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Adoption of single-use systems and more flexible systems drive innovation.
The major purpose of aseptic manufacturing equipment is to ensure the production of products that are free from contamination. As drug products become more potent, workers must be protected as well. The use of new barrier technologies, the introduction of greater automation and single-use technologies, and the development of more efficient systems are helping pharmaceutical manufacturers maintain safety and quality while increasing productivity and reducing costs. Christian Treitel, head of business development for pharma with Bosch Packaging Technology, Matthias Poslovski, technical sales director at Optima Pharma, and Tim Kram, general manager of Rommelag USA spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about the key attributes of effective aseptic-filling equipment and drivers for recent and future advances in the technology.
Flexibility with risk minimizationPharmaceutical Sciences, Manufacturing and Marketplace Report: What are the top qualities that pharmaceutical companies are looking for in aseptic-filling equipment for parenterals and why are these characteristics important?
Poslovski (Optima): The requirements placed on aseptic-filling machines depend heavily on the product being processed. Generally speaking, however, the safety of operators and patients always ranks at the top. For instance, when dealing with toxic products, suitable barrier systems, such as isolator technology or closed restricted access barriers (cRABS), are a must. Very high-priced products demand techniques such as 100% in-process control to continuously optimize filling accuracy so that the product batch is nearly fully utilized. On the other hand, very small batch sizes require extremely flexible facilities. In cases where further technology, such as freeze-drying systems, need to be integrated, the turnkey expertise of the machine builder is in great demand.
Treitel (Bosch): Pharmaceutical companies are looking for safe and flexible equipment for their varying aseptic-filling processes. Advances in oncology and immunology have led to an increased use of highly potent and cytotoxic substances.
When high-potency pharmaceuticals are used, manufacturers must pay more heed to protecting both the product and all persons involved in the production process, which adds significantly to the complexity in manufacturing, as processes have to be defined early and concepts must be fit for implementation.
Flexibility is also necessary for the pharmaceutical industry as batch sizes decrease and more fill-finish operations are performed by contract manufacturing organizations (CMOs). The equipment must be applicable not only for current but also for future products and containers.
Kram (Rommelag): Customers want to have consistent and reliable production capabilities and minimize risk by controlling all of the components that go into the production of parenteral products. Aseptic-filling systems need to have high overall efficiencies with only scheduled maintenance. Blow/fill/seal technology is a highly automated process that does not require regular operator input and has very high overall equipment effectiveness (OEE).
With blow/fill/seal technology, the raw plastic resin from which the containers are formed is the only material that must be supplied that is not found in a normal aseptic facility, which minimizes the supply chain and on-site storage requirements that are associated with systems that use pre-formed glass or plastic containers.
Advanced barrier technologyPharmaceutical Sciences, Manufacturing and Marketplace Report: What recent advances have been made with respect to aseptic-filling equipment used for parenteral drug formulations, and what have been the drivers for these advances?
: Barrier technology is becoming increasingly important because it allows fully enclosed, sealed, and pressurized units completely separated from the operators. It also offers far greater sterility assurance than conventional cleanrooms and can significantly lower costs associated with more traditional fill–finish methods. The processes for production with isolators have also been refined. More and more customers are building up experience for daily work with isolators and generating additional output at lower cost.
The other big advance is the introduction of single-use components. When processing biotech products, the cleaning and validation of parts is an expensive and time-consuming procedure. Single-use components decrease the cleaning time, validation efforts, and save considerable costs.
Kram (Rommelag): Advances in blow/fill/seal technology have focused on three primary areas: compatibility, efficiency, and automation. It is important to adapt blow/fill/seal systems to better allow sensitive products to utilize the technology. Two examples include the development of a cool-filing process for heat-sensitive biotech products, such as live attenuated vaccines, and coextrusion technology to place barriers into the container walls for products that are gas-(i.e., oxygen, CO2) sensitive.
With respect to efficiency, customers like to have larger systems that allow for better cost of goods and lower overall operating costs. With recent developments, it is possible to achieve a return on investment in six to eight years when only considering the raw-materials savings over traditional systems.
Automation, meanwhile, helps achieve the major goal of aseptic manufacturing, which is the production of products free from contamination. The primary source for that contamination is people in and around the aseptic systems. Therefore, raising the automation level helps minimize the interventions that are necessary into and around the blow/fill/seal process.
Poslovski (Optima): There have been many innovations and developments to increase the flexibility of machines, especially for new biopharmaceutical drugs and small batch sizes, such as using up to three different dosing systems (e.g., rotary piston pumps, peristaltic pumps, and time pressure). Modular concepts are also relatively new in the pharmaceutical industry and make it possible to alter functionality or increase performance. For safety devices that protect against needle-stick injuries, for example, flexible assembly systems that can also process backstops are available. In addition, robotic technologies are increasingly used for flexible processes.
Separately, disposable tanks, pumps, hoses, and filling needles are frequently used today when processing highly potent ingredients, which helps minimize the risk of cross-contamination.
The benefits of PATPharmaceutical Sciences, Manufacturing and Marketplace Report: Does process analytical technology (PAT) have a place in aseptic-filling processes, and if so, what are equipment manufacturers doing in this area?
Poslovski (Optima): There are different aspects to process analytical technology, such as 100% in-process control, optical control for stoppers, and crimp quality control, and glass surfaces are often monitored for scratches and damage. There is also a trend to use early controls because rejecting a container due to an imperfection after filling would mean discarding a potentially high-priced product.
Other aspects include the software analysis methods that are specially developed for filling and packaging machines. The OEE of machinery can be determined, and areas that might cause downtime can be identified in many cases.
Treitel (Bosch): The main goal of PAT is to ‘build quality into products’ instead of inspecting quality after the product has already been manufactured. Equipment manufacturers are developing in-process technologies that closely monitor all process steps. In larger lines, dozens of parameters are monitored, and corrections are triggered, for instance through temperature control of the sterilizing tunnel, or sophisticated in-process control of net weight at high speeds. The residual oxygen level after gassing is also monitored, and feedback loops are established.
In parallel, we still see the need for inspection of parenterals for particles and cosmetic container defects at the end of the production process. Manual, semi-automated, or fully automatic inspection machines are used to ensure 100% quality of the pharmaceutical products
Kram (Rommelag): Rommelag has recognized this need for real-time automated inspection capability, and in response has developed a system that enables measurement of the critical quality attributes (CQA) of final containers. The results are then used as feedback parameters to control the critical process parameters (CPP) in the blow/fill/seal system.
Looking aheadPharmaceutical Sciences, Manufacturing and Marketplace Report: What issues remain that have not yet been addressed? What are parenteral drug manufacturers looking for in the next generation of aseptic filling equipment and why?
Kram (Rommelag): Aseptic product quality standards and regulatory requirements are ever increasing. Processes for the filling of products into glass containers struggle to increase their speed and efficiency while at the same time overall glass quality seems to be decreasing (size specifications, cracks, chips, beads, and delamination). Fortunately, inspection systems developed to prevent the release of unacceptable products continue to improve in ability and speed. In fact, better and new inspection methods are being developed by many companies.
Treitel (Bosch): Every drug manufacturer will always be searching for faster, more efficient and cost-effective machinery. Equipment manufacturers will continuously be challenged to fulfill these requirements. Rising cost pressures in production will also press manufacturers to further improve productivity with respect to OEE while still offering the highest quality possible.
The optimization of machines in terms of flexibility, automation, easy changeover, and scale-up also enables manufacturers to develop new drugs and bring them to market more rapidly, while still complying with strict regulations. One big challenge we see is to support our customers in handling flexible equipment while gaining high OEE as well as achieving even higher outputs with our barrier systems.
Poslovski (Optima): We believe that there are two areas that promise increasing potential for plant operators. On the one hand, line flexibility can be further developed. If the line flexibility can be successively increased, the productive time and profitability of an investment can be further enhanced. In addition, plant availability can be improved. Time-consuming processes, such as cleaning-in-place and sterilization-in-place with high temperatures that require a subsequent cooling phase and isolator decontamination cycles, are examples of nonproductive down times that need to be minimized.
Customer-driven solutionsPharmaceutical Sciences, Manufacturing and Marketplace Report: What are equipment manufacturers doing to try and overcome these issues? What new technologies are on the horizon?
Kram (Rommelag): Blow/fill/seal technology produces a new container that inherently does not have the quality problems that are found in glass, but BFS containers are still required to meet the same inspection requirements driven by glass containers. This situation is specifically the case with injectable products. The optical qualities found in the plastic resins used in BFS containers limit the ability to accomplish vision-based inspections systems. There are several near-term inspection solutions being developed with better camera systems linked to more computing power and new higher-energy inspection methods. From the container-manufacturing side, Rommelag is working to introduce plastic resins with better optical qualities.
Poslovski(Optima): Robotic technologies are increasingly finding their way into pharmaceutical engineering. Processes can be flexibly designed to transport containers through equipment or for handling, assembly, and other functions. As an example, the liquid level in aseptic containers must remain constant, and this need creates an important opportunity for robot transport functions for unsealed containers, such as the new robot control for the handling pharmaceutical liquids that Optima Pharma developed.
Catalytic aeration, a technology also introduced by Optima Pharma, has been successfully tested and implemented as a retrofit solution for existing isolators. It significantly reduces non-productive downtime (by up to 50%) because the aeration phase is the most time-consuming cycle during H2O2 decontamination.
Treitel (Bosch): Bosch Packaging Technology is working on innovative solutions for higher productivity combined with the highest quality and flexibility. Improved processes, easy handling, and reduced product loss are the main focuses of our development teams. We combine proven technologies with new promising approaches to provide drug manufacturers with short time to market and flexible machinery.