Therapeutic products enter our daily lives in many and differing channels. Beginning with the nutraceuticals we take to supplement our diets and the pain medications we take for common ailments, to the cardiac and cancer treatments for serious life threatening illnesses, these products provide health benefits in our everyday lives. The global drug development pipeline attributed to research organizations in the United States increased to 82% in the past decade. In the U.S. about $68 billion per year is spent on biomedical research, while the biotherapeutics world wide market was valued at over $100 billion in a recent survey and is projected to grow at 8.2% to reach $160 billion by this year.1 Biopharmaceuticals constitutes a rapidly growing industry with a focus on cell culturing of vaccines and antibodies (mAbs) to treat a variety of aliments and is increasing its scope and breadth of such products.
The use of disposables in biopharmaceutical production facilities started in the late 1990’s via filtration devices connected to polymeric bags and has evolved to include innovative Single-Use Systems (SUS) products from upstream bioreactors/clarification filtration to downstream separation and purification applications, TFF, membrane chromatography, and virus removal. These on-going application developments provide a broad scope of SUS technologies that permitted biopharma to integrate various unit operations into a fully disposable automatable single-use system. These products are designated as ‘Plug-n-Play’ or Ready-to-Use.
PROCESS PRODUCTION COSTS/COST OF GOODS SOLD (COGS):
The huge capital and time resources needed to produce a new biopharma drug places high risks of loss in the earlier phase 1 & 2 clinical trials. To bring a biopharma production plant on-line, from brick and mortar through qualification and validation, usually requires years of investment and costs between $150M to over $1.0B. This investment for large scale manufacturing is generally for a stainless steel, aseptic processing hardware facility dedicated many times to just one therapeutic product. This risk and other factors, e.g, labor and change control, provide the resultant consequence of higher COGS.
SUS significantly influence the production process and engineering from the bench-top to pilot scale to full scale production. The plethora of articles and papers on this subject detail the reduced start-up investments, lower production costs, reduced utility and labor costs, and lower chemical and disposal costs. These reductions coupled with shorter qualification and validation lead times of SUS than comparable stainless steel hardware systems, shows the advantages of faster ‘Time-to-Market’, lower ‘Risk Assessment’ and increased ‘Production Efficiencies’ that prove out for SUS for cost controls and resultant lower COGS2
Examples include; direct labor costs for cleaning (CIP) and re-sterilizing (SIP) SS hardware as well as the utility costs for water (PW/WFI), steam production for autoclaving/SIP and cleaning chemicals will be significantly reduced or completely eliminated with manufacturing processes that 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 – footprint of SUS greatly reduces the need for permanent hardware installations and offers flexibility to move equipment within the manufacturing facility.
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 the responsibility of the SUS product suppliers thereby reducing costs and time burdens on the end-users to meet regulatory compliance.
Maintenance and downtime for hardware is significantly reduced. Less upkeep and maintenance costs lowers COGS.
Reduction or elimination of cleaning solutions and chemicals reduces 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 can act as containment vessels.
Chemical cleaners waste stream costs will be reduced with less CIP requirements of SUS products. Disposal costs can be multiple times more costly than the chemicals themselves. And the PW and WFI consumption can be reduced, another significant cost of CIP cleanup operations.2
PRODUCTION ADAPTABILITY & DESIGN FLEXIBILITY
Early biopharma manufacturing focused on ‘speed to market’ and left figuring out production efficiencies to another time. Now is that time. As biosimiliars enter the market and new governmental pressures mount for increased production, e.g., vaccines/bioterrorism threats, and lowering drug costs, the need for production adaptability and flexibility can be met with SUS, while meeting or exceeding the cGMP requirements (§211.65 Equipment construction.) that such equipment …’shall not alter the safety, identity, strength, quality, or purity of the drug product…’3
Single-Use Systems’ flexibility permits faster implementation to adapt to process changes directed by Process Development from pilot plant through to full-scale production. This flexibility permits Contract Manufacturing Organizations (CMOs) to provide their customers the assurance of high quality, low cross-contamination risk in product facilities that might handle multiple products from differing sources. This adaptability provides the elasticity to configure SUS to meet the often unique application requirements, such as downstream processes involving TFF, adsorptive aggregate removal, viral filtration, and chromatography stages, in essence the ‘Plug-n-Play’ concept.
AUTOMATION, FLEXIBILITY AND COST EFFECTIVENESS
The ‘Plug-n-Play’ unit operations lend themselves easily into automation and digital control for both upstream and downstream applications. As is evidenced by the use of Supervisory Control and Data Acquisition (SCADA) in running Single-Use Bioreactors (SUB), e.g., O2, CO2, DO, pH automated control through disposable sensors and feedback loops. The principle is the same whether monitoring and controlling small scale, <50 liter or large scale > 250 to 2000 liter SUBs. The interfacing and control loops are one and the same. Similarly, downstream applications can be adapted to these SCADA systems with predicable costing models for scale-up; e.g., Tangential Flow Filtration, membrane chromatography, virus removal, and the attendant single-use measuring sensors. These engineering scaling schemes, design concepts and automation of these applications may be individual unit operations comprised of hardware holders and skids with SUS disposable components or part of a complete process operation from upstream bioreactor with feeds to the various downstream process equipment and disposables. In essence an automated ‘Plug-n-Play’ approach that increase flexibility, adaptability and efficiencies while reducing costs.
The integration of SUS in biopharma production processes utilizing basic unit operation designs with reusable stand-alone skids that may be coupled and combined as process development engineers and optimizes the manufacturing process provide the opportunity to implement the ‘Plug-n-Play automated flexibility concepts.
1.Pharmaceutical Research and Manufacturers of America
Pharmaceutical Industry Profile 2011 (Washington, DC: PhRMA, April 2011).
2. ‘Single-Use and Disposable Systems and Devices in Biopharm Industry’ ,
A. Mark Trotter, Pharmaceutical Processing, January 2012.
3. CFR—Code of Federal Regulations Title 21, Part 211, “Current Good Manufacturing Practices for Finished Pharmaceuticals,” n