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Ballrooms Reduce Capital & Operating Costs but Are Savings Worth It?

Mark F. Witcher, PhD
Ballrooms Reduce Capital & Operating Costs but Are Savings Worth It? - ISPE Pharmaceutical Engineering

Manufacturing biopharmaceuticals has many challenges requiring a clear understanding of every product’s goals and priorities. These challenges will only increase as more sophisticated products and therapies are developed.1 One of the recent advances in manufacturing facility design is the shared flexible space facility (SFSF), or ballroom layout that provides significant capital cost reduction and operating cost savings.2 The shared flexible space facility approach commingles many process unit operations (UOs) for one or more products within a large operating area. Advances over the last few decades in single use technology (SUT) have enabled commingled layouts by creating process systems that can shift product segregation control from a facility-based room-by-room separation to functionally closed single use technology process equipment that minimize, under normal operating conditions, cross contamination risks.3

For any layout, operating control strategies (CSs) must be developed to provide the three requirements of any control strategy system (control, proof of control, and assist with return to control). 4, 5 CSs are developed during the facility’s lifecycle design stage based on Quality Risk Management (QRM) exercises for structuring and evaluating the operating risks. Using the manufacturing enterprise’s process, facility, and infrastructure elements, operating risks are controlled to meet the above three control strategy requirements.5 For Shared Flexible Space Facility layouts, the facility’s internal segregation control capabilities are minimized to reduce capital costs and provide flexible personnel movement among the process unit operations. The shared flexible space facility layout strategy shifts controlling cross contamination risks from the facility to the process (SUT) and infrastructure (procedural and timing controls) elements to assure reliable and continuous control over operating threats. Thus, the flexibility and cost saving of the shared flexible space facility comes at a price of a more constrained, less flexible process and infrastructure elements for assuring appropriate process separation.

Quality Risk Management (QRM) exercises for a shared flexible space facility are typically done under normative conditions in which all the process and infrastructure systems perform as expected. Under normal operation, connections remain closed, the integrity of single use technology bags and containers is maintained, operators make all the correct connections, etc. Under normative risks situations, single use technology systems can be validated to assure the required closure and appropriate performance. However, as the shared flexible space facility layout is challenged, the control strategy systems must be planned and designed for more descriptive operating conditions that include possible system failures and schedule interruptions. These challenges include: Multiproduct operation, increasing numbers of unit operation (UO), and more intensified operations such as continuous processes (perfusion and rapid refed bioreactors, simulated continuous or rapid cycle chromatography, etc.). Additional challenges can also include more complex operating schedules (faster product change-overs, process scale changes, etc.) to meet changing product manufacturing requirements.

Recently developed more sophisticated Quality Risk Management (QRM) methods that includes structuring threats and risks using a system risk structure (SRS) provide a method of analyzing both normative and descriptive risk situations.6 A system risk structure for the operating area is initially constructed by starting with a process flow diagram (PFD) of each train’s unit operation sequence in the shared space. Each train is then expanded to show the operating sequence for each unit operation. For example, a single use bioreactor (SUB) would be expanded to include its setup, inoculation, operation, harvest, and clean-up sequence. The resulting composite process flow diagram describes all the trains and their operating sequence required for the entire operating area to function.

The purpose of the composite process flow diagram is to show the possible threat interactions between all the unit operations as they are run through their respective operating sequence. The composite process flow diagram for a single train in a single room is considerably simpler than a complex composite process flow diagram for several trains operating in a single space. The composite process flow diagram can be used as a basic system risk structure to understand how each unit operation, as it goes through its operating sequence, threatens all the other unit operations as they go through their operating sequence. For complex operating spaces, the primary tool for controlling these threat interactions is scheduling all operations relative to each other to minimize the possible interaction threats during normal operation. For example, the inoculation of single use bioreactor #1 would be separated in time from the harvest and clean-up of single use bioreactor #2 to prevent any possible perception of cross contamination (i.e., the difficult – proof of control goal). Environmental monitoring and personnel flow control might also be used to assure that one operation does not threaten another. Using the System risk structure, the appropriate control strategies can be identified to satisfy the requirements for control.

The basic system risk structure can aid in scheduling all manufacturing operation within the ballroom. Large ballrooms with several process trains running at a steady operating rate under normative conditions are fairly easy to schedule to minimize possible undesirable inter unit operation interactions and threats. A QRM exercise based on the basic system risk structure can also be used to assess and prioritize the various risk uncertainties of the inter- unit operation threats and possible risks associated with various unit operation failures or schedule interruptions.

For a more complete understanding of threat interactions, the system risk structure can be further expanded to include potentially important risks associated with possible failures of supporting processes such as a weak SOP, operator mistakes, compromised environmental conditions, single use technology component failures, and other threat inputs. (6) For well-time separated operations, some support processes can be designed to be fault tolerant (i.e., extra time provided for redoing a failed single use technology setup process, etc.). The Achille’s heel of single use technology is that personnel, using infrastructure elements (SOPs, training, experience, etc.) are required to setup, operate and change-out the single use tubing, bags, and systems. The system risk structure that describes the complete system’s operation should include personnel specific activities (“processes”) that may be subject to human error.7, 8

Thus, a complete system risk structure may include any threat inputs, such as SOPs, training, and personnel experience for each of the unit operation’s operating sequences. The complete system risk structure provides a more complete risk analysis tool that can be used to identify weak SOPs, inadequate training programs, and possible over-reliance on highly experience personnel to complete critical operations without failures. Thus, all support processes should be evaluated and improved as necessary to assure that the likelihood of these support process’s failure is acceptable.

As the manufacturing production challenges associated with production schedule changes, product change-over, and scale changes continue to increase, the initial layout flexibility of the ballroom decreases the facility’s operational flexibility and increases operating risks. At high operating rates, the rapid sequencing of operations resulting in the increased risks of one failure impacting other operations creating an even greater possibility of additional failures. In extreme situations, the operating sequences can result in “unit operation train wrecking” were compounding failures cause additional failures of systems that may be operating normally. In such cases, the control strategy requirement of proof of control can be seriously compromised for many process operations within the commingled space.

While shared flexible space facility ballrooms provide significant cost and operating advantages, those advantages need to be compatible with the business objectives of the company. These business objectives may also include a wide variety of product manufacturing challenges associated with rapidly developing new products requiring highly flexible manufacturing resources. Depending on the company’s priorities, appropriate trade-off between operating and capital costs with operating flexibility may necessitate more flexible layout options.9