Single-use technologies for biopharmaceutical manufacturing
By Chuck Mina
Long a standard in R&D labs and medical facilities, single-use technologies are appearing in late clinical and even commercial production within biotechnology manufacturing. Their benefits mesh well with the current state of the biotechnology industry. With another major patent cliff occurring seemingly every month, the overall pharmaceutical industry is shifting focus away from the small molecule blockbusters that defined it for decades. The focus is increasingly on biotechnology products, which are more difficult to manufacture and frequently targeted at a smaller population. Rather than hitting the jackpot with a single blockbuster molecule and then investing heavily in the manufacturing capacity for it, companies will require rapid development of one new biotechnology process after another to stay competitive.
Single-use technologies fit well into this business model and are therefore seeing wider use each year. A major advantage is they are pre-sterilized, eliminating the need for installation of complex Sterilization In Place (SIP) and Clean In Place (CIP) systems. They can also drastically reduce equipment delivery times, as long-lead tasks, such as vessel fabrication, can be eliminated. The reduced complexity of equipment translates into shorter design, construction, and qualification schedules. This all adds up to a shorter time between project concept and startup.
Companies and individuals involved in pharmaceutical automation should take note of and prepare for the impact of these trends. Because while the physical systems may be changing form, the expectation of process automation to provide the same benefits expected in traditional manufacturing is not changing. Whether for process development, compliance, or troubleshooting, the established benefits of comprehensive data collection and historization are still present. The same Good Manufacturing Practice (GMP) regulations that push manufacturing to use automation to help ensure compliance still apply to manufacturing using disposable systems.
There are a variety of established and emerging single-use technologies, and automation professionals must have at least cursory knowledge of them to fully appreciate their impact on the industry.
Often the focus of a single-use technology discussion is on the bag systems that replace traditional vessels. Flexible bags can be purchased pre-sterilized and can be custom designed with integral connectors as required by a process.
The most basic use of such bags is to replace stainless steel vessels or glass bottles for storage. Manufacturers use bags ranging from just a few liters to 10,000 liters to store buffers, media, or biological product (though due to sheer logistics, individual bag size is more common in the 2000 L-and-under range).
Beyond storage, single-use bags can be used with mixing systems to prepare solutions. Disposable mixing systems can include agitation, jackets for temperature control, load cells, and a variety of analytical sensors, such as pH or conductivity, to monitor the solution.
Further increasing in complexity are single-use fermentor or bioreactor systems. This is the first example where the blend of disposable and automation becomes essential. The bioreactor process is no different in a steel vessel or a plastic bag, so the same control requirements apply to both. Precise monitoring and control of agitation, temperature, gas flows, such as nitrogen or oxygen, dissolved oxygen level, etc., all may be required for a given process. Such systems will often be sold as a package, including a support structure for the bag, accompanied by a fixed “control unit” containing piping connections, instruments, and controls necessary for the process.
Equally important but sometimes overlooked are single-use aseptic connectors and tubing. These devices provide a means to make sterile connections or disconnections while manufacturing a product. A typical device might be used to connect two separate sets of disposable tubing. But other configurations and products allow for connecting disposable tubing to fixed vessels or steel piping. Such hybrid disposable and steel configurations can allow for sterile additions and transfers between vessels and bags.
As with bags, single-use connectors and tubing are provided pre-sterilized and can be pre-configured into custom assemblies to include combinations of tubing, connectors, and inline filters custom to any process.
Additional applications for single-use technology are emerging, such as single-use filling lines (with all product contact surfaces disposable), single-use tangential flow filtration systems, and single-use chromatography columns. Custom innovative applications, such as hybrid steel and single-use systems, are also emerging.
Benefits, impacts of single-use technologies
Automation professionals could put together a list of pros and cons of the impacts of single use on their discipline, but such an exercise would miss the point. Single-use technologies have benefits specific to the current state of the overall biotechnology industry and therefore will see increasing usage in projects for years to come.
Single-use technologies are typically supplied in sterile packaging and gamma irradiated, allowing manufacturers to effectively outsource the cleaning and sterilization associated with their processes. So all tasks associated with cleaning and sterilization can be either reduced or eliminated, depending on the extent to which disposables are used. This could include purchase of clean steam generators or CIP skids, design and installation of utility piping, programming of automated CIP and SIP cycles, and validation of the cleaning and sterilization processes. This aspect alone drives project leaders to consider single-use technologies.
Delivery time is another major factor driving single-use technologies, as a vessel fabrication could be the single longest lead item in a project. The use of tubing and connectors can also decrease the complexity and total installed length of piping and associated instrumentation, reducing engineering and installation times further.
Use of disposables also tends to increase process flexibility, which is essential for emerging biotechnology processes that could still be under development. When an extra mix or hold step is required, instead of designing and installing a piping manifold and new vessel, a modified tubing assembly may be all that is needed. This flexibility also comes with risk, as it relies more than ever on the expertise of operators.
With these larger factors at work, biotechnology projects that are well suited to single use technologies will migrate to them regardless of the impacts on automation. For some projects, the upfront cost and schedule decrease could be the factor that allows a previously marginal project to advance. But the move to single-use technologies does not negate the need for a well-planned automation strategy.
Impact to process automation
Whether working with an operating company, an original equipment manufacturer (OEM) specializing in disposable systems, an engineering firm, or a software integrator, automation and controls professionals in the pharmaceutical industry will be impacted by the increasing use of single-use technologies in biotechnology manufacturing.
Most apparent is the speed and scope of projects utilizing single-use technologies. Where design and construction of a biological manufacturing train may have taken two years with fixed systems, it may take only one year using disposables. So the deployment of usable software systems must be accelerated. But accompanying this decrease in schedule is also a decrease in scope. CIP and SIP may be reduced or eliminated from a facility. Complex valve manifolds may be completely replaced by manual connections and tubing. Instead, the focus moves to monitoring and controlling the core processes.
The reliance on operators in such processes increases. Operators must effectively build the entire system anew for each batch, and with each manual action comes increased risk of errors. Automation systems, therefore, should focus more on intelligent prompting through complex steps and alerting operators to mistakes where possible. For example, a line blockage may be unlikely in a hard piped system, but an operator can easily forget to open a connector or clamp. Software designers must re-examine the usual failure modes and resolutions they consider.
The rapid pace of projects will also bring together new business partners that may not have worked together in the past. Software designers will find more customers from scientific disciplines who may still be researching and refining a process. While the established best practices for software development dictate clear and detailed process definition, this may not be possible within a rapid disposables project, as the process and equipment may be developed in parallel. Software designers should consider an increased focus on a user-friendly flexible design, providing systems easily customizable by customers who will not be programmers by trade. Phased approaches of software delivery may also be appropriate, first providing a system focused on allowing the user to run the equipment in a variety of manual modes and frequently modifying parameters, and later delivering a more complete solution with step-by-step sequencing.
OEMs focusing on disposable systems may find the normal functionality and documentation provided for a lab are questioned when the system will be used for manufacturing of sellable product. Engineers accustomed to specifying particular hardware and software standards may find OEMs unwilling or unable to cooperate with what they see as typical requests. Both parties will need to focus on the essential requirements and agree on them as early in the design process as possible.
Instrument designers and metrology professionals will need to educate themselves on common practices for single-use technologies. Some probes are truly disposable, which raises the question of how can you calibrate something that can only be used once? Some manufacturers may provide “reference” probes, manufactured to the same specifications as ones used in process, but a company’s calibration policies may need to be revised to accommodate this. Even reusable probes will need to be removed and reinserted into a new bag, and variances are inevitable in the installation from one batch to the next.
Even project planners and estimators may need to consider the impact of single-use technologies. Conceptual estimates for automation costs often rely on metrics such as cost per I/O, expected number of I/O per type of system, or automation cost as a specific percent of total project cost. The change in automation and instrument scope could render these metrics invalid. Planners may need to adjust metrics to be specific to single-use technology projects.
Points to consider
It is unlikely single-use technologies will replace traditional pipe-and-vessel type systems; large volume, well-established processes would often see a net increase in operational costs from the high cost of bags and other disposable items. But for the case of a process that is still under refinement, to be done at moderate volumes, single-use technologies are a great fit. In these cases, the removal of the upfront barriers of cost and schedule associated with fixed systems could be the make or break factor in getting a small volume of product to market rapidly, while still operating under GMP regulations. These cases will become more frequent as more specialized biotechnology products are developed. So automation professionals would be wise to understand these drivers and adapt their practices to accommodate this trend.
When presented with a project that intends to make use of single use technologies, consider the following as an automation strategy is developed:
- What expectations/requirements will you put on the OEM vendors you will likely rely on to deliver some of the core systems? How will you integrate these systems into data historians, manufacturing execution systems, batch systems, etc.?
- How will you manage disposable instrumentation? Do you have calibration and maintenance policies and procedures to accommodate these?
- Have the instruments and single-use items overall been assessed against their intended usage conditions (e.g., temperature, pressure, chemical resistivity)?
- Where will controls equipment, such as electrical cabinets and workstations, be located relative to the process? Has the complete layout of disposables been modeled to ensure operator flows are known, and therefore ideal locations for terminals?
By determining a well-thought-out automation strategy early in the design process, it is possible to bring the same benefits to single-use technology projects now expected for traditional fixed systems.
ABOUT THE AUTHOR
Chuck Mina (Chuck.Mina@sanofipasteur.com) is deputy director, Automation Engineering, with Sanofi Pasteur vaccines in Swiftwater, Pa. He has a chemical engineering degree from the University of Virginia and has worked on biotechnology automation projects for Amgen and Eli Lilly in addition to Sanofi.