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Single-use components in the fill–finish line provides increased flexibility to multiproduct manufacturers.
The surge in the number of biologics in the drug-development pipeline, over 900 according to the latest report from the Pharmaceutical Research and Manufacturers of America, introduces pressure on manufacturers to handle increasing numbers of small-volume products (1). In fill-finish operations, this means manufacturers must have the ability to quickly and efficiently switch their fill line from product to product without compromising product quality or sterility. Manufacturers are beginning to take advantage of the benefits afforded by single-use technologies to address these needs.
Single-use technologies are now widely-accepted tools in drug manufacturing, particularly manufacturing of biologics. A recent biomanufacturing survey in Pharmaceutical Technology indicated that 66% of respondents use at least some disposable components in their manufacturing operations, and an additional 9% of respondents indicated that they use all disposables (2). Disposable upstream-processing tools, such as bioreactors and media storage containers have made a natural transition from bench-top to large-scale cell culture, and have evolved in size and complexity to fit the special needs of manufacturing-scale operations. Disposable downstream-processing tools have also been adapted to meet the demands of large-scale bioprocessing. At the very end of the biomanufacturing line is the fill-finish operation, where single-use technologies are just beginning to make inroads.
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Fill-finish is the last step in the manufacturing operation, after which the product is passed to the patient. As such, product quality and the possibility of contamination are of special concern when a manufacturer is considering whether to implement single-use technologies. The fill occurs downstream of the last filtration step, so there is a heightened sensitivity to sterility risks and the introduction of particulates. As with all disposable applications, product/material interactions and extractables and leachables are also concerns.
In some cases, manufacturers may be reluctant to switch to a disposable line from a well-validated stainless-steel fill line, where process engineers have extensive experience in cleaning and validating the system and are confident in their quality control operation. Kent Payne, vice-president and general manager of Development Services at Catalent Pharma Solutions indicated that in general, a big obstacle to adopting single-use technologies in other parts of the manufacturing process has been a reluctance to change. "The biggest challenge we faced in successfully applying single use systems elsewhere was first changing mindset to be open to new approaches from what we were used to," he says. For single-use systems, validation of sterility and integrity is done by the supplier of the components, rather than the manufacturer. Handing these important quality checks over to another party requires a leap of faith that some may not be comfortable making.
On the other hand, single-use technologies offer advantages over stainless systems in control of contamination. In the PharmTech survey, a majority of respondents listed reduced risk of contamination as an advantage to single-use systems (2). A single-use filling line can be configured to have fewer connection points than a fixed-pipe line, thus reducing the risk of microbial contamination. Moreover, since the line is only used for a single product, there is no risk of carryover contamination. Althea Technologies uses disposable technologies in all of its fill operations. According to Chris Duffy, vice-president of operations, "Preventing cross-contamination is an issue that Althea takes very seriously. To ensure that there is no carryover from project to project, Althea has stringent changeover procedures and operates its fill facility with disposable technology in virtually 100% of our fill operations, from small-scale Phase I clinical supplies to commercial manufacturing."
Time savings and flexibility
Perhaps the biggest benefit to be gained by implementing a single-use filling line is the savings in time gained by eliminating the cleaning and validation steps. Nathan Beyeler, process engineer at Merck Sharp and Dohme, cited the decrease in changeover time as being an important factor in the decision to implement a single-use fill line. "Market pressure and good business sense dictate that we need to use our filling assets for manufacturing product, not for getting ready to manufacture product," he says. "The need to get the most product out of the process is increasingly critical to the business. That said, the paradigm of a few blockbuster vaccines allowing for long campaign operation and few product-to-product changeovers is under pressure as products portfolios become more focused on multiple (lower annual volume) biologics. This means that a production facility is faced with the challenge of more frequently changing the facility and equipment over to process different products. The reduction of changeover time has therefore become one of the primary influences in our decision to implement single-use technology for current filling facilities."
Indeed, Beyeler reported a reduction in changeover time from 16 hours to two hours when switching to a single-use line. In addition, a recent report produced by authors from Millipore demonstrated a similar reduction in total processing time, from 19 hours to 1.5 hours, when switching from a stainless system to a single-use system (3).
On average, biotech companies outsource 81% of their fill-and-finish requirements. Biotech and pharmaceutical companies with in-house capabilities outsource 40% of their requirements (4). This means that CMOs are handling a large variety of filling operations, and can benefit from the flexibility afforded by single-use systems to handle multiple products. Althea's Duffy notes, "Stainless equipment requirements vary from client to client. When not in use, these must be stored and when they are placed back into service must be cleaned again." The ability to quickly reconfigure the line to accommodate different size runs, different biosafety requirements, or different product containers adds greater flexibility to the filling operation.
Evolving equipment requirements
It is often the case that equipment evolves to fill an unmet need, and this is the case with disposables for fill-finish. At its simplest, a filling line can consist of a product container bag, a pump and a filling needle, all connected by plastic tubing. Disposable filling lines, suitable for smaller-scale fills are available as "plug-and-play" systems, where the line comes fully assembled and presterilized, ready to be used. Such systems are adequate for small-scale fills, but do not operate at high speed and may not be suitable for high-viscosity products.
Pump technology has improved to the point where disposable filling lines are feasible, but further improvements are possible. Peristaltic pumps have only recently achieved the accuracy required for fill applications. They are still limited by speed, and the tubing that runs through the pump is subject to degradation and deformation over time. Plastic, disposable, rolling-diaphragm pumps are currently available and offer an alternative. However, more rigorous applications requiring high volume, high speed, or high pressure, may be places where stainless steel continues to be the better choice.
There is plenty of room for new technology to adapt to these challenges. Beyeler says, "At the moment, I think what has been offered is that which is the easiest and least risky to develop from the equipment vendors, a single-use version of what is already on the market. Some equipment suppliers for upstream processing have innovated beyond the 'also in single-use' type of approach and have developed specifically new technologies. As vendors increasingly see the potential competitive advantages for single-use technologies I am looking for them to specifically invest R&D in developing innovative filling technologies." The requirements for speed and cost-effectiveness in multiproduct manufacturing will drive the development of new disposable technologies for fill-finish operations.
1. Biotechnology Medicines in Development. PhRMA (September, 2011).
2. M. Hoffman, "Bioprocessing and Sterile Manufacturing" supplement to Pharm. Tech. 35, s6 (2011).
3. E. Jenness and V. Gupta, supplement to BioProcess Int. 9 (s2), 22–25 (2011).
4. J. Hartingan and W. Downey, GEN 31(10), (2011).