In a recent article in the Pharmaceutical Sciences, Manufacturing & Marketplace Report, Tony Pidgeon, senior manager of global science and technology with the CMO Patheon, described the company’s first experience employing a single-use system for the fill–finish of an API that was sensitive to oxygen and stainless steel. After realizing savings in time and cost with respect to cleaning-related activities in addition to achieving improved product-quality consistency, the company decided to adopt single-use technology for an entirely new filling line. In this issue, Pidgeon discusses the development and implementation of the new single-use system.
Flexibility was key
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What were the main considerations when choosing single-use equipment for the new filling line?
Pidgeon (Patheon): First, we wanted to ensure that we installed a completely disposable filling line for aseptic vial filling that provided a quick turnaround time with minimal solution losses. Because most of the products were expected to be water-based, we also wanted to include the use of peristaltic pumping. Of course, the filling system also had to meet requirements for extractables and leachables and be fully validated. Importantly, it also had to be flexible enough to enable the range of batch sizes (2 L to 200 L) expected in this facility for the manufacture of clinical-trial quantities.
Three segments: compounding, filtration, and filling
Pharmaceutical Sciences, Manufacturing and Marketplace Report: How did you choose the specific single-use equipment for the filling line given these requirements?
Pidgeon (Patheon): As before, we broke the line down into three major segments: the compounding section, the filtration section, and the filling section.
For compounding, it was determined that different containers were needed depending on the size of the batches. For smaller batches, we elected to use glass or plastic as needed for each API. While plastic is much lighter and easier to handle, glass is ideal when heating is required during the compounding step. Off-the-shelf plastic and glass bottles were available up to 80 L. For larger batches, we elected to use off-the-shelf plastic flexible carboys, knowing that we had the capability of developing customized vessels if necessary.
For the filtration segment, we elected to use capsule filters, but collaborated closely with vendors to develop a set of ready-to-use sterile filtration lines that were suitable for the different batch sizes we would be handling in the facility.
The filling segment included both receiving vessels and the fill sets as well as the Flexicon peristaltic dosing system. An IMA F97 Monobloc vial-filling machine that is integrated with a vial washer and sterilizing/depyrogenation tunnel was selected. In the Flexicon peristaltic dosing system, all of the product contact parts consist of disposable silicone tubing. For the receiving vessels, we chose off-the-shelf 5-L to 200-L flexible carboys (bags or floor standing) while three fill sets were developed with the assistance of vendors. The three fill sets were designed to cover a filling range from 0.5 mL to 22 mL, but have since been validated for the range from 0.1 mL to 33 mL when using water-like liquids. All are supplied clean, sterile, and ready to use.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: Has the single-use vial-filling line performed up to expectations?
Pidgeon (Patheon): This single-use system was designed to support clinical-trial manufacturing, but it is also capable of meeting the needs for small-volume commercial manufacturing as well. We have been able to validate filling doses well above and below that originally anticipated, which has been very beneficial. The peristaltic pump has also been very effective for all of the water-like liquid products that we have processed. However, the viscosity and rheology of products do need to be taken into consideration before using this filling line because peristaltic pumps have difficulty with highly viscous materials.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: Have the anticipated benefits of implementing this single-use vial-filling system been realized?
Pidgeon (Patheon): In fact, we reaped greater benefits than we expected. Initially, the installation of the peristaltic pump and the need for vessel supports (trolleys and totes) added approximately $85,000 to the cost of the facility. On the other hand, cost savings were achieved because there was no need to purchase several large vessels and dosing pumps. As a result, the overall savings with respect to the capital investment were approximately $100,000, or about 10% of the total project cost.
There are ongoing savings as well in terms of both time and cost. With this single-use filling line, there is no longer any need for pre-use or post-use equipment cleaning, and the time required for equipment preparation, sterilization and set-up is a fraction of that previously required with stainless-steel equipment. As a result, the total processing time has been reduced from 19 hours to 1.5 hours, which translates to a more rapid product turnaround time, significantly reduced cleaning-related costs, and a dramatic boost to our competitive position in the marketplace.
There are other additional benefits that should not be ignored. With the single-use system, we have eliminated the risk of contamination and reduced the number of aseptic connections. There is less downtime (which translates to increased capacity), and we have greater flexibility while suffering minimal losses.
A few considerations
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What, if anything, would you caution other manufacturers about when moving to single-use systems for fill–finish operations?
Pidgeon (Patheon): With single-use systems, there needs to be a very strong relationship with the suppliers of the disposable components, and companies must have good control over their stocks of single-use items. Careful selection of single-use pumps is also important, particularly if there is an expectation that the handling of higher-viscosity solutions will be needed. Finally, European Union and US regulatory agencies do focus on extractables and leachables (E&Ls), so pharmaceutical companies must be fully aware of this issue and work closely with vendors of single-use systems to properly investigate potential E&Ls for each product being processed on a single-use filling line and resolve any concerns. By being proactive about E&Ls, we have to date not had any issues.
The preferred approach today
Pharmaceutical Sciences, Manufacturing and Marketplace Report: How does the company view the implementation of single-use systems for fill–finish operations today?
Pidgeon (Patheon): We have introduced single-use filling systems in other facilities, such as one in Italy that incorporates both peristaltic and non-peristaltic pumping for more flexibility. At this point, whenever we can, we will opt for single-use systems, and single-use technology has become the preferred approach for new facilities.