May 15, 2008 (Vol. 28, No. 10)
Low-Speed Operations Abound, but High-Speed Systems Remain a Technical Challenge
The use of disposable components in downstream processing and final-fill operations is increasing as the technology for performing these steps in a single-use mode advances. This evolution has created significant demand for systems that support single-use purification, formulation, and filling operations.
Four factors are largely responsible for driving this increased demand. First, is the desire to realize increased processing efficiency through the elimination of preparative steps like CIP and SIP for product-contact equipment and parts. For example, presterilized, single-use tubing and bags can be used to replace stainless steel piping and tanks that have to be cleaned and steamed between uses.
Second, is the need to reduce validation efforts related to the product path, in particular the elimination of cleaning validation. Products that are hard to clean, or are highly potent or toxic, often require dedicated product-contact parts. This is because existing cleaning processes are inconsistent or simply do not work to remove certain products to safe levels.
Third is the imperative to contain toxic products. Disposable systems can be removed, bagged, and disposed of without breaking connections and exposing the product to the environment. Finally, there exists a desire to match existing single-use upstream processes, particularly for biopharmaceuticals.
In the past, filling-line equipment was commonly dedicated to a single product. This approach is no longer economically feasible. Most filling lines today support multiproduct operations, with the exception of the highest-volume drugs, which support nearly continuous filling operations.
Traditional multiproduct operations require validation of the level of product carryover after cleaning operations to ensure subsequent products are not contaminated. Certain product-contact parts are hard to clean to acceptable levels and are therefore dedicated to specific products.
An alternative to filling-equipment dedication is the use of single-use parts and assemblies. These systems can include components like bulk product bags, capsule filters, silicone tubing, and other plastic fittings and parts. Many of these parts can be purchased precleaned and presterilized as well as double or triple bagged for easy use within cleanrooms. Filling operations are critical enough to require that entire single-use systems be assembled and sterilized together rather than having to piece individual components together at the point of use.
Presterilized, single-use products have been around for awhile, with several off-the-shelf filling systems using peristaltic or gravimetric dosing. These existing systems are designed for low-speed, small-batch filling operations. Scale-up of these systems for high-speed filling creates technical obstacles that include a relatively slow dosing speed, lower filling accuracy and precision, and difficulty dosing products with variable temperature and viscosity characteristics.
Peristaltic dosing is ideally suited for disposables. Single-use peristaltic systems are typically composed of a product hold bag, supply tubing, and a filling needle, all of which are bagged together and sterilized using gamma irradiation. The assembly is removed from the bag and connected to the filling system, which can be as simple as a single peristaltic pump, immediately before use.
High-quality peristaltic pumps can precisely dose water-like solutions at slower speeds. Accuracy, however, is directly influenced by the tubing; accuracy drift is common as the tubing that is located in the pump head changes shape over time due to wear. Characterizing and compensating for this drift is mandatory. Peristaltic pumps also dose at slower speeds, which means that high-speed peristaltic systems require more pumpheads to dose at the same rate as the equivalent piston, time-pressure, or rolling-diaphragm systems.
Gravimetric dosing uses optical sensors to dose at a certain volume based on calculation of the interior volume of a given length of tubing or glass. The entire product path is supplied as a single-use, presterilized assembly. Accuracy and precision of the system with water-like solutions is comparable to other dosing systems, with speed and accuracy directly related to fluid temperature and viscosity. Dosing time is based on the speed at which a liquid will flow through the tubing based on gravity. Thicker solutions flow more slowly and are therefore dosed at a slower rate.
Relatively small temperature changes over the course of a filling event can affect product viscosity enough to have a significant effect on the volume filled. Like peristaltic systems, more pumpheads are required to dose at the same rate as the equivalent piston, time-pressure, or rolling-diaphragm systems.
Current single-use, presterilized dosing systems are based on the scale-up of technologies designed and used for small-scale filling operations. A better approach is to convert an existing high-speed dosing technology to single use. The three most common commercial systems are piston pumps, rolling-diaphragm pumps, and time-pressure dosing. All three of these systems would require significant technical improvements and modifications to be converted to disposable use.
Piston pumps rely on a precise physical tolerance between the pump body and piston to provide dosing accuracy and to ensure that product does not leak during use. Pump bodies and pistons are commonly matched when they are fabricated to ensure that they don’t fail during use. Existing piston pumps for pharmaceutical dosing can be made using stainless steel or ceramic components. Neither material can be used to make a disposable pump due to the high cost of manufacturing.
Plastic components are an alternative but they cannot be fabricated to the correct tolerances to ensure accuracy. Excessive wear and leaking would also be issues. A catastrophic loss of function would likely result without the use of o-rings, lubricant, or both to separate the moving plastic surfaces. Plastic particles, elastomeric particles in the case of o-ring use, or lubricant would also likely be shed by the pump and introduced into the product stream.
The rolling-diaphragm pump was originally developed by TL Systems, now Bosch Packaging Technology (www.boschpackaging.com). It is composed of a stainless steel pump, with a headpiece and a diaphragm making up the liquid chamber. Dosing occurs by actuating a piston that is attached to the diaphragm.
A rolling-diaphragm system is similar to a piston-dosing system, the big difference being that the diaphragm keeps product from contacting the piston and other internal components. The only stainless steel part in contact with the product is the headpiece (Figure). Making this system out of plastic requires the use of o-rings, lubricant, or both to separate the moving piston from the body. Since these surfaces are separated from the fluid path by the diaphragm, contamination of product stream is not an issue. The tolerances for each part are not as critical as with piston pumps, as dose accuracy is related to accurate piston stroke, which maintains consistent dimensions in the fluid chamber.
Time-pressure systems are designed to dispense using a pressurized product supply and timed valve openings. A portion of the product path from the supply manifold to the filling nozzles is made of elastomeric tubing, which is used in association with an automatic tubing-pinch mechanism to create the valve.
The use of disposable tubing seems to make this system a good candidate for single use. This is not the case though. Time-pressure systems often use a small surge tank for product supply, and this tank must be pressurized to 10 psig or more. Replacing this tank with a bag would require that the bag be pressurized beyond its normal design pressure. There is currently no good solution for pressurization of a surge-bag system for use with time-pressure filling.
Other Technical Hurdles Exist
Ensuring that a single-use system dispenses at high speeds and is also durable enough for commercial use requires rigorous testing. No dosing system is appropriate for commercial use without proof of accuracy and precision. The run duration of commercial systems is typically a week or more, involving 500,000–1,000,000 dosing cycles per station. This is well beyond the design specification of existing single-use dosing systems.
The plastic filling needle limits all single-use, presterilized dosing systems at this time. Current plastic needles are not designed for commercial filling operations. Most are too wide to penetrate small containers and/or too short to perform bottom-up filling. Bottom-up filling, where the filling needle penetrates the container and is drawn out during dosing, is common with high-speed filling to reduce product splash and foaming.
In addition, plastic needles are not shaped to fit correctly within needle holders on common commercial filling systems, requiring custom fixtures to use them on existing machines.
High-speed filling requires needles made to tight tolerances, particularly the needle diameter, which influences dosing accuracy and precision. As high-speed needles travel during and after dispensing, needle drip between doses has to be eliminated. Precise needle opening size and opening shape is also required. Substituting plastic needles with ones made from stainless steel can solve most of these issues, but this is too expensive for single-use assemblies.
There are tremendous advantages to the use of single-use, presterilized dosing systems for commercial filling operations. Increased processing efficiency through the elimination of preparative steps like CIP and SIP, reduction of validation efforts including elimination of cleaning validation, containment of toxic products, and matching existing single-use upstream processes are all compelling arguments for these systems for product-filling operations. Significant technical achievements, however, must be realized before a system can be scaled for high-speed filling operations.
Jeff Jackson is director of product management, North American
pharmaceutical operations, at Bosch Packaging Technology.
Web: www.boschpackaging.com. Phone: (763) 493-6133. E-mail: [email protected]