Disposable technologies are quickly beginning to change the face of pharmaceutical cleanroom facility design and economics
By Steve Tingley
Editor's note:This is the first in a two-part article on evolving disposable manufacturing practices and technologies. Part II will run in the May CleanRooms Biotech supplement.
Observers of trends in the biopharmaceutical manufacturing world over the last 25 years have recognized a movement in technology adoption from a relatively unsophisticated, labor-intensive “people process” toward a fully automated one that often includes ready-to-use separations devices.
Over the years, leading pharmaceutical manufacturers have realized that reducing their reliance on human operators to execute standard operating procedures (SOPs) in reliable and reproducible ways leads directly to increased productivity, improved product quality and regulatory compliance.
A reassessment of costs in manufacturing operations has led to a change in manufacturing strategy. The potential cost of quality, yield losses and delays in getting new drugs to market, often inherent in more manual manufacturing processes, has led to the adoption of seemingly more expensive options. Ultimately, the adoption of capital-intensive products such as barriers, steam-in-place (SIP) filters and sophisticated supervisor control and data acquisition (SCADA)-based process control systems has given rise to current manufacturing strategies. Also influential has been the use of ready-to-use process separation devices such as single-use filtration cartridges.
The industry is taking the next step, in which valuable, highly educated manufacturing personnel will be focused more on the production process than on preparation and clean up after manufacturing. Manufacturers will accomplish this change by employing disposable manufacturing technology.
Disposable manufacturing defined
The ultimate vision of the most ambitious biopharmaceutical companies is a completely disposable manufacturing process. In the case of a recombinant biotech product, this means that each unit process operation, from fermentation through purification, to final fill-and-finish, ideally should be redesigned and retooled to enable the economical single use (as shown in Fig. 1).
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The primary challenge is to remove all permanent fluid paths from the manufacturing process. Chief among these permanent fluid paths are stainless steel pipes, tanks, fermenters, filter and chromatography housings.
A disposable manufacturing option can potentially offer significant savings in time to market, perhaps saving as much as six months within a 30-month validation process. Process capital-intensive projects can be reduced by 25 to 30 percent if the disposable option is pursued.
Disposable manufacturing benefits
The benefits of disposable manufacturing are many; their relative significance depends on the type of drug to be manufactured and the focus, size and resources of the individual biopharmaceutical company. These benefits include economy, speed to market, capacity and drug process security.
Economic benefits: Depending on individual circumstances, disposable manufacturing is expected to provide multiple opportunities for cost savings. Detailed cost-of-goods (COG) assessments of existing manufacturing processes have shown that the replacement of steel tanks with plastic flexible containment systems can result in direct running cost savings of eight percent.
The savings are realized primarily through labor reduction and the relieving of production “bottlenecks” that reduce overall efficiency. As far as facility expansion is concerned, there is further opportunity for economic advantage through the reduction of capital investment.
In its most evolved state, the disposable process will not require steam sterilization, autoclaves or clean-in-place (CIP) utilities. By minimizing the sizes of utility plants and facility footprints, the pharmaceutical company can realize significant savings in its validation efforts. These types of economies can significantly impact capital investment and minimize startup delays by reducing engineering, validation and regulatory inspection burden.
Speed to market: This benefit is important to all biopharmaceutical manufacturers, but especially to the small or virtual companies who do not have their own manufacturing capabilities. The potential revenue loss associated with a single day's delay in market approval is often counted in millions of dollars. Clinical trials are often a leading cause of approval delays.
Before the trials begin, sufficient drug product must be manufactured in multiple batches. For those companies who do not have that manufacturing capacity, the disposable manufacturing option offers different solutions. Disposable manufacturing can help by facilitating the speedy production of small-scale clinical manufacturing and multi-product contract manufacturing.
Minimizing sterilization and CIP processes allow faster process turnaround and provide for increased facility capacity. In the same way, disposable manufacturing facilitates multi-product manufacturing, potentially offering contract manufacturers a way of increasing capacity and producing multiple small-volume batches of different drugs.
Manufacturing capacity: Increasing capacity is often difficult in fixed facilities; furthermore, multi-product facilities often require additional equipment. Disposable manufacturing can increase manufacturing capacity by reducing the turnaround time of bottleneck process steps and by making it easier for existing facilities to increase production efficiency.
Drug product/process security: Logically, disposable manufacturing products and practices also have the ability to improve drug product quality by minimizing contamination. Without including lost opportunity costs or the economic impact of liability and market recall, the manpower, documentation and regulatory compliance efforts associated with security alone would cost hundreds of thousands of dollars.
A 2001 Parenteral Drug Association (PDA; Bethesda, Md.) survey identified the most common causes of aseptic processing failure (see “Identified causes of aseptic processing failures”). Disposable manufacturing provides opportunities to directly improve many of the practices associated with aseptic processing failure.
People are the single largest source of microbiological contamination; it is recognized practice within the industry to minimize direct operator contact with manufacturing processes. The barrier properties of disposable manufacturing ensure the separation of people and process. The use of pre-sterilized process steps and novel connection systems replaces the reliance on SOP-dependent aseptic connections with secure sterile connections. Single-use containers and novel transfer systems enable the use of outsourced sterilization processes such as gamma irradiation.
As in previous examples, disposable manufacturing facilitates the switch from less robust operator-dependent processes to greater automation. The use of gamma irradiation to replace SIP and autoclave sterilization, as well as the use of sterile transfer systems in place of aseptic rapid transfer port (RTP) systems for material transfer, has the capability to further improve process security and drug product quality.
Range of applications
Disposable manufacturing is broadly applicable across the range of manufacturing processes and drug types, even if the specific derived benefits differ. The current status of disposable manufacturing can best be described as incomplete.
Biopharmaceutical companies have been using disposable filter technology in the form of capsule filters, which have been available for nearly 20 years. In the last 10 years, four or five companies have developed and introduced single-use flexible containment systems, which have been dubbed “bags.”
The significance of this perspective should not be lost when considering the disposable manufacturing option. When companies consider what they expect to gain from the disposable option, they must carefully assess the form, fit and function of each disposable system.
Small-scale bioreactors are now available and have been placed into service for up to 200-L fermentation. Recently commercialized technologies include single-use virus removal technology and large-surface-area, single-use microporous membrane capsules. Development programs are underway aimed at single-use disposable process steps for cell harvest, clarification, chromatography and ultrafiltration.
These types of purification processes do not typically require state-of-the-art cleanroom facilities, unlike the final fill-and-finish cleanrooms. Hence, the principal benefits of disposable manufacturing provide cost savings by minimizing CIP operations and validation, increasing the flexibility and efficiency of the manufacturing process and enhancing product safety. This enhancement is provided by minimizing the risk of chemical contamination from drug to drug and batch to batch, and by minimizing the risk associated with the chemicals used to CIP stainless-steel systems.
Technology for barriers
Once the bulk active pharmaceutical ingredients (API) have been manufactured and purified, they require final aseptic processing. Most biotech products are proteins that are heat labile and unavailable as an oral dosage form, and that, therefore, requires aseptic processing. Ultimately, these drugs are sterile filled into liquid or freeze-dried formulations.
These final fill-and-finish aseptic processes are conducted using barrier technology, either in the form of a cleanroom or barrier isolator. The purpose of these barriers is to maintain the sterility of the drug liquid and the dosage format components (such as vials, stoppers and needles) as they are brought together to fill the parenteral liquids in the open containers.
Barriers maintain this sterility by maintaining very clean, controlled environments in which particles and microbiological contamination is kept to an absolute minimum. Poorly designed work flows and materials flows can cause significant problems with barrier validation and operation.
Disposable manufacturing can play a major role in improving the effectiveness of final fill-and-finish barrier operations. New, single-use technologies are continually being developed. They have three major purposes: to keep people away from the fill-and-finish area; to minimize chemical cross contamination; and to minimize the microbiological challenge to a final fill process.
Like the presence of operators in the area, microbial challenge introduced during material transfer is another significant source of potential contamination. Consider a filling operation of 100,000 vials per shift. At 3,000 stoppers per container, that operation requires over 30 transfers. With each transfer there is the accompanying risk of contamination transfer. This risk is a significant part of the microbiological challenge presented to a filling operation. It is recognized as an intervention risk as the type, number and time of transfer must be included in process simulation media fills.
Disposable transfer technology
Material transfer into final filling operations always presents challenges. Common questions that arise include: How do I sterilize the filling components, stoppers and needles? How do I transfer them across barrier to barrier without contaminating the progressively cleaner environments? How do I develop a system to transfer my sterile drug solution for filling?
Most of the currently used transfer systems for moving sterile materials into a filling operation involve the use of an aseptic wiping procedure. Simple wipe and pass systems are used to move pre-packed sterile components to progressively cleaner environments. These systems operate by requiring the simple removal of a dirty outer bag and/or a complete wipe down with a sanitizing agent before passing sterile materials through a simple air lock.
This process is repeated for each barrier until packaged components finally pass inside a Class A environment. The operator, usually working above the component hopper, must open the bag and empty the components into the distribution hopper. This is undesirable from a number of perspectives:
- Potentially dirty packaging materials are moved into the Class A environment.
- An operator must put at least the head and arms inside the Class A area.
- The packaging is opened and emptied, introducing particles and creating significant movement inside the Class A environment.
- The filling line may have to be stopped.
- All these activities must be included in the bi-annual process simulation validation.
Even more sophisticated systems, such as the alpha/beta transfer system currently used for barrier isolators, have their limitations. The newer “beta bag” systems avoid the need for packaging materials to be passed inside the Class A environment, but still require a sanitization wipe down. This wipe down is required to minimize the microbiological challenge to the filling area from the “ring of concern.”
A gasket on the alpha door of the beta bag transfer system causes this ring of concern. During the materials-handling process, the outside of the alpha door and this gasket are exposed to the environment surrounding the Class A filling area, usually Class B or D. Hence, the gasket is dirty. When the alpha and beta doors are mated, this dirty area is trapped between the alpha and beta doors and sealed tight by the gasket situated between the two doors.
This gasket is also dirty and is extruded from between the sealed doors into the Class A environment. The gasket extrudes by about 1/8 inch; it's this dirty gasket area exposed to the filling environment that is dubbed the ring of concern.
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The contamination risk is addressed by an operator-executed alcohol wipe down procedure. This process is subjective, time-consuming and cannot be properly validated.
These systems are used for making multiple transfers during a shift, perhaps as many as 30 or more. They are also used for long-term sterile fluid-path connections, which are made only once per shift but are in contact with the filling environment for many hours at a time. Both of these situations can be described as high-risk connections and transfers to the filling environment, which by definition, place a significant microbiological challenge to the final-fill process.lll
Steve Tingley is director of biopharmaceutical marketing at Millipore Corporation (Billerica, Mass.). He can be reached at [email protected].