Plastic Factory, Part II: The final pieces of the disposable puzzle
06/01/2003
Evolving plastic technologies aim to help biopharmaceutical makers eliminate expensive utilities, clean steam, CIP fluids, WFI, and autoclave facilities
By steve tingley
Editor's note: In Part I of "Plastic Factory" (see CleanRooms, February 2003, Biotechnology Supplement, pg. 4; or, cleanrooms.com), Millipore's Steve Tingley defined his vision of the completely disposable manufacturing process, the benefits that can be realized, the range of applications for disposable components, as well as issues surrounding final filling operations. In Part II, Tingley completes his examination of this revolutionary processing mindset by taking a look into related sterile transfer systems, disposable filling, and disposable fluid path technologies.
Sterile rapid transfer systems (SRTP) offer process protection and economic work flow planning for materials transfer challenges. As the risks associated with materials transfer process have become better identified and investment in high-tech barriers has increased, so too has the demand for more robust and secure transfer systems.
Two systems in particular have been developed that automatically sterilize the interface between the flexible transfer container and that Class A environment. Both systems use flexible packaging in which the components can be pre-sterilized. This combination gives both systems the advantage of minimizing operator interventions into the filling environment; in neither case is it necessary to have the packaging materials passed into the filling environment.
Technology developed by Central Research Labs (CRL; Red Wing, Minn.) uses a modified, automated alpha/beta door, in which the ring of concern is sterilized by a six-minute dry-heat sterilization cycle to sterilize the transfer interface.
Millipore's (Billerica, Mass.) SafePass sterile transfer system provides the same sterile transfer materials handling capabilities as the CRL system. The two systems differ in technical approach. The CRL system is, in essence, a re-engineering of the well-known alpha/beta systems, using beta bags as transfer containers. The SafePass system, on the other hand, is a port design featuring an easy-load docking system (no rotation required) and an intelligent interface that assesses the integrity of the docking and sterilization cycles. A failure in either of the SafePass subsystems and the intelligent interlock system prevents the opening of the port, thus protecting the Class A filling environment from accidental contamination.
Two other significant differences in these SRTP systems stem from the sterilization source: dry heat in the case of the CRL systems and 3-minute 254-nanometer (nm) ultraviolet (UV) light sterilization in the case of SafePass. Lastly, the SafePass sterile transfer container uses a patented, simple, molded interface collar that attaches to the transfer container bag, making for a simple, low-cost sterile transfer container system. Extensive validation data is available to demonstrate the effectiveness of microbial kill during the sterilization cycle.
One of the greatest benefits of the sterile transfer system is the ability to design newer, perhaps smaller, barrier-filling facilities where the barrier is housed in only a Class D environment. Another benefit is the power to transfer materials directly from an unclassified staging area into a Class A environment.
The potential benefits to be gained from reduced manual materials preparation, handling preparation, and operator-based SOPs should not be underestimated. The regulatory question concerning the appropriateness of placing a barrier filling system inside anything but a Class B environment is being addressed.
Proposed wording in the U.S. Food and Drug Administration's (FDA) recently published draft concept paper on aseptic processing clearly indicates a willingness to see barriers placed in environments less stringently controlled than Class B. The corollary to this wording is that the risks associated with material transfer for each manufacturing design option must be evaluated and understood. Further, the material transfer systems and processes selected should provide an appropriate level of security based upon the environment in which the barrier is placed.
Disposable filling
In much the same way that disposable materials transfer systems can augment the application of barriers to the final fill process, so too can the advent of a disposable filling system. This developing technology replaces the piston pumps and surge tank assemblies integrated onto the conveyor systems, which must be cleaned and sterilized before each filling run.
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This process requires facilities intervention in the filling suit to break down and assemble the fillers. Even the most modern fillers with CIP/SIP capabilities still take hours to prepare for a subsequent product run, and may require engineering intervention if pump sets are to be changed before changing drug product formulations.
The Acerta disposable filling system, for example, is essentially a pre-sterilized assembly of a small 1.25 L plastic bag that acts as a capacitance reservoir and feeds the fill needles. This technology provides a volumetric fill driven by gravity, which does not require the use of a pump or a pressured system. The system comprises a hardware component and a disposable pre-sterilized assembly of tubing, reservoir, and filling needles. The disposable component is discarded after each filling operation, obviating the cleaning and sterilization of the product contact surfaces.
The single-use device also prevents the possibility of cross-contamination between batches, allowing for the segregation of drugs using the same filling lines.
The example dispensing system (Figures 1 and 2) is based on a gravimetric volumetric fill principle, and works with a fill and discharge cycle. The reservoir, which is filled to a set level with the sterile drug from an external supply tank, serves as a capacitance buffer and is fed from a sterile holding tank. The volume of liquid in this reservoir is controlled by a sensor located external to and behind the reservoir, which detects and maintains the liquid level to approximately 0.5 L. This control is achieved by a feedback loop from the sensor to a peristaltic pump or a pinch valve fed from the sterile holding tank.
When the upper pinch valve opens, liquid, driven by a small head of pressure, flows from the reservoir into the measuring tube (see Figure 1). The upper sensor on the measuring tube recognizes the liquid meniscus and closes the upper pinch valve (see Figure 2). The measuring tube is now filled with a reproducible volume of liquid. The charged measuring tube is now ready for dispensing to the vial.
Depending on the number of filling heads required for the line, the reservoir may feed several measuring tubes. To allow for the equilibration of pressure in the measuring tube with the reservoir head space, the top of the tube is vented back to the reservoir. This provision serves to maintain the sterility of the liquid to be dispensed by forming a closed circuit.
Disposable filling meets all requirements of enhancing barrier technology: the absence of aseptic connections, minimal operator intervention, reduced validation burdens, and a reduced risk of chemical and microbiological contamination.
Disposable fluid path
To create a disposable fluid path, an end user can construct a single-use fill system from a filter capsule, tubing, a flexible process container as the sterile holding vessel, more tubing, and the disposable filling assembly. This technology is already in use, supplied by several source companies. Further, all this could be delivered into a clean area through a barrier and sterile transfer port.
The last challenge is "connectology." If one has ready-to-use, pre-sterilized fluid path systems, how can one connect them in a secure and validatable manner without putting the aseptic connections at risk?
This is an area of new developments. One answer pioneered by several pharmaceutical companies is the use of tubing welders. These assemblies provide great flexibility as long as the pre-sterilized fluid path components include C-flex-type tubing. These tubing stubs provide the points for numerous flexible sterile tubing welds to be made, connecting a wide variety of sub-assemblies (such as filters and bags).
How will disposable manufacturing technology change the face of pharmaceutical manufacturing facility design and economics in the years to come? The dependence on expensive utilities, such as clean steam, CIP fluids, water for injection (WFI) and autoclave facilities can be eliminated or minimized.
In the construction of a new facility, the impact of a disposable strategy on the capital cost and speed could be particularly beneficial. Every advantage that disposable technology brings to existing facilities is dramatically increased by its introduction into a new facility, with its freedom from the constraints imposed by traditional equipment and technology.
Steve Tingley is director of biopharmaceutical marketing at Millipore Corporation (Billerica, Mass.). He can be reached at [email protected]