A flexible fill

Containment technology has emerged as one of the major trends in the processing and manufacture of pharmaceuticals. Part of the reason for this is continuous quality improvement. However, there has also been a trend leading to more active pharmaceuticals for more targeted applications as well as a rise in biopharmaceuticals and anti-virals, which are highly potent in nature.

Drugs, such as cytotoxic agents and hormonal applications, pose a higher health risk in the event of cross-contamination or dust exposure.

These substances are important 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 10 years ago just 5% of drugs were seen as highly potent - today nearly 30% of all API's are considered high potency.

In addition, the potency of a drug at the stage of clinical trials is, more or less, an unknown, which makes containment necessary for a wider range of pharmaceuticals.

As the need for containment technology grows, interest in isolators has also grown. These discussions have been fostered by positive information from the FDA and other organisations, which see them as a highly effective method of preventing cross-contamination. However, while the industry is embracing isolators, the technology has limitations if simply added to existing lines. Integrated isolation has the potential to increase efficiency, offer more flexibility, and improve the quality of the total process.

Bosch Packaging Technology has approached containment holistically in developing integrated isolation systems for capsule filling. The company recently introduced GKF HiProTect, a capsule-filling machine with integrated isolation for processing potent substances. The new machine answers the growing need of pharmaceutical researchers and producers to completely isolate operators from active substances during operation, maintenance, and cleaning. HiProTect does this through an array of automated processes and complete internal containment, which minimises contamination due to human error.

The system tackles the changing trends not through one technology, but through an integrated array of technologies and processes that take into account the entire landscape of pharmaceutical market trends. The key features behind the design of this modular system are: containment, flexibility, quality controls, cleaning, and accessibility. Moving beyond simply adding isolators to a filling line, HiProTect provides a quantum leap for processors and developers to meet the rising challenges in the marketplace.

micro-gram containment

Containment is a relative term depending on the material being handled as well as the goal for limiting exposure. The benchmark for this measurement is the Occupational Exposure Limit (OEL). While the requirements of OEL's vary, Bosch's goal with HiProTect was to offer the highest level of operator protection <1µg/m3 of active products in workspace air over an 8-hour shift. This level of protection depends on the product and must be validated with individual materials, however, its very high standard is achievable with the system. This is accomplished through highly reliable interfaces, by allowing intervention in the production processes, and safe and quick filter changes.

Air management is key to the success of such a system. By creating a vacuum in the production area with an overpressure in the machine area, air is managed as well as particles of the material being filled. In addition to this, a sealed cabin incorporating several internal control mechanisms protects operators. This includes an inflatable rubber gasket as well as a redundant passive gasket at door openings to ensure the integrity of the seal.

HiProTect also provides for flexible interfaces depending on the OEL requirement. These include Alpha/Beta ports, shutter systems, and tri-clamps each adaptable to different functions. For example an empty capsule infeed would use an alpha/beta port while product infeed would use a shutter system and the lock out of parts would require an RTP port.

Of course, a completely sealed system that did not take into account maintenance or intervention would hardly be realistic. Gloves for intervention during production are necessary in most isolators. The HiProTect system is no exception, providing glove access strategically throughout the modules. Gloves ports are planned so as to not interfere with the production section. In addition, gloves do not get contaminated if they are not in use. All of these measures minimise the glove exposure to contamination streamlining cleaning and maintenance.

HiProTect also features a Push-Push filter change system to ensure streamlined filter changes with no exposure to harmful substances. The system features two filters one behind the other. The contaminated filter is pushed out in the containment system by the new filter. This simple system minimises downtimes and ensures a closed system at all times.

Process automation

Quality control through automation is possible through two different methods. One is automatically checking quality and making necessary corrections. The other method leverages automation to provide more consistent and thorough cleaning.

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, HiProTect integrate Process Analytical Technology (PAT). This is the FDA’s risk-based approach which improves 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.

monitored quality

Integrated PAT 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 Near Infrared (NIR) system verifies 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.

HiProTect features a particular philosophy of weight controls. Using statistical gross and net weights in addition to 100% net fill weights of all produced capsules ensures at different station fully leverages HiProTect's modular construction. In addition to weight checks, HiProTect also offers the option of a spectroscopic measurement which shows the absorption band of a given molecule vibration for a given frequency range. These results can be compared with reference data for more precise quality control.

Automation of troubleshooting helps ensure reduced downtime but it also ensures that the closed integrity of the isolation system is not broken during production. Problems are not just identified; they are fixed along the way in a closed loop, which identifies faults before they can significantly reduce downtime.

flexible options

Economic factors require greater flexibility in product output. Flexibility provides not only for the changing nature of markets today, but an ability to increase production or change product categories quickly.

For capsule filling this means an ability to quickly switch between fill combinations or add capacity as business evolves. These fill combinations include pellets+powder, tablets+powder, tablets+pellets, pellets+pellets for example. In addition hard gel and all other capsule types such as HPMC can also be filled.

Combination filling is made possible by HiProTect's modular design, which is fully expandable to adjust to the changing needs of the marketplace.

Postproduction cleaning can also be automated by 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.

Another feature essential to automatic cleaning is an all 316L stainless steel construction, which allows cleaning with strong acids, caustic solution, and 80 degree C desalinated water.

In addition, automatic cleaning employs a closed system of telescoping spray nozzles and drains. The entire sealed system sits on a drain bevel with draining and suction. Various parameters can be saved depending on the product being filled. All of these elements result in a 'one-button' cleaning process with repeatable results every time it's used.

The benefits of HiProTect's automated cleaning are reproducible results, isolation of the machine from the operator, and all parts remaining safely in the cabin for the cleaning. These verifiable results mean safer operation and consistent quality.

added protection

As containment becomes more of an issue, isolators are increasingly being encouraged by government organisations such as the FDA who see them as a way to both protect pharmaceutical workers as well as ensure quality and integrity in the pharmaceutical production process.

As global pharmaceutical markets move from general treatment to highly targeted therapies and cures, the materials are also becoming more potent, diverse, and individualised. To profit and still be innovative, pharmaceutical production will have to automate, isolate, and be flexible. This ensures a quality product, safe work environment, and a profitable overall operation.