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
- 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.”
Goals
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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