely enclosed system.”

Additional Features
While single-use technologies get a lot of the attention in the Madison facility, other features of the building and its design contribute greatly to the facilities success.
For example, in the bulk fill room where material is taken out of the disposable bag and put in a transport container and shipped to the client features a very robust air handling system. Air in that room is completely separate from the air using in other areas. In fact, over 25% of the build out cost was from HVAC. Jenkins explains. “If you want to get the maximum number of runs from your process you want to keep these areas separate – it becomes very expensive in terms of air-handling. We have great capacity in our suites and you get there by investing heavily in separation of product – and HVAC is a huge part.”
The flow of people and product through the facility was also carefully thought through. The lab areas are separate from the office areas. Personnel enter the GMP production areas through an entrance corridor and exit through an exit corridor. This is a key compliance item and one of the keys to being Phase III compliant, which Catalent is looking at for the facility in the future. Commenting on the facility design and work area segregation, Jenkins points Catalent’s GPEx® technology as a major reason. “Almost every cell line we work with is from our GPEx® technology, but we also work with non GPEx® cell lines and we have a special lab to work with these cell lines until they have been tested enough to be released into the facility. We have great separation between the GMP areas and the development areas.”

Final Thoughts
There is little doubt that the implementation of single-use technologies and Catalent’s own intellectual property has created a world-class Phase I and Phase II biologics manufacturing facility in Madison, WI. By leaving stainless steel in its past the team at Catalent has reduced costs, increased production and improved quality. Looking toward the future the team is exploring expanding the facility to include manufacturing of commercial scale products and there is definitely a sense of anticipation in the air. “It’s a real exciting place to be,” says Jenkins.

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