Today there is a continued accelerating evolution in CMO and traditional biomanufacturing to Single-Use Systems (SUS) and disposable technologies. While this term, ‘disposable’ has been used since the inception of the technology in the 80’s, the polymeric device manufacturers found the ‘single-use’ moniker a more ‘green’ label for their products. This change from disposable plastic product to single-use is not limited to the biopharma industry as we have witnessed in many other industries.
The expansion of SUS equipment usage from the 1990’s simple bag/tubing and filter capsule combinations to today’s upstream and downstream applications is indicative of the wide industry acceptance of the SU technologies. The initial single-layer 1-5 liter polymeric IV-type bag used for media and buffer storage has evolved to advanced designs for large volume (2000 liter+) complex bioreactor systems using multi-layer 3D bag technology coupled with stirred tank mixing equipment. High area 30” filter cartridge-capsules, durable single-use pH and DO sensors, larger volume 2000 -5000 liter polymeric container/chambers/bags, cleaner and more versatile polymeric tubing materials are innovations driven by the demands of biopharm process development and manufacturers for better and larger scale SU devices and systems. Although the absolute up-scaling of these SUS has approached engineering maximums, the development of high density and higher yielding (10 fold + increases) cell culturing and fermentation processes results in decreasing the overall batch/lot size volumes. The need for very large 15,000 – 30,000 liter bioreactor/fermentors for biopharmaceutical production is generally being replaced by smaller SU bioreactors (250 -2000 liter.) The subsequent downstream separation, clarification and purification steps, e.g., depth filtration/TFF/ membrane and gel chromatography/viral clearance and final sterilizing filtration, also lend themselves to down scaling. The overall result is a much smaller process footprint with general processing cost reductions that regulatory agencies encourage for lowering the cost of medications. The major drivers for these cost and efficiency factors are important for process development and manufacturing engineers and scientists to understand and consider when designing new systems or upgrading legacy production lines.
Major Market Drivers to Implement SUS
There are numerous journal articles, end-user surveys, conferences and meetings that address the economics and advantages of SUS over traditional hardware that is stainless steel and reusable components and equipment. In summary the following overview of the major market drivers will assist in directing focus on those internal operations that will have significant impact on costs and ultimately the profitability of the drug manufacturing process;
• Time to Market
• Costs of Goods Sold
• Production Efficiencies
• Process Control - Risk Assessment
• Qualification & Validation
• Meets/Exceeds Regulatory Compliance & Industry Specifications.
Time to Market (Process Development & Scale-up) “He who is first wins!”
Reducing the timelines to a marketable drug product generally means millions of dollars of potential sales. Therefore knowing or having a solid estimate on what the development to production scale-up timelines and costs are can provide early feasibility projections. Utilizing the significantly shorter lead times in qualification and commissioning processes and systems through the use of prefabricated, ready-to-use polymeric devices and systems can provide the flexibility in process and device design not usually possible with stainless steel (SS) hardware. Additionally, the reduced change control documentation costs and timelines are achievable by using prequalified and acceptable polymeric materials with known risk evaluations. This is one of the major drivers for CMOs’ readily accepting SU technologies.
Cost of Goods Sold – Process Production Costs
The direct labor costs for cleaning (CIP) and re-sterilizing (SIP) SS hardware as well as the utility cost for water (PW/WFI), steam production for autoclaving/SIP and cleaning chemicals will be significantly reduced or completely eliminated should the manufacturing processes utilize SUS technologies. Overhead costs and other production costs can similarly be reduced or eliminated, for example:
• Capital investment in SS hardware tanks and piping are minimized as SUS may require reusable/collapsible containment pallets, tubing replaces SS piping, providing for lower initial capital investments.
• Floor space – the footprint of SUS greatly reduces the need for permanent hardware installations and offers flexibility to move equipment within the plant.
• Capacity for WFI and steam may be limited and create shortages and bottlenecks for these key production utilities. Through the reduction or elimination of CIP/SIP production capacity has increased potential.
• Cleaning validation and qualification requirements are placed upon the SUS product suppliers thereby reducing costs and time burdens to meet regulatory compliance.
• Maintenance and downtime for hardware is significantly reduced. Less upkeep and maintenance costs lower COGS.
• Chemical cleaner waste stream costs will be reduced due to the decreased CIP requirements of SUS products. Disposal costs can be multiple times more costly than the chemicals themselves, and the PF water and WFI consumption can be reduced, another significant cost of CIP cleanup.
Increased Production Efficiency
Through the reduction or elimination of the CIP/SIP manufacturing step many processors can achieve better cycle times and reduce the take-down and set-up time for the next production run. Many of these processes can reduce the handling operations, however it must be noted SUS often require many more hands-on assembly connections than hard plumbed systems. Generally SUS do offer faster make-up connections provided one uses prefabricated assemblies and systems, e.g, SU bioreactors factory ship with connections and tubing set in place as the entire system is shipped sterilized.
As discussed above the usually reduced floor space results from the smaller footprint of SUS. The advantage would be more SUS producing more product in the same footprint space. As the bags/chambers arrive collapsed the storage/inventory footprint is a fraction of similar volume sized SS tanks. As the production volume increases through market demand, the optimization processes of production scale-up, change control documentation, regulatory filings and qualification is greatly reduced should the materials of construction and SOP remain unchanged. By maintaining the same materials and conditions, a simple tank or bioreactor upgrade may be considered a minor or moderate change, thusly reducing the regulatory filing necessitated by the scale-up.
Process Control – Risk Assessment
Batch cross contamination through inadequate CIP procedures or failure to implement proper SOP can be reduced or eliminated by SUS. Since each system is clean, sterile and assembled prior to use then discarded after, there is no risk of cross contamination. Similarly, microbial contamination in either the upstream mixing or preparation of media and buffer along with the downstream product storage/aseptic filling can be reduced. The number and frequency of bacterial contaminated lots has shown to be reduced using SUS, (Media Fill Contamination PDA 2001 Aseptic Process Survey.)
Extractables and leachables from polymeric devices/systems have been extensively qualified by the device manufacturers and are found to meet or exceed regulatory requirements and industry specifications. The need for leachables assessment is a regulatory requirement that the drug/therapeutic manufacturers must be in compliance, (see CFR 211.65/CFR 211.94/ICH Q7A.) Through the reduction or elimination of cleaning solutions and chemicals the risk of residues or excessive exposure to operators is achieved. The concerns for bio-hazardous materials containment and disposal may be lessened with the use of SUS, which act as containment vessels.
Qualification and Validation
Typically the vendor or SU device manufacturer is responsible for providing the proper documentation to demonstrate their products meet or exceed regulatory requirements and industry standards. The number and breadth of these qualification tests and standards is beyond the scope of this article, however herein are several major testing categories you should expect the device supplier to provide as validation/qualification guides and data sheets. See Figure 1.
• Physical Tests
• Biological Tests
• Chemical Compatibility
• Extractables Tests
• Sterility Assurance
• USP & cGMP Requirements and Specifications
Regulatory Requirements and Industry Standards:
There are multiple guidance documents world-wide from the FDA, EMEA, ICH, ISO, etc. With so many differing regulations and guidance documents for extractables and leachables as well as the various device manufacturers’ quality testing, many are vague and contradictory. The partial listing here is a handy reference and is focused on the primary extractables and leachable concerns of global regulatory bodies. There are several other major concerns expressed by FDA, such as the burst strength and microbial and vapor integrity of the bag layers or skins. The bag manufacturers have developed a variety of physical tests along with microbial test to qualify their products. These ‘Validation Guides’ are available from most suppliers.
Compendia tests: USP <87, 88, 381, 661, 1031>
• The biological tests <87, 88> Bioreactivity tests, acceptable predictors of toxicological activity but do not identify extractables or leachables.
• USP <381> Elastomeric Closures for Injectables: physicochemical tests are typically done in water, drug product or solvent vehicle. Test is gravimetric NVRs and is nonspecific.
• USP <661> Container Performance Testing, leaching polymers with PW, analyze for NVRs, residue on ignition, heavy metals. Do not identify specific leachables.
• USP <1031> Biocompatibility Materials in Drug Containers, Medical devices and implants: extracted polymers do not alter stability of product or exhibit toxicity. (see <87, 88>)
FDA Title 21 Code of Federal Regulations;
• CFR 211.65 Equipment Construction
• CFR 211.94 Drug Product Containers and Closures
• ICH Q7A Guidance for Industry:
Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (8-2001)
The continued accelerated growth and penetration of single-use systems and technology in the biopharmaceutical development and manufacturing process will change the fundamental methods and means of producing 21st century drugs and therapeutics. We know global regulatory authorities are keenly interested in promoting these new SU technologies to achieve increased patient safety, lowering risks and drug costs. The industry looks to increasing productivity, time to market, and ultimately greater profitability and shareholder return. All are part of the major market drivers that promote further innovation and increasing acceptance in the biopharmaceutical development and manufacturing industry.
About the author
Mr. Trotter, President and principal consultant of Trotter Biotech Solutions, provides consulting services and training programs in the pharmaceutical, biologics, & bioprocessing industries.
He completed his post-graduate studies at Long Island University, C.W. Post College, earning his MS in Medical Microbiology and continuing on for his MBA in Finance. He has specialized training and work experiences in filter membrane technologies, including sterilizing, prefiltration, chromatography as well as single-use disposables technologies. Upstream fermentation to downstream applications, including separations, clarification and purifications processes technologies, are subject matter expertise he brings to the training, technology transfer and consulting services.
Mr. Trotter, with over twenty-five years experience in the pharmaceutical and life science industries, has a broad range of work experience, from pharmacologic chemistry research project leader to marketing management in the laboratory & process equipment industries. This extensive background in the biopharmaceutical sciences is coupled with an in-depth regulatory knowledge that supports his expertise in these areas of process validation and qualification.
Mr. Trotter has published numerous technical articles, book chapters and has contributed expert editorial comment on these subjects. He is a member of PDA (Parenteral Drug Association), ASM (American Society of Microbiology) Society for Biological Engineering (SBE-AIChE), International Society for Pharmaceutical Engineering, (ISPE.), and the American Society of Quality, (ASQ.) Mr. Trotter actively participates on various technical committees and presents papers at society meetings and for interest groups.