Automation and modular designs are changing the way that pharmaceutical processors view containment, argues Felix Nink, Bosch product manager for capsule filling and checkweighing machines
Pharmaceutical development and manufacture gets more challenging as products become more complex, which makes clinical trials and drug production more difficult. To remain competitive, pharmaceutical companies need to develop products faster and more cost effectively. At the same time, they need to protect workers from increasingly hazardous drugs in both the clinical trials phase and during the manufacturing process.
To meet these trends, companies need to increase automation and flexibility within their facilities,* while separating operators from the production environment. Combining these initiatives within a single technology platform would enable companies to compete effectively.
Capsule filling sits at the crossroads of these trends, as companies seek safe, efficient methods of creating liquid and powder filled capsules, as well as tablets. Building capsule filling systems with fully integrated isolators for processing hazardous substances answers the growing need for researchers and manufacturers to be completely isolated from active substances during operation, maintenance, and cleaning. These systems have an array of automated processes and integrated isolators that minimise contamination due to human error.
Integrated filling systems with isolation technology preclude contact between operator and hazardous pharmaceutical substances more effectively than any other containment technology. Containment technology also eliminates the need for expensive and awkward air suits, masks and other safety equipment.
Pharmaceutical formulations are becoming increasingly more targeted in their applications. Many oncology drugs are designed to target only the effected cells. Such drugs tend to have larger molecules and are more potent and present a danger to operators.
Growth in biopharmaceuticals and anti-virals is also creating a demand for minimal dosage options due to their high potency levels. Dust created during the production of these drugs, which often have cytotoxic properties and contain hormones, can create a cross-contamination risk.
These volatile substances represent a growth market. There are 245 pure vaccines and 11 combination vaccines in development today. With fears of worldwide pandemics and large foundations funding vaccines on a global scale, this market is set to accelerate production in the near future. Only 10 years ago, a mere 5% of drugs were seen as highly hazardous, today nearly 30% of all active pharmaceutical ingredients are considered as such.
In addition, because the potency of a new drug is often an unknown, containment is a necessary precaution during the early clinical phase. Integrated isolation technology achieves this in a cost-effective manner. This approach also provides for equivalent production environments during scale-up.
Finally, pharmaceutical companies need the flexibility to change frequently from one product to another with minimal downtime. However, changeover requires thorough cleaning processes for safety and quality and often requires time consuming re-validation. Without automated cleaning processes, producers risk exposing workers to harmful substances or compromising quality - manual cleaning is just not a realistic or safe option.
These trends present significant opportunities to the pharmaceutical industry, but many of the solutions in today's market for dealing with them simply will not scale-up to tomorrow's needs. For example, many of these operations require workers to wear airtight protective suits. These suits are time-consuming to put on, can only be worn for a maximum of two hours, and a require shower before they can be removed. Even with these costly precautions, protection is not assured.
In other words, containment solutions are not all equal in terms of cost, flexibility, and opportunity for error. Moreover, these gaps in technology will become more acute as trends in potency and new product development evolve more rapidly.
For operator safety, levels of exposure are typically measured as occupational exposure limits (OEL) 1 to 5. An OEL Level 5 exposes workers to < 1µg/m3 of active products in workspace air over an 8-hour shift. Ideally, this level of OEL should be maintained consistently to ensure that no special protective clothing is required.
This goal can only be achieved through isolation technology. Unlike other containment methods, isolators seal off the production mechanisms at all times, i.e. during production, cleaning, and maintenance - planned or unplanned. Isolation is achieved through some basic principals in design. Air management is perhaps the most important aspect of isolation. With controlled air pressure, a controlled and filtered air supply and a vacuum unit separate from the machine system, harmful elements are kept out of the air supply around the production systems. Isolators also employ redundant sealing systems to ensure that, even if a sealing element fails, workers are still protected and the isolator environment maintains its integrity.
Of course, a sealed system is only the first level of creating an optimal isolation system. Different types of port systems are required for practical production. In capsule filling, for example, recommended interfaces for empty capsule in-feed requires an alpha/beta port while product in-feed requires a shutter system.
Worker interface can be solved via glove systems specifically designed so they can be changed and cleaned easily and sealed when not in use to prevent unnecessary contamination.
These are the basic elements behind isolation technology, yet it is really only the beginning - in order to gain the full advantage of isolation technology, automation is necessary.
Automating the production of pharmaceuticals further adds to maintaining high levels of safety and quality standards. Today's automation goes beyond simple production tasks, encompassing anything from cleaning through to troubleshooting to ensure maximum efficiency.
To increase accuracy, safety, and efficiency, many packaging, processing applications integrate Process Analytical Technology (PAT), the FDA's risk-based approach that enables high efficiency and quality assurance in pharmaceutical manufacturing by introducing inspection and controlling systems throughout the entire process. This is called closed loop control nothing advances to the next step unless a problem is either fixed or a faulty element is rejected from the system.
The industry offers an array of equipment that allows for effective in-line analysis and control of critical process parameters for filling capsules and liquid pharmaceutical products. Using solid capsule filling as an example, filling process quality parameters are monitored and controlled. In preliminary sorting, capsules of a sub-standard quality are identified and eliminated. Compressed air- and vacuum-monitoring units constantly check operating pressure and stop the system before malfunctions arise.
Spectroscopy technology is able to verify the active ingredient content, and the filling weight is monitored by a check weighing system operating in closed-loop control with the filling system to automatically increase or decrease the powder-dosing amount to match the correct specification.
Problems are not just identified; they are fixed along the way in a closed loop, which identifies faults before they can significantly increase downtime.
Automation of troubleshooting helps reduce downtime but it also ensures that the closed integrity of the isolation system is not broken during production. Postproduction cleaning can also be automated, further extending the benefits of isolation.
Automatic cleaning actually starts with eliminating unnecessary waste. Systems can employ a simple "no cap / no fill" function which means that the capsule filling function does not activate if a capsule isn't present. Another factor essential to automatic cleaning is all 316L stainless steel build, which allows the use of strong acids, caustic solutions and 80°C de-salinated water.
In addition, automatic cleaning employs a closed system of telescoping spray nozzles and drains. An entire sealed system can sit on a drain bevel with draining and suction. Various parameters can be saved, depending on the product being filled, and can then be loaded, resulting in a "one-button" cleaning process with repeatable results every time it is used.
The most common fear with a closed system is that it is rigid and cannot be easily accessed, upgraded or expanded. This does not need to be the case. Modular design is possible with filling systems integrated with isolators. Bosch's new GKF HiProTect features individual stations situated around a circular transport conveyor.
GKF HiProTect is suitable for a wide range of filling combinations, from powder, tablets, pellets to liquids. The machine is also upgradeable and additional stations can be easily added to accommodate future production needs making it adaptable to exact customer applications.
This level of flexibility is important in enabling the development of multiple products that are necessary in order to stay ahead in such competitive pharmaceutical markets. Government organisations, such as the FDA, are encouraging the use of isolators as a way to both protect pharmaceutical workers and ensure quality and integrity in the pharma production process.
As global pharmaceutical markets move from general treatment to highly targeted therapies and cures they are also becoming more hazardous, diverse, and individualised. To profit and still be innovative, pharmaceutical production will have to automate, isolate, and be flexible. Isolated capsule fillers ensure a quality product, safe work environment, and a profitable overall operation.