One of the world’s leading biopharmaceutical companies,
Shire Human Genetic Therapies (HGT) focuses their work on life-shortening,
neuro-muscular conditions such as Fabry disease, Gaucher disease and Hunter
syndrome. These diseases are treated by enzyme replacement therapies that are
now being produced in one of the company’s newest and most unique facilities.
Project Atlas, in Lexington,
MA is Shire’s third cell culture
facility and one of four buildings on the Lexington Technology Park (LTP)
campus – the global center for Shire’s HGT division. The Atlas facility
supports the manufacture of Replagal® (for Fabry disease) and VPRIV® (for type
1 Gaucher disease).
While a number of features make Project Atlas stand out,
perhaps the most intriguing is Shire’s first-ever implementation of extensive
single-use technologies at commercial scale. And at the heart of this ambitious
project are a number of unique and customized processing solutions that were
developed during design and construction.
Pioneering Single Use
In its 200,000 square feet of production space, Atlas
provides multi-product upstream and downstream operations for two simultaneous
production runs. This is complimented by three completely sterile trains; two
2,000 L and one 500 L perfusion cell culture bioreactors, with the 500 L
reactor capable of being upgraded to a 2,000 L reactor without layout
modifications or utility upgrades.
With speed to market as the primary driver in combating such
vicious diseases, Shire researched and analyzed the use of single-use
technology versus stainless steel. The main challenge was that single-use
process technology had yet to be proven at the 2,000 L scale. However, CRB, the
project’s design and engineering firm, helped discover a number of benefits
that fortified the company’s decision to make Atlas a single-use facility:
• Single-use led to a significantly shorter construction
time.
• The disposable nature of the system meant nearly all CIP
and SIP considerations were eliminated, cutting additional costs and saving
time.
• Aseptic bags, a closed process, and single use bioreactors
and tubing help reduce the potential for contamination.
• Production schedules can be compressed since there is no
need to clean vessels. The savings realized by reducing the number of media and
harvest hold vessels was approximately $350,000 per bioreactor, and since no
vessel would ever be out of use for cleaning, Shire was able to eliminate three
3,000 L vessels per bioreactor, saving roughly $1 million.
Also, although it is counterintuitive to believe that
technology utilizing single-use plastic bags is better for the environment, it
proved to offer some very green benefits:
• The use of caustic cleaning materials is decreased by 95
percent.
• Bags can be reused at certain points along the sterile
train, such as in media hold.
• 87 percent less water is consumed.
• Facility footprint was shrunk by 38 percent.
• Single-use translates to 30 percent less energy being
needed for process equipment and 29 percent less energy for HVAC.
• 25.5 percent less CO2 is emitted.
Additional benefits for Shire in implementing this approach
included:
• Improved safety. In the event of instrument malfunction,
the operator can see what’s going on and react more quickly.
• Culturing new products is made easier by the uniformity of
instrument connectivity and interface. Single-use equipment will always be the
same in all facets of production. To take a product from the lab to clinical or
from clinical to commercial, one need only define a small number of scaling
parameters.
• Flexible, single-use tubing allows for piping
modifications that would be more difficult with stainless steel.
• An operator can change out one bioreactor bag or
centrifugal insert more quickly than it would take to clean stainless steel
piping and vessels. So Atlas can switch production focus in a couple of shifts,
rather than days or weeks.
• Due to the closed nature of the technology, clean room
space is optimized by moving some systems out of classified space and into
controlled non-classified space. This cuts costs while improving maintenance
access.
When asked about lessons learned in implementing a
single-use approach, Jerry Justin, Shire Plant Manager offered the following
advice:
• "Fluid mixing and temperature control are important
considerations as the scale of the operation increases.
• "Be open to working with vendors in seeing what
type(s) of new technology is available or been successful.
• "Understand the impact that leachables and
extractables will have on your process.
• "While initial capital costs may be lower with
disposables, also pay attention to how on-going operating costs may be more
expensive."
An Industry First
During facility design, no single-use 2,000 L bioreactors
were in use anywhere in the world because of the difficulties with agitation in
a bag so large. Shire’s design team worked with Xcellerex to design a system
that would provide mixing at the top and sides of the bag without creating
shear around the impeller. The solution was a single-use, bottom-mounted,
magnetic impeller pre-packaged with the 2,000 L bio-bags and driven by an
external motor.
Another significant equipment innovation was the highly
integrated control system spearheaded by Honeywell. The single-use bioreactors
were packaged with their own control software for consistency and ease of use,
but Shire felt it important to have a uniform interface across all their skids.
A unique element on the Shire project was the construction of a full, mock
working system that was built by Xcellerex and supported by Honeywell in
working out any issues of the single-use system in advance of the actual
implementation.
Custom designing the software would permit Shire to control
the centrifuge and bioreactor as a single unit. This came at significant cost -
approximately $750,000, but according to the company, the result was a uniform
interface that will reduce errors and training time, while permitting seamless
data integration and collection.
The automation control system also executes batches in a
controller, rather than a server-batch application. This eliminates extra
hardware costs and time spent on infrastructure development by reducing the
number of components required to implement the automation. Additional benefits
include:
• Functionality can be better distributed between the batch
procedural levels, so there’s a series of standalone subsystems that can run
for several weeks without intervention.
• The user does not have to take the entire batch management
system out of service to make configuration changes—only the affected areas.
• Fewer communication points that could be connected by
mobile laptops outside washdown areas, which use a wireless mesh network,
simplified the overall automation system.
Additional equipment-based production benefits realized from
the implementation of the single-use system included:
• A disposable tangential flow filtration (TFF) system was
selected for easing scalability and changeover between multiple batch sizes.
• A risk-based assessment led to the determination that a
purified water system had no direct impact on product quality. So Shire
switched control of the purified water to a less demanding system that is
faster and less expensive to operate.
• 162 limit switches were eliminated after the design team
determined they were not necessary on GMP (good manufacturing practices)
utility valves, saving Shire another $350,000.
• A final component of Shire’s strategy was based upon the
concept of “briefly exposed.” For example, the media and buffer preparation
operations are open processes that require powder additions. Since the process
is open, the room environment is typically classified and the solution is
filtered. The Atlas facility locates the preparation vessels in classified
space, but considers the process closed as the material is delivered to the
transfer panel. At the transfer panel, a connection is made between the media
hold bag and the transfer panel that is “briefly exposed” (i.e. the clean
outlet port of the valve is exposed briefly to the room environment in order to
make the connection). Assessment led to declassifying the entire media and
harvest hold room. The team was able to declassify over 7,000 square feet,
saving time and money.
While no one element can be given all the credit, the
portions of the design and engineering plan detailed here all played a crucial
role in the successful completion of the Atlas project. In addition to getting
life-saving medication to their customers more quickly, Atlas opened five
months ahead of schedule and $10 million under budget. While single-use may not
be the best approach for every facility, Shire credits it with taking the Atlas
project to greater level of success