There is a significant movement within the biotech industry to evaluate and implement single-use (SU) manufacturing systems in order to improve manufacturing efficiency, flexibility, and reduce costs.i The focus of many industry conferences and technical meetings centers on expanding the industry’s body of knowledge around SU system design and applications.ii
Many organizations that are investigating the implementation of SU systems have current manufacturing operations that are based on the traditional stainless steel (SS) manufacturing components found in both upstream and downstream operations. The SS model has been the foundation of biomanufacturing for the first three decades of the industry and will continue to play a key role in the future expansion of global manufacturing capacities and capabilities. Being “rooted” in SS manufacturing platforms does not mean that the implementation of SU systems should be viewed as a risk or inefficient cost alternative. However, to implement SU systems within an existing SS manufacturing operation does come with some unique attributes and challenges.
This article will explore some of the aspects of SU implementation and identify areas of focus to ensure that there is synergy between the different manufacturing platforms and operational philosophies.
There are many different business and technology drivers which influence companies in the decision to implement SU systems. In a recent Industry Forum on Next Generation Manufacturingiii, some of these key drivers identified by an industry panel included:
• Risk reduction/mitigation for multi-product manufacturing
• Speed to market
• Capital cost reduction
• Operational cost reduction
• Improved equipment reliability
• Flexibility improvement
• Expandability/scalability improvement
For many companies, the primary drivers are related to cost reductions and increasing the flexibility aspect of key manufacturing processes. To this end, how to adapt SU systems into a SS-based facility will be driven by some different and often conflicting parameters.
Reduction of Capital and Operating Costs
Many companies move into SU systems based on the reduced cost models that have been presented in a variety of articles and industry forum presentations.iv These reductions may stem from reduced space requirements within manufacturing facilities, the reduction or elimination of SS-based equipment and systems such as CIP/SIP, or the reduction in required classified manufacturing space based on implemented closed system design associated with SU components.
The opportunity for these reduced costs can best be described by reviewing the manufacture of components. In a SS-based manufacturing process, there are often a large number of fixed vessels, often of varying volumes, that are required for the preparation, hold, and transfer of components within classified spaces. Developing SU capabilities for these unit operations removes the need for many fixed assets but leaves the question as to whether to leave them in place or physically remove them in order to gain valuable manufacturing space.
The removal of fixed components has a high associated cost and can also have significant schedule impacts due to the time required to complete demolition and removal efforts, repairs, and recertification of classified spaces. But leaving fixed components in-place also has issues centered on accessibility, logistics, and maintenance. So what to do?
The Hybrid Project
The result of tech transfer and process and operational evaluations often leads to the use of a “hybrid” approach, where both SS and SU components and systems are implemented to produce a resulting project definition that provides levels of value associated with cost, flexibility, and operational efficiency. Two case scenarios clearly provide examples of this approach.
Scenario I - To increase both capacity and product opportunities in an existing cell culture-based SS facility, Company A completes a tech transfer study and determines the need for increased capacity in the preparation and hold/transfer of media and buffer components. With limited ability to expand the current SS-based capabilities, SU systems are implemented to support the expanded media and buffer operations.
The execution of a process development effort results in the design of new SU-based media and buffer systems that are installed within the existing facility to feed the current 50L, 250L, and 2000L SS bioreactor systems and the existing fixed chromatography columns. The resulting manufacturing system implements both technologies and allows for the necessary development and tech transfer activities without impacting current operations in the SS-based media and buffer areas.
Scenario II - A CMO has a new client opportunity for bulk drug substance manufacturing. The scale of the new process is within a range that is not compatible with their current SS-based manufacturing systems. Cost and schedule constraints result in the investigation of new platforms in SU manufacturing for both upstream and downstream operations.
The current facility has adequate systems for the manufacture of media and buffer components in existing SS vessel configurations and transfer systems. The goal then is to provide new SU upstream and downstream primary equipment that will be supported by existing SS-based systems for media and buffer preparation and hold/transfer.
The first critical step in developing a plan for SU implementation is defining the process assumptions and the operational philosophy of the process. Defining unit operations should focus on the development of detailed Process Flow Diagrams (PFDs) that clearly represent the equipment/components necessary to support the manufacturing process (Figure 1). Having this pictorial representation of the process will be beneficial in the review process, allowing for the confirmation of process assumptions.
Figure 1: Initial purification PFD example
Process Assumptions - Developing a SU implementation approach will require that a set of process assumptions be confirmed and analyzed against potential manufacturing risks that could impact product quality and/or manufacturing viability. These assumptions will likely not be complete but must be representative of the available collective process knowledge at the time of development. They will include:
• Scale of operations
• Staging approach
• Vendor data
• Cycle times
• Tubing requirements
The development of the written process description should be the first step. The “details” of each unit operation step must be clearly recorded and verified for all unit operations, upstream and downstream. These narrative descriptions will be important as the logistics of executing SU operations are reviewed with respect to the location of equipment and the space that will be allocated for personnel and components. These descriptions (Table 1) should also identify where support equipment is necessary so that layouts of the adapted space can be completed.
The assumptions should also capture all equipment and components necessary to support the manufacturing process. This includes identification of all utilities required for manufacturing and any special requirements that may arise during process development (Table 2)
Equipment Analysis - It is important to complete a thorough cost analysis of the equipment/components for each unit operations step. The analysis does not have to be complex; simple spreadsheets (Table 3) can provide significant information for evaluation.
The implementation of SU platforms into existing facilities comes with some elements of risk that need to be clearly identified and addressed in a timely manner. These risks may not be obvious in terms of process or facility attributes. The risks may be technical, operational, and/or economic in nature. And the risks may not manifest themselves until a thorough review of the step-by-step unit operation activities is executed.
Some key areas of risk focus should be:
• Equipment Selection: Using a QbD-based evaluation process of the equipment technology is important. The identification of the Critical Process Parameters (CPPs) early during process development will be critical since in many instances they may be different between SS and SU-based systems. An example would be in the mixing properties for SU components compared to the properties for a “similar” SS vessel.v
• Processing Time Analysis: Development of Gantt charts may indicate similar overall process times, but there may be variances in individual unit operations that will require additional analysis. The implementation of new technologies may require more manual participation in set-ups and transfers but reduce overall processing times. The logistics and support infrastructure must be analyzed.
• Economic Evaluation: While a key driver for SU implementation may be overall cost reduction, analysis of cost elements may uncover economic risks. The economic evaluation should include:
• Fixed Charges – financial, taxes, maintenance, administrative
• Fixed Capital – parts/components, engineering
• Investment Costs – production
• Variable Charges – media, reagents, utilities
• Compliance: SU systems will require new protocols, SOPs, and training.
Risk analysis should also investigate specific facility attributes that would be potential product-impact issues. These attributes would include:
• Segregation/viral clearance
• Process closure
• Process transfers
For existing manufacturing operations there is a high likelihood that there will be a mixture of both fixed and “portable” equipment that will be located in spaces that may be designated for potential SU implementation. In the situation where an area of an existing manufacturing space will go through a demolition process to make space available for new SU equipment, the focus on the facility drivers will center on:
• Utility/Service Distribution
• Layout & Space Allocations
• Flows & Segregation
This represents the least risk scenario to SU implementation, yet also comes with a potentially high cost and schedule impact.
Where fixed equipment is planned to remain as SU elements are added, the geographic layout of the process within the space and the attributes of the facility become a much more complex puzzle to work out.
Layout - One of the key advantages of SU systems is the flexibility afforded due to their ability to be moved in and out of areas. This flexibility requires a certain measure of “process architecture” implementation as the logistics of equipment, materials, and personnel movement are choreographed in order to determine the optimal layout.
Figure 2 provides an example of defining general footprints for components as the first step in defining layout feasibility. The review of overall footprint requirements will allow for confirmation of logistics movement, equipment arrangement and accessibility, and process adjacencies. But it should not be the only layout review.
Figure 2: Defining a general footprint for components is the first step to determine logistics
movement, equipment arrangement and accessibility, and process adjacencies.
Figure 3 provides another critical step in the design process, the identification of unit operations (equipment, components) to confirm locations of hook-ups, access to “bench” items, instrument access, and tube-set details. The design of tube sets, either by internal resources or third party vendors, should detail all necessary connections and fittings in order to assure a complete, operational design basis.
Figure 3: Courtesy of Thermo Scientific
Utility Services - One of the attractions for SU systems is the lack of need for complex, fixed process support systems such as CIP and SIP. This may also include the elimination of fixed drops for WFI or product/component transfer lines depending on process requirements. This results in a focus on the availability of electrical power and utility services such as gases. Accessibility to the necessary services then becomes an exercise in layout and approach.
Staging and Storage - The staging and storage of SU components, particularly bags and tube-sets, must be well planned. Bags must go through a through visual inspection as one part of the overall quality control process. For larger scale operations, this will require ample space for bags to be folded open and accessible. This space needs to be open, level and easily cleanable, and free of obstructions.
Component storage must take into consideration for both in-process activities and waste removal. As the logistics of the process are evaluated and defined, where portable vessels and palletainers are staged has to be included in the overall layout evaluation. The bag removal and disposal process will require specific requirements in terms of space and flows, segregation (for potential decontamination), and removal from the facility.
The biopharmaceutical industry’s movement into implementing single-use manufacturing systems provides companies with a number of options in terms of new vs. adapted facilities. Many companies are exploring how to adapt existing stainless steel based manufacturing platforms to include single-use components, creating a win-win scenario that meets corporate goals for cost reduction, flexibility, ands operational improvements. This path will continue to be one that the industry will implement for many years to come.
iLanger, Eric and Joel Ranck “ The ROI Case: Economic Justification for Disposables in Biopharmaceutical Manufacturing” Bioprocess International, October, 2005
ii BioPlan Associates, 9th Annual Biomanufacturing Industry Report, 2011
iii Next Generation Facility Forum, NC State University Bioprocess Training and Education Center series, January 31, 2012
iv LoMonaco, Jennifer and Todd Rumsey, “The Economics of Single Use Systems” BioProcess International, October, 2006
v Krishnan, R, and Hao Chen, “A Comprehensive Strategy to Evaluate Single-use Bioreactors for Pilot-scale Cell Culture Production” American Pharmaceutical Review, vol. 15 (3), April 2012