Biopharm manufacturers can see improvements in contamination levels, manufacturing costs, and production times
By Gary MacEachern, NP Medical
It’s no secret that biopharmaceutical companies are moving rapidly toward disposable products for the production of protein therapeutics and vaccines. In university and pharm/biopharm laboratories, disposables have been in use for more than 20 years because of their small scale, versatility, and lack of contamination issues. As the commercial demand for designer drugs has increased, drug manufacturers have increased their use of disposables in parallel. And for good reason: Biopharmaceutical companies are adopting a “fail early, fail often” business model, and therefore need faster, cheaper discovery processes and clinical trials. This compels researchers to not only drive out as much cost as possible early on but also to speed up the process so less time is needed in cleaning and validating expensive bioreactors before bringing them back on-line for the next project. Today, the use of disposables has become commonplace in 97% of biopharmaceutical companies.
When considering the design and construction of manufacturing facilities, biopharmaceutical manufacturers-and especially start-ups-need to consider several criteria.
Safety. Cross-contamination is a major issue. There is not only the possibility of chemical contamination from the water-based cleaning solutions in reusable systems but also that of biological/microbial contamination from fluid pathways and liquid transfers. Yeast, bacteria, mold, and viruses are all either used in producing drugs or can be considered biological contaminants. Disposable, sterile, pre-filled media bags and pre-sterilized fluid path components such as tubing, filters, connectors, and valves all offer significant safety advantages, save time and money, and increase efficiency.
Versatility. Most biopharm manufacturers can’t afford to be “one-trick ponies.” With fewer blockbuster drugs on the horizon, smaller markets, and target-specific treatments, product diversification requires a flexible research and manufacturing infrastructure that enables them to quickly change product development gears.
Cost. When looking at the impact of disposables on cost, the savings with regards to sterilization alone are significant as disposable systems eliminate clean-in-place (CIP) and steam-in-place (SIP) sterilizing between batches and changeovers. Validation issues are also eliminated because all components are supplied sterile and certified. Cross-contamination is minimized, if not eliminated, by the use of unidirectional disposable valves and single-use filters.
Changeover procedures can often be reduced to essentially “stop and swap,” a significant reduction in time that enables disposable bioreactors to be up and running in hours-sometimes even minutes-compared to the weeks necessary to make stainless-steel reactors ready after a changeover. Validated cleaning, replacement of product-contact fluid path components, and sterility retesting that follows is time-consuming and expensive. Disposable component manufacturers now offer a wide range of unidirectional valves to help control flow and prevent backflow during fluid transfer and sampling.
Small vs. large scale processes
Currently, disposable bioreactors are best suited for small-scale R&D and manufacturing, in the range of several hundred liters. While large-scale disposable manufacturing is not yet feasible (production is still limited to about 2,000 L), scalable smaller-volume manufacturing is. In fact, it may be hard to push the size of disposable systems into the realm of large-scale manufacturing due to the inherent structural weaknesses associated with large plastic bags. However, with growing demand, new technologies for better yields and improved drug delivery, increased cost pressures, and a trend toward “boutique” therapeutics and personalized treatments, manufacturers have been driven to produce smaller batches while improving yields for higher volumetric productivity.
Biopharm manufacturers must improve production flexibility to meet periodic capacity shortages and produce smaller, higher yield batches, while dealing with reduced R&D budgets and health care reform constraints. This points to disposable bioreactors as an ideal solution. In some cases where manufacturing volumes are in the hundreds to low thousands of liters, manufacturers can simply run several, say, 200 L bioreactors in parallel, giving them the advantage of both the volume they need and the flexible scalability to increase or decrease production based on the products being run and the market needs at the time of manufacture.
What about retrofitting stainless-steel bioreactors?
With all the discussion about disposable systems, you’d think the death knell had been sounded for all those big stainless-steel systems, but to paraphrase Mark Twain, rumors of stainless reactors’ demise “have been greatly exaggerated.”
Rather, large, established manufacturers are beginning to use disposables to provide added flexibility and efficiencies to their existing stainless-steel facilities. By incorporating disposable components, particularly in the fluid path systems, they are able to reduce cleaning costs as well as turnaround time.
Disposables are also being used to cut lead time when performing product changeovers. With fixed stainless-steel systems, a changeover between drug runs usually requires piping redesigns and modifications that can take six to twelve months to complete. By using disposable fluid path systems to replace SIP stainless-steel connections, bioreactor lines can be reconfigured quickly, often cutting the project completion time by several months. Plastic tubing can be quickly and easily custom cut to fit a system and the process of cutting with a hot blade anneals the plastic to create a sterile seal. Retrofitting stainless-steel systems with pre-sterilized disposable pathways enables secure connections to be made in Class B, C, or even D environments while maintaining sterility-that means saving time and money even with expensive, reusable stainless steel systems by being able to operate them in less-than-optimal sterile environments.
Operating expenses
When discussing operating expenses, the conversation quickly turns to comparing the two types of systems in terms of the cost of consumables. Here the comparison between the two can get a bit murky because comparing consumables can be like comparing apples to oranges.
Stainless-steel systems actually use more consumables than most people realize-the cleaning chemicals and thousands of gallons of purified water needed for the cleaning process, along with their disposal expense, as well as utility costs associated with steaming and cleaning. In addition, there’s the cost of all the fluid contact components between drug runs-tubing, gaskets, valves, O-rings, filters, and connectors that are too hard to clean and revalidate. It’s less expensive to simply replace them. In fact, despite the conventional wisdom that a reusable stainless-steel bioreactor system has less environmental impact than a system that uses a lot of disposable plastics, studies show that the impact of increased plastic consumption associated with disposable systems is typically offset by the amount of reusable system cleaning water and chemicals and the utility service consumption required to process them.
 |
Approximately one-third of the labor cost for reusable systems is associated with cleaning and sterilization. By using disposables, critical, skilled-employee tasks such as testing and documenting validation associated with sterilization are eliminated, reducing the cost of labor. In addition, using disposable bioreactors, without all the CIP/SIP piping and components, decreases the complexity of the overall system, which may reduce the labor time involved in system construction and/or set-up.
 |
Time can also be considered a consumable and the use of disposables not only reduces the overall maintenance and operating time, it also enables biopharmas to simplify standard operating procedures (SOPs) and use less skilled labor for certain tasks. Pre-sterilized components, unidirectional disposable valves, and diaphragm pumps with in-line filters, in conjunction with simplified SOPs, enable workers to perform the work and avoid mistakes and contamination while transferring fluids and taking samples. Increased regulatory compliance requirements (and, in some cases, internal company policies) have increased the need and frequency of sampling. A variety of available disposable valves, such as pressure activated, Luer, and in-line check valves, would help facilitate a wide range of sampling-from single samples to multiple, extended-duration process sampling. The bottom line is an increase in the speed and efficiency of sample-taking and a reduction in labor costs and risk.
Making the case for disposables
While a case can be made that the cost-of-operation difference between disposable and reusable systems is not as great as often stated-upfront construction expense, consumables, and high cleaning and sterilization costs can offset some of the expense of disposable systems-the fact remains that disposables still have a higher cost-per-batch. Currently, a complete, small-batch disposable bioreactor costs about $200 to $300 per unit, including bags, tubing, connectors, valves, and mixing system. However, if time-to-market is crucial for successful production introduction, disposable systems are the clear winner when it comes to batch-to-batch speed and versatility. As we’ve seen, reusable systems, with lengthy sterilization, testing, and validation processes, clearly fall behind in the speed department. This can be mitigated to some degree by incorporating disposable fluid pathway components such as tubing, connectors, filters, and valves into the stainless-steel system. Only in this way can biopharmas reduce maintenance and operation time and speed up batch changeovers.
 |
But even assuming that it costs more to run disposable bioreactors vs. stainless steel, the economic stakes in drug development are so high, the cost difference becomes negligible. Put another way, if the potential is there for making dollars on an R&D investment that (relatively speaking) costs pennies, what’s a few cents more in the cost of operation between a stainless-steel system and a disposable one? Improved speed, efficiency, flexibility, and time-to-market more than outweigh a few pennies.
Gary MacEachern is director of marketing/new product development at NP Medical (www.npmedical.com). He can be reached at [email protected].