In order to meet these trends cost effectively, many pharmaceutical companies will need to increase automation and flexibility within their facilities while separating the production environment from operators. Combining these initiatives within a single technology platform is making it economically feasible to meet these challenges and still 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. As issues of potency, efficiency, and a need for greater flexibility arise, the industry is looking toward technology suppliers for solutions.

Building New capsule filling systems with fully integrated isolators for processing potent substances answers the growing need for pharmaceutical researchers and manufacturers to be completely isolated from active substances during operation, maintenance, and cleaning. These systems do this through an array of automated processes and integrated isolators which minimize contamination due to human error.

Integrated filling systems with isolation technology eliminates contact between operator and potent pharmaceutical substances more than any other containment technology. Containment technology also eliminates the need for expensive and awkward air suits, masks and other safety equipment.

Changing Markets

The pharmaceutical market landscape is changing quickly. Pharmaceutical formulations are becoming increasingly more targeted in their applications. For example, many oncology drugs are designed to target only the effected cells. These types of drugs tend to have larger molecules and, thus, are more potent, and present a danger to operators.

In addition, growth in biopharmaceuticals and anti-virals is creating a demand for  minimal dosage options due to their high potency levels. These drugs, which often have cytotoxic properties and contain hormones, have a high risk of cross-contamination from harmful dust exposure.  

These volatile substances are also growth markets.  In fact, 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 ten years ago just 5% of drugs were seen as high potency, today nearly 30% of all active pharmaceutical ingredients are considered high potency.

In addition, the level of potency of a drug during clinical trials can be uncertain.  Containment is thus a necessary precaution during the early clinical phase.  Integrated isolation technology achieves this optimally while doing so most cost-effectively and allowing for equivalent production environments during scale-up.

Finally, pharmaceutical companies need to be flexible changing from one product to another with minimal downtime. However, changeover requires thorough cleaning processes for safety and quality and often time requires 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 rising 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 to tomorrow's needs.    For example, many of these operations require worker to wear airtight protective suits.  These suits are time consuming to wear, can only be worn for a maximum of two hours, and 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 chance for error.  Moreover, these gaps in technology will become more acute as trends in potency and new product development evolve more rapidly.

Goals in Containment

For operator safety, levels of exposure are measured in OEL Levels.  OEL or Occupational Exposure Limits are measured from a level of 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 worker protection clothing required.

This goal can only be achieved through isolation technology. Unlike other containment methods, isolators seal off the production mechanisms at all times, e.g. 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 suction 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 sealing elements fail, workers are still protected and the isolator environment retains 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 specially 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 Containment

Automating the production of pharmaceuticals further adds to maintaining high levels of safety and quality standards.  Today's automation goes beyond simple production tasks.  From cleaning to troubleshooting, many complex tasks can ensure maximum efficiency.

To increase accuracy, safety, and efficiency, many packaging, processing applications integrate Process Analytical Technology (PAT). PAT is 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, 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.  A 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 reduced 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 doesn't activate if a capsule isn't present.  Other functions essential to automatic cleaning is all 316L stainless steel production, which allows cleaning with strong acids, caustic solution, and 80 degree 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.  These saved parameters can then be loaded, resulting in a 'one-button' cleaning process with repeatable results every time it's used. 

Flexibility is Key

The most common fear with a closed system is that it is rigid and cannot be easily accessed, upgraded or expanded upon.  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 conveyor. GKF HiProTect is unique on the market because it 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 to staying ahead of competitive pharmaceutical markets where multiple products in development are necessary to succeed in clinical trials and in final production.

Containment on the Rise

As containment becomes more of an issue, Isolators are increasingly being encouraged by government organizations such as the FDA who sees them 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 potent, diverse, and individualized.  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.