June 1, 2010 (Vol. 30, No. 11)
Flexible Assemblies Can Reduce Downtime Associated with Cleaning and Validation
Manufacturers across every industry need to continuously boost manufacturing speed and efficiency, and therefore, rely on new technologies that can be easily integrated into their existing production processes. One solution bioprocessing manufacturers are increasingly implementing is single-use systems—particularly single-use transfer lines and tubing assemblies, which can deliver significant value through added flexibility, improved asset/equipment utilization, and increased cost savings.
Unlike hard piping, the flexible tubing incorporated into single-use transfer lines does not require costly and time-consuming cleaning and validation. This allows manufacturers to manage business cycles by quickly changing process steps or converting over to a new product. This is a key advantage for multiple product facilities in which process requirements change depending on the drug being produced. Innovative manufacturers now incorporate single-use tubing assemblies throughout the bioprocess from seed trains to final fill applications.
The key benefit of single-use transfer lines is the ability to boost productivity and accelerate time to market by reducing downtime associated with cleaning and validation of the processing equipment. Between each production batch, fixed tubing and re-usable valves need to be cleaned to maintain desired sterility. Single-use systems are provided presterilized, helping to eliminate the need for traditional cleaning and sterilization.
Additional cost savings result from reduced labor, chemical, water, and energy demands associated with cleaning and validation. Not only do single-use systems reduce cost, they also improve the safety of drug development and delivery. Presterilized, single-use tubing assemblies reduce the risk of cross contamination that may lead to product loss or reduced yields. This benefit is further magnified for companies that produce multiple products within single facilities.
Modern bioprocessing facilities scale up inoculum from a few million cells in several milliliters of culture to production volumes of up to 25,000 L or more. This process requires aseptic transfer at each point along the seed train. Traditional bioprocessing facilities accomplish scale-up using a dedicated series of stainless steel bioreactors linked together with valves and rigid tubing.
To prevent contamination between production runs, a clean-in-place (CIP) system is designed into each bioreactor, vessel, and piping line to remove any residual materials. These CIP and steam-in-place (SIP) systems require extensive validation testing, and the valves and piping contained in these systems can create additional validation challenges.
Advances in single-use technology allow bioprocess engineers to replace most storage vessels and fixed piping networks with single-use storage systems and tubing assemblies (Figure 1). Single-use eliminates the need for CIP validation for many components and reduces maintenance and capital expense by eliminating expensive vessels, valves, and sanitary piping assemblies.
Single-use media storage systems are routinely manufactured for volumes from 20 to 2,500 L. Media storage systems arrive at the bioprocess facility sterilized by gamma irradiation and often are fitted with integrated filters, sampling systems, and connectors. Using an SIP connector like Colder Products’ Steam-Thru® Connection allows operators to make sterile connections between these presterilized single-use systems and stainless steel bioreactors for aseptic transfer of media.
Similarly, single-use tubing assemblies may be used to transfer inoculum between bioreactors using either a peristaltic pump or head-space pressure. Such transfer lines can reduce the number of reusable valves required for transfer and eliminate problem areas for CIP and SIP validation. Terminating each presterilized transfer line with a single-use SIP connector provides sterility assurance equal to that of traditional fixed piping, at lower capital costs.
With the acceptance of single-use bioreactors, some bioprocess engineers are using these systems for both seed trains and small-scale production. These systems are connected to a cell culture media storage bag (either by aseptic welding or aseptic connectors such as AseptiQuik®) using flexible tubing. Flexible tubing with aseptic connectors are used as transfer lines between each reactor in the process.
For production volumes over 1,000 L, a single-use bioreactor typically seeds one or more stainless bioreactors. SIP connectors can link the single-use and stainless sections of a seed train (Figure 2).
Final Fill Operation
The final production step is transferring the new medium from the transfer vessel or bags and into vials for distribution. Traditionally the final fill operation consisted of stainless steel equipment connected via reusable valves, rigid tubing, and steel pipes. Again, this equipment requires validation and must be subjected to a CIP cycle after each filling cycle is completed. Today, many process engineers are designing this operation with single-use tubing assemblies in place of stainless steel piping to reduce sterilization time and cost.
One example of integrating single-use systems in a final fill operation is for simplifying mobile stainless steel transfer tanks. These tanks are designed to transfer product from formulation suites to storage areas and ultimately to filling suites. To allow sterile connection to and from these vessels, designers traditionally add three-way valve assemblies to fill and drain ports to facilitate SIP operations.
The design of these three-way valves makes it difficult to validate cleaning procedures. Replacing these heavy three-way valve assemblies with single-use tube sets and connectors eliminates cleaning, validation, and maintenance.
Single-use tubing assemblies can either be attached prior to equipment sterilization with single-use SIP connectors (used as either steam access or condensate drainage sites), or steamed separately, just prior to fluid transfer.
For vessel outlet, combining a number of single-use components into the transfer line can create a robust system to ensure product safety. For example, outlet transfer lines could incorporate a single-use SIP connector to attach to the sterile holding tank.
Then, a through-the-wall fluid transfer system is used to bring a portion of the transfer line into the filling suite. Next, a sterile connector is used to attach the transfer line to a separate portion of the transfer line that has already been steamed onto the filling machine with a single-use SIP connector. Finally, disconnecting the transfer lines using a quick disconnect coupling that has been validated as an aseptic disconnect enables the processor to confidently make an aseptic disconnection from the storage vessel or bag.
Figure 3 depicts a mobile stainless bulk storage vessel with a single-use transfer line feeding the final fill equipment. The stainless vessel could also be replaced with a single-use bulk storage container.
As more manufacturers take advantage of the benefits of single-use systems, their integration with traditional stainless equipment will continue to grow. Single-use tubing assemblies are not limited to upstream or downstream processes, and the benefits can be seen in unit operations in new or existing facilities. Whether it’s connecting within a process or across different processes, this is a technology with bottom line advantages throughout the manufacturing operation.