March 15, 2007 (Vol. 27, No. 6)
With Smart Design and Disposables Technology, CMOs Tout Options and Advantages of Flexibility
Although multiproduct manufacturing facilities have been in use for years, they are relatively rare for biologics processing. As they increase, the need for speed, flexibility, and efficiency is putting them at the forefront of flexible manufacturing.
Speaking at IBC’s “Flexible Operations and Capacity Planning” meeting in Orlando, Avecia (www.avecia.com) outlined its “empty bedroom” approach, which relies heavily on disposables and skid mounts for maximum flexibility.
The company said its two-stream ABC 5000 validation and launch facility scales from 150-L to 3,500-L quantities and accommodates all common microbial expression systems and a full range of downstream processing technologies.
It is designed for phased expansion, according to Bruce Williams, commercial engineering manager. The first expansion occurred when the 2001 terrorist attacks increased the need for Avecia’s plague and anthrax vaccines. “That affected the volume of the fixed tanks in the purification suite, so we ended up using disposables more extensively,”actually performing mixing and cooling in bags.
The approach used by Cobra Biomanufacturing (www.cobrabio.com) could be called a partially furnished bedroom. It employs large, fixed pieces for things that can’t be replaced easily, reserving disposables for tanks and chromatography components that are difficult to clean, according to Paul Stockbridge, Ph.D., corporate quality assurance director.
“Facility layout is a key factor in the ability of multiple products to be produced while ensuring there is no cross contamination,” according to Robert O’Hagan, director of quality operations, Abbott Bioresearch (www.abbott.com). The mechanical considerations are related to HVAC design, closed systems, and automatic cleaning systems, but people and processes also have an effect. Each factor varies, depending upon whether multiproduct suites are designed for a specific product or type of product, or for a series of campaigns.
New facilities can benefit from history and the build-in flexibility that helps them adjust to process changes and advancements years later. Bioreactors, O’Hagan said, are the capacity-limiting factor, yet advances in cell culture productivity make it feasible to triple production within the next decade.
Construction for Abbott’s Bioresearch Center began in 1990 with flexibility in mind. A cell culture and purification suite was designed first, adding other flexible suites as new products advanced. This approach had two benefits. “Working closely with the FDA regarding the facility’s design and management helped the site be more effective in getting the product approved,” O’Hagan said. Designing the suites singly allowed Abbott to learn from prior suite installations as well as to incorporate new technologies.
Equipment Tailored to the Product
“Disposables supply a direct connection to the most flexible facility possible,” asserted Jonathan Hardy, associate director of purification at Lonza (www.lonza.com). The company eliminates hard plumbing, encouraging companies to develop a product based upon requirements rather than a product based upon the fixed equipment in a given facility.
“With fixed equipment, you usually have a process development organization working with the client to develop the process to fit what you have. With disposables, there’s slightly more flexibility,” agreed Dr. Stockbridge.
Because disposable systems may be completely contained, they can free up cleanrooms. Thus, they eliminate some clean-in-place validation requirements. The downside is that products that are light-sensitive or that need freezing may need to be rethought.
Closed System Design
The ability to transform previously open systems, like bulk fills and inoculum operations, into closed systems is a compelling reason to consider disposable manufacturing. Hardy presented a bulk fill example where the traditional method took four operators six to eight hours and required environmental monitoring. The product was filtered in an open environment under a Class A hood, admitting the possibility of contamination. Using disposable technology, the same procedure required only two operators and two to three hours and occurred in a closed system, minimizing the risk of contamination and eliminating the need for environmental monitoring.
Likewise, in his inoculum scale-up case study, sampling took only five minutes, compared to more than 15 minutes using a bottle or spinner. Tube welding ensured the connections were sterile. The traditional method, Hardy said, “could have upwards of 10 sterile boundary intrusions for a spinner split,” and also required more time to clean the equipment. Furthermore, he said, “the volume of culture needed for large seeds makes bottles or spinners impractical.”
“Larger volume buffer makeups can be performed and dropped into smaller bags for cost and time savings,” Hardy said. Bioprocess containers can be used as storage vessels, and because they are available in many different volumes, can provide more flexibility than fixed tanks without the same space restrictions or cleaning and steaming requirements.
Some of those benefits transfer to the customer, too. For example, point-of-use filtration increases process safety, and solutions can be held longer in a bioprocess container than in a tank because the limiting factor tends to be validation rather than chemical stability. It also takes less time to change over production from one product to another, using disposables, Hardy added.
In terms of efficiency, disposables can eliminate the need for clean-in-place and steam-in-place validation, saving up to 12 hours. “If the bag has a tear, you just requisition a new one,” said Hardy.
On the other hand, tanks’ routine maintenance takes from one day to one week, depending on the system. With disposables, “You now no longer worry about that. This adds up in a big facility,” Hardy pointed out. Consequently he said, downtime, maintenance, labor, and rework time decrease significantly. Sample-bottle cleaning is eliminated entirely, replaced by disposable containers.
Reducing Dead Spots
From a CMO’s perspective, using disposables eliminates the need for additional tanks as solution volumes change among projects and cleaning validation of buffer hold tanks can be eliminated. Flexible processes also can reduce dead spots in production by eliminating changeover time or down time as processes are introduced or scaled up.
“The issue for CMOs is changeover time,” emphasized Klaus Hermansen, Ph.D., senior specialist, NNE (www.nne.biz). “Time is money, and a six- to twelve-month changeover equals lost capacity.” Shaving changeover time to six months represents a sizeable gain.
For maximum efficiency, Avecia began a debottlenecking process using dynamic modeling for E. coli and Pichia pastoris. “The difference,” Williams explained, “is that E.coli grows very, very quickly, while Pichia grows very slowly, so the overall batch times are very different,” thus exacting repercussions on both upstream and downstream utilization.
Williams found, for example, that although the purified water generation was sufficient, it needed careful management to ensure that the demand for water could still be met despite the delays caused by heat sanitization, which drops the levels of purified water in the tanks. An ozone purification step could eliminate that concern, he said, “but it’s not a bottleneck for us at present.”
Restructuring the shifts in this 24/7 facility further enhanced productivity. “There are some differences (between fixed and flexible facilities) because we’re constantly running different processes,” Williams said. “Resource requirements change, so you need greater flexibility in timing processing, which means changing shift patterns.” Adjustments resulted in a 40% capacity increase.
“Disposable technology is a philosophical change,” Hardy emphasized.
Companies must be open to new ideas and be prepared for additional work. They must agree with their customers about cutting-edge ideas and technologies. That requires a thorough understanding of the process. “Once the process is fixed, you have a very limited scope in which to change it, but clients don’t necessarily know the process, and aren’t necessarily aware of the regulatory aspects,” Dr. Stockbridge pointed out.
Generally, more time must be spent upfront on process design to ensure regulatory and client approval. That includes performing validation and extractable studies, stability, and expiration testing.
Because many plastics migrate from the plastic to the product, regulatory bodies often are requiring companies that plan to use disposable manufacturing systems to also use disposables throughout their testing phases. Because many processes run in a CMO are similar, however, validation and extractable studies from similar processes can be leveraged, thus decreasing the number of validations required for new processes.
Switching from fixed to disposable manufacturing facilities complicates the supply chain by sometimes increasing lead times and by allowing the potential for overstocks or custom parts designs. In terms of supply, it now becomes critical to ensure you have guaranteed sources for customized parts and that convenient items haven’t become critical raw materials. Dr. Stockbridge advised working with companies that can ensure delivery because secondary sources aren’t always possible.
With that in mind, just-in-time delivery may not be an option, as “some processes for a CMO may require you to have 1,000 bioprocess containers on hand to maintain a six-week supply,” Hardy said.
After Avecia expanded, it found it needed additional buffer hold bags, which may eventually require more space in the process areas of the facility. If space or the personnel to track supplies and ensure quality are in short supply, disposables may not be a good choice.
Williams recommended managing the buffer supply in a way that ensures an always-available supply and planning for in-line dilution of buffers. Doing this, and handling caustics separately, roughly doubled productivity, he said.
Disposable manufacturing limitations become particularly evident as the product scale increases. “It’s easier to scale up buying two 500-L bags than installing and validating one 1,000-L tank,” O’Hagan said.
The point at which fixed equipment becomes more practical, however, is open to discussion. O’Hagan likes a 1,000-L limit. Dr. Hermansen doubles that, while Avecia’s facility scales up to 3,500 L.
Flexible facilities clearly have their merits but they’re not right for every situation. “There is a break-even point,” O’Hagan said, beyond which flexibility decreases productivity. Where that point lies depends on the overall use of the facility.