Use of disposable components in product downstream processing and final fill operations is increasing as technology improves for performing these steps in a single-use mode. There is a high demand for systems that support single-use purification, formulation and filling operations.
First, there is a desire to realize increased processing efficiency through the elimination of preparative steps like clean in place (CIP) and steam in place (SIP) for product-contact equipment and parts. For example, pre-sterilized, single-use tubing and bags can be used to replace stainless steel piping and tanks that have to be cleaned and steamed between uses.
The second driver is the reduction of 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 because existing cleaning processes are inconsistent or simply do not work to remove certain products to safe levels.
The third driver is containment of toxic products. Disposable systems can be removed, bagged and disposed without breaking connections and exposing the environment to product.
A fourth driver is the desire to match existing single-use upstream processes, which are available for new products-particularly biopharmaceuticals and other protein-based drugs.
In the past, filling line equipment was commonly dedicated entirely to a single product. However, this approach is no longer economically feasible except for the highest-volume drugs that support nearly continuous filling operations. Today, most filling lines support multi-product operations, which 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, so they are 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 pre-cleaned and pre-sterilized, and double- or triple-bagged for easy use within clean rooms. However, filling operations are critical enough to require entire single-use systems be assembled and sterilized together rather than having to piece individual components together at the point of use. The dosing system used for filling also affects the characteristics of the single-use components.
Current Systems Have Limitations
The pre-sterilized, single-use concept has already been realized with several off-the-shelf filling systems using peristaltic or gravimetric dosing. The existing systems, however, are designed for low speed, small-batch filling operations. Upgrades of these high-speed filling systems create 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, as peristaltic tubing is used for much of the product path. Single-use peristaltic systems are typically comprised of a product hold bag, supply tubing and a filling needle that 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 be precise at dosing water-like solutions at slower speeds.
However, accuracy is directly influenced by the tubing. The tubing that is located in the pump head changes shape over time due to wear, so accuracy drift is common. Characterizing and compensating for the drift is required. Peristaltic pumps also dose at slower speeds, which means high-speed peristaltic systems require more pump heads to dose at the same rate as the equivalent piston, time pressure or rolling diaphragm systems.
Gravimetric dosing uses optical sensors to dose a given volume based on a calculation of the interior volume of a given length of tubing or glass. The entire product path is supplied as a single-use, pre-sterilized assembly. Accuracy and precision of the system with water-like solutions is comparable to other dosing systems.
However, dosing speed and accuracy can be 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 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 pump heads are required to dose at the same rate as the equivalent piston, time pressure or rolling diaphragm systems.
Existing Scalable Dosing Systems
The current single use, pre-sterilized dosing systems are based on scaling-up technologies designed and used for small-scale filling operations. However, 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 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 the product does not leak during use (see Figure 1 below). Pump bodies and pistons are commonly matched when they are fabricated to ensure they do not gall 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 manufacturing cost. Plastic components are an alternative, but cannot be fabricated to the correct tolerances to ensure accuracy. Excessive wear and leaking are also issues. A catastrophic loss of function will likely result without the use of o-rings or a lubricant (or both) to separate the moving plastic surfaces. Plastic particles-elastomeric particles in the case of o-ring use-or lubricant will also be shed by the pump and introduced into the product stream.
The rolling diaphragm pump is comprised of a stainless steel pump with a diaphragm. A headpiece and diaphragm make the liquid chamber. Dosing occurs by actuating a piston that is attached to the diaphragm. It is similar to piston dosing, except the diaphragm keeps the product from contact with the piston and other internal components. The only stainless steel part in contact with the product is the headpiece (see Figure 2 below).
Constructing this system from plastic requires the use of o-rings or a lubricant-or both-to separate the moving piston from the body. Unlike the piston pump, however, these surfaces are separated from the fluid path by the diaphragm, so contamination of product stream is not an issue. The tolerances for each part are not as critical as with piston pumps because dose accuracy is related to accurate piston stroke while maintaining consistent dimensions in the fluid chamber.
Time pressure systems
However, these systems often use a small surge tank for product supply, and this tank must be pressurized to 10-psig (or more) for the system to function. Replacing this tank with a bag would require pressurization 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 a single-use system dispenses at high speed while being durable enough for commercial use requires rigorous testing. No dosing system is appropriate for commercial use without proof of accuracy and precision throughout its operating lifetime. The maximum intended run duration for commercial systems can last as long as a week or more and involve 500,000 to 1 million dosing cycles per station. This is well beyond the design specification of existing single-use dosing systems.
A limitation to all current single-use pre-sterilized dosing systems is the plastic filling needle. The current plastic needles are not designed for commercial filling operations. Most are too wide to penetrate small containers and/or are 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. The plastic needles are not shaped to fit correctly within needle holders on common commercial filling systems. Custom fixtures are required to use them on existing machines.
High-speed filling requires needles be made with tight tolerances, particularly the needle diameter, as this influences dosing accuracy and precision. Because high-speed needles travel during and after dispensing, needle drip between doses must 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 is too expensive for single-use assemblies.
Summary
There are tremendous advantages to single-use, pre-sterilized 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. However, significant technical achievements must be realized before a system can be scaled for high-speed filling operations.
Pumps & Systems, March 2008