Setting the Stage
In testimony given 2013 during a congressional modernization hearing, FDA Director Janet Woodcock clearly outlined the regulatory impetus for the industry’s continued drive to implement continuous manufacturing platforms.1 She challenged the biomanufacturing organizations to take advantage of advances in process and facility design to help achieve improved manufacturing reliability, increased process robustness, and lowering of manufacturing costs.
Move forward to 2017 when CDER finalized the guidance, “Advancement of Emerging Technology, Applications for Pharmaceutical Innovation and Modernization"2 Again, the driving focus of regulatory policy is to promote technology that can produce a more robust manufacturing process with fewer interruptions in production and ensure that facility assets can support these advanced platforms.
Yet continuous biomanufacturing is not a recent phenomenon. Perfusion-based bioreactor operations have been in use for over 25 years. The focus use was on high-value and labile proteins from low yield expression systems. These systems had many production and regulatory challenges. But with new platform technologies, advanced equipment designs, and advances in automation/control systems, continuous manufacturing is rapidly gaining acceptance across a wider spectrum of manufacturing operations.
Traditional State vs. Future State
As the industry sees production costs rise in an expanding global market forecast to surpass $200 billion (US)3 there is a focus on optimizing the product-process-facility relationship. Current advancements in manufacturing science are resulting in increasing titers which translates to shrinking bioreactor capacity for the same throughput. Perfusion bioreactor operations can provide much higher capacity utilization allowing smaller equipment for the same throughput.
The “traditional” fed-batch biomanufacturing facility and its equipment have some common attributes.
- Complex manufacturing and utility systems
- Process designed for lower average yields and cell densities resulting in inefficiencies
- Cleaning and contamination control for each batch are expensive and often difficult
- Complex, large, fixed stainless steel-based equipment platforms
- High operation and maintenance costs
- Resource and maintenance intensive
- Inflexible, process dedicated designs
- Extensive stainless steel piping systems
- Inflexible equipment configuration
- High operational costs and resourcing requirements
- Increased risk in numerous complex in-process material transfers
- Complex stainless steel CIP/SIP cleaning systems
- Risks due to temperatures, chemicals, loads, and automation control
If you focus more on the specific process design attributes in traditional upstream and downstream manufacturing, addressing the need for large volumes of expensive complex media, microbial control concerns, complicated change-over protocols for large chromatography columns, and complex validation execution are normal.
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The traditional fed-batch facility requires significant amounts of physical and controlled manufacturing space (Figure 1) when compared to a continuous facility approach for similar production output. The reduction in space is because continuous systems have a much higher utilization rate of expensive resources than fed-batch processes that have lower average titers and significant overhead associated with batch changes.
Facility layout is driven by a complex set of relationships between unit operations, equipment design and configuration, flows and segregation and control strategies.
When companies embark on continuous manufacturing implementation, there should have been a decision process similar to that shown in Figure 2.4
From such an analysis, key attributes of what will become the facility design will begin to evolve.
For continuous manufacturing these attributes would include:
- Design to support a 24/7 operational approach
- A synchronized process flow through all unit operations
- Equipment/unit operations that support high cell densities, high yield expression systems
- Facility design focused around a “scale-out” approach
- Elimination of hold steps
- Process control platforms implementing PAT-driven active control strategy
- Flexible equipment platforms that support significant cleaning reductions and changeover, particularly this associate with single-use technologies.
The Look of Continuous Manufacturing
There are some key success metrics around implementing continuous versus fed-batch manufacturing operation that impact facility design. In the three reference studies shown in Figure 3, there are three downstream chromatography operations implemented; the actual number of columns may vary depending on purification strategy.5
From a process design view, there are multiple options around continuous process implementation. For a typical MAb cell platform, these would be as follows.6 (Figures 4, 5, 6)
Each approach will have design strategies that impact facility design related to layout, orientation, and segregation strategy. For option 1, high density cell banking in bags and the implementation of an intense closed system design approach will significantly reduce upstream footprint. In option 2, high throughput and multi-column chromatography permits a more efficient use of resins and a reduction in buffer consumption per gram of product. It may also permit the use of pre-packed SUS columns. For option 3 where the entire process becomes a continuous operation, in-line dilution layered with multi-column chromatography operations will further reduce buffer volumes. And for this option, multi-column chromatography purification coupled with perfusion bioreactors supports an efficient, validated continuous manufacturing platform.
Multi-column chromatography to support continuous manufacturing allows for the use of smaller columns with reduced bed heights which are easier to load and operate and can be run at high cycle rates or in simulated moving bed configuration. This simultaneous processing allows for the same processing time while using less resin, up to a 50% reduction in resin volume.7 In one business case, moving from a traditional fed-batch chromatography operation to a multi-column rotating chromatography process resulted in a 275% increase in productivity (g/Lresin hr) and resin cost reductions of over $750,000 at 2000L scale.8
Taking a closer look at one of the key design approaches shows the significance of the facility impact. The traditional batch approach for buffer prep/hold in large vessels shown in Figure 7 requires significant space, and utility and operational support.9
In-line dilution of buffers allows for process buffers to be produced “just in time” and at the “point of use”. It is a simple approach for mixing buffers using one (or more) concentrated stock solutions with water added as needed to optimize large volume buffer production and eliminate hold requirements. Implementing an in-line dilution scheme (Figure 8) can move the platform from stainless to single use quite easily and can lead to a significant reduction in (30 – 70 %) buffer vessel size, as well as increased flexibility in meeting future volume requirements.10
The challenges of this approach must also be addressed in the facility design. These include the fact that some required concentrated buffers might be more corrosive resulting in higher safety and material specifications. Temperature and pH changes during the mixing operations must be controlled on a continuous basis with high-level automation control. By design, these systems are more complex system to operate, also leading to a greater level of control automation.
Results
How does all of this translate into manufacturing optimization? There are many examples of data available. The data examples shown below gives some stark contrasts between the traditional fed-batch and continuous operation results.11
Continuous manufacturing also has a number of quality advantages that are possible during the facility design development.
- Shorter residence time at higher titers; reductions from 14 days down to 3 days reduces equipment sizing and space requirements
- Protein/resin interaction will now be measured in hours vs. minutes which results in shorter processing time
- Shorter processing time will lead to less/shorter intermediate hold times
- Real time process control means that there will be faster feedback control response time to reduce process drifting and deviations, improving quality and reducing risk
- Generation of large amounts of on-line data will require advanced PAT-based control platforms that will increase process understanding through increased process control using QbD concepts
- It opens the door for the option for real time release testing from building in quality rather than relying on testing in quality
- Increased reproducibility and on-line control, targeting a state of “in control” rather just maintaining “steady-state” conditions which is an enabler defined by the FDA for an active control strategy.12
What’s Next?
Both industry and the FDA are supporting the paradigm shift to continuous manufacturing.13 The continued movement to integrate both drug substance upstream and downstream operations can be seen by the number of companies moving into this operational space.
The benefits of this shift will be:
- Promising business case improvements in productivity, resulting in lower CAPEX, OPEX requirements
- Facilities that will be smaller with less work-in-progress materials
- Improve product Quality & Safety
- Enabling faster response to market demand changes
References
- Federal Record, Congressional testimony, December 12, 2013; Janet Woodcock, M.D., CDER Center Director
- US FDA, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/UCM478821.pdf
- Wairikoo, V , 2017 Biopharmaceutical Trends: Bioprocess online; 2012
- J. Odum, et. al, “Do’s and Don’ts in Continuous Manufacturing Facility Design” Workshop at 2nd Annual CCP Summit, Boston, 2018
- Study 1: Pollock, J., et al., Biotechnology & Bioengineering, Volume 110, 2013, 206-219 Study 2: Walther, J., et al., J of Biotechnol. Volume 213, 2015, 3-12 Study 3: Godawat, R., et al., J. Biotechnol. Volume 213, 2015, 13–19
- J. Odum, et. al, “Do’s and Don’ts in Continuous Manufacturing Facility Design” Workshop at 2nd Annual CCP Summit, Boston, 2018
- R. Lu, “Multicolumn Chromatography: A First Step Toward Continuous Purification”, ISPE Biomanufacturing Conference, December 2018.
- ibid
- J. Odum, et. al, “Do’s and Don’ts in Continuous Manufacturing Facility Design” Workshop at 2nd Annual CCP Summit, Boston, 2018
- ibid
- ibid
- L. Lee, “Regulatory Initiatives for Supporting Innovation in Pharmaceutical Manufacturing” PDA/FDA Joint Regulatory Conference, September 2015
- FDA Voice posted by Lawrence Yu, http://blogs.fda.gov/fdavoice/index.php/2016/04/continuous-manufacturing-has-a-strong-impact-on-drug-quality