Monday, September 21, 2015

Closed Systems in Biomanufacturing Offer a Variety of Benefits

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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