Operating Aseptic Facilities
Bringing online, maintaining, and enhancing any aseptic processing facility presents numerous challenges. By using history as a guide, coupled with an understanding of today’s latest technology and applications, the path to being a more flexible operation in the future becomes much clearer. Staying ahead of the proverbial compliance-efficiency-cost curve, while maintaining flexibility, requires more detailed thought and planning.
Paying attention to the industry trends, ensuring the best practices are leveraged, and understanding where you add value are a few of the pieces to the puzzle which determine the platform technologies that will provide the desired standardization you are seeking, yet the customization you need. Equipment, facility and process design all contribute to an operation’s ability to meet or adapt to market needs.
Depending on the lens through which we view our regulatory landscape, lifecycle costs, process design or capital investment options, there are many technologies, applications and exciting things happening in drug product manufacturing.
Caps/seals entering the capping bowl under barrier isolation. Photo: Cook Pharmica
In this article, we will explore the trends in the industry by examining a variety of technologies, methods, and components being used by manufacturers to more efficiently deliver high quality products to patients. For example, think for a moment about what you see and hear now about sterile, disposable connection devices compared to what you saw and heard 3-5 years ago.
Single-use technology is not new, of course, but it certainly seems like it is more readily being deployed. Industry has long understood the benefits of utilizing single-use technology: ease-of-use, changeover, and potential cost savings. We all love the last part, right? Savings! The cost savings or effectiveness can be even greater for multi-product facilities. Reducing the amount of product-dedicated equipment and associated validation, cleaning, maintenance and storage issues leads to increases in efficiency and turn-around-time, resulting in decreased costs and shorter project timelines.
The gap that seems to have prevented some from moving toward implementation has narrowed. More specifically, the ease of implementing and leveraging single-use materials has gained traction because of innovation by the solution providers.
Solution providers have demonstrated the ability to provide a variety of ready-to-use, ‘customized’, single-use systems. Formulation vessels, filtration assemblies, and filling assemblies are not only able to be phase implemented because of their specific application, but these items can also be integrated easily with a little upfront design around quick connect devices. Additionally, on the formulation side, flexibility is included as you can go down to 10% of total working volume in a disposable mixing bag system.
The filling side is dynamic as well, as unofficially, it is estimated that 50-60% of the filling lines being delivered today are integrated with peristaltic pumps, which can be better incorporated with disposable product contact parts. We have moved from mostly discussing to actually taking action because the industry has qualified and is using single-use technologies. Gone is the fear of the unknown around sterility assurance.
Rotary piston pumps, time-pressure filling systems, and the occasional rolling diaphragm pumps have been the more traditional choices when it comes to automated filling technologies, but it seems peristaltic pumps are being favored for an increasing number of applications. As reliable as common rotary piston pumps have been, compared to other choices that have equal fill accuracy, the high cost of parts, cleaning requirements, and potential product handling make this filling mechanism a little antiquated for today’s consumers. Time pressure filling reduces some of the dedicated product contact parts, and is a flexible option given its ability to gently handle a wide range of products and viscosities. Peristaltic filling systems have attracted a renewed interest and focus given their ease of use/set-up, improved dosing accuracies, and disposable nature.
Barrier Isolator Technology
Over the past twenty years it could be argued that no technology topic has seen more discussion and debate than Barrier Isolators. What we know, based on these spirited evaluations is:
1. Restricted Access Barrier Systems (RABS) and Barrier Isolators provide a higher degree of assurance for aseptic filling compared to traditional cleanrooms
2. The lines between a cRABS and Barrier Isolator are becoming more blurred
3. Barrier Isolators provide the highest level of aseptic processing due to the validated decontamination cycles
4. While Barrier Isolators are very capital intensive to acquire, install, and validate, they are also the most cost effective solution when considering the reduced footprint required to build and operate, reduced environmental monitoring, reduced gowning costs, and personnel training.
Syringe tub configuration processing under barrier isolation. Photo: Cook Pharmica
Historically, the time required for decontamination in an isolator has been a drawback that limited the ability to reach processing times equal to that of RABS and other systems. In recent years, however, decontamination cycle times have been dramatically reduced. Just a few years ago, it was commonplace to have an isolator decontamination cycle take 8 hours or more. Now, large syringe and vial filling lines are fully decontaminated in 3-4 hours. And as the technology continues to improve in vapor hydrogen peroxide distribution and aeration; someday 3-4 hour cycles will seem long.
Ready-to-use materials and various co-polymer plastic containers seem to be generating the most interest on the component side of things. Whether discussing a small operation that does not have the infrastructure to wash, siliconize, and sterilize stoppers, or a larger scale manufacturing operation that focuses on the value added formulation and filling steps of parenteral manufacturing, suppliers have grown their repertoire in order to meet client's needs. There are other exciting developments coming in the future including ready-to-use vials, and even nested ready-to-use syringes. Think of the possibilities, particularly for the smaller volume products and the clinical trial supplies. Ever try to order a small quantity of vials with a higher quality level? Minimum order quantities can be large.
The use of plastic containers has always had its supporters and advocates. Depending on the product, extractables and leachables profiles can be improved with designer plastics. Tighter tolerances, less variability, and even reduced overfill is possible given the manufacturing process and co-polymer properties. For example, plastic does not wet like glass and everything drains to the bottom, so you can reduce your overfill and minimize waste. Overage can become expensive when making high-tech products. If you can cut your overfill by even a tenth of a milliliter over several batches, it can really add up.
There is more to the debate regarding glass versus plastic. Certainly, recall notices on delamination have garnered some attention over the years. Fewer particulates and complications from glass breakage, and product differentiation all have contributed to the consideration for plastic. As we see more expensive biologics entering the market, breakage becomes more of a concern. Time will tell if these or other reasons will drive products into plastics. In Japan, for example, it is already happening as plastic seems to be preferred over glass for biologic products due to its elegance and reduced container defects.
Although both ready-to-use and plastic containers promise advantages, they do come with a higher cost. The specific application, product type, product phase, end user – to name a few – are influences in the decision process.
Safety and Drug Delivery Technology
Pre-filled syringe technology has been around since World War II. The advantages of using pre-filled syringes are well known, and the growth of this sector stands at 7% to 12%annually. Future growth is predicted and pre-filled syringes are no longer exclusively used for specialty drugs.
As the use of pre-filled syringes has increased, so have the innovations in terms of safety devices and drug delivery systems. The current trend seems to be to moving toward automated safety mechanisms that are either assembled onto the syringe or auto-injector, or integrated into the syringe itself. This virtually eliminates the opportunity for the administrator or end user to incur a needlestick injury. Passive systems provide the best protection given the mistake-proof design.
With the clear trend towards the utilization of safety devices, companies also need to consider selection of a safety device to be of use across their portfolio of products to be outfitted with safety devices. This is because there is no standard platform for safety device assembly. Outside of a purely manual process, assembly automation is specific for each type of device. This poses a greater challenge for contract manufacturers and should be taken into consideration when seeking to outsource this activity. With assembly requiring an additional manufacturing step, we are now seeing innovations that incorporate the safety device in the syringe itself. This could be a major step forward in process efficiency. However, it remains to be seen how well these new syringes will fit into existing filling lines.
No one can say what innovations will arise in the coming years, but there are some interesting shifts and technologies in focus within the industry. Biologics and biosimilars growth are pushing boundaries and, in many cases, are creating a push for product differentiation and processing efficiency. A synergistic convergence of components, equipment technology, disposables, and innovations will be needed to make it all work.
Although opinions vary, what everyone can agree on is that the increasing pipeline of large molecule and injectable products, the maturation of branded products, and a changing healthcare system will continue to provide opportunity for innovation in aseptic processing and components that can have a meaningful impact on the industry’s bottom line and the health of patients.