Introduction

Highly potent active pharmaceutical ingredients (HPAPIs) represent significant innovation for pharmaceutical companies in preparing new medicines for patients. They employ new, small molecules which are active in lower doses, with reduced side effects. A significant proportion of new active ingredients under development will be classified as highly potent, suggesting an increase in the therapeutic efficacy of these products. While most of the HPAPIs will be used as anti-cancer, others may be classified as hormones, narcotics, and retinoids.

The introduction of highly potent APIs incurs new manufacturing problems and challenges. Indeed, containment of highly potent APIs in a pharmaceutical manufacturing environment has not always been compatible with efficiency. On top of that, as it involves hormones and cytostatic drugs, HPAPIs production can have carcinogenic or mutagenic effects to exposed operators. They should therefore be handled with specific precautions.

While containment technology provides necessary safety features for operators and the environment, it has historically added complexity, time, and inefficiency to manufacturing processes, and was typically batch oriented. However, recent advances in containment on pharmaceutical process equipment based on streamlined design and automation have made containment features more efficient and capable of running on continuous production lines.

Ideally, these add-ons perform their safety duties without interrupting overall production workflow. Generally, it can be assumed that high containment features added to process equipment do not improve the process in any way and, conversely, may have at least a minimally adverse effect on production. Logic dictates that creating one or more barriers or safeguards to protect operators may restrict or complicate certain equipment operations.

Of course, any potential impediments have huge upsides. The first, of course, is safety. Another is freedom of movement: these barriers usually allow the operator to work in the production room without full PPE and respirators and can help reduce other production site containment measures that might otherwise be necessary.

Containment Features

Let’s discuss the types of containment barriers typically utilized on two of the pharmaceutical industry’s most prominently used equipment categories: tablet presses and complementary tablet dedusters.

• α/β split butterfly valves can be connected on inlet and outlet ports of tablet presses or dedusters. These valves allow disconnection and reconnection in a contained manner. When disconnected, the outer surfaces of the valve remain clean while its inside is contaminated; some come with liners for easier disconnection.

A drawback is that, since they are typically stainless steel, α/β split butterfly valves tend to be quite heavy and require adequate support, often in the form of a dedicated cart or support arm. To counteract this pitfall, lighter, semi-disposable versions of split butterfly valves comprised of sanitary polymer have been introduced in the last few years and are starting to be installed more frequently on process equipment. In addition to being significantly lighter, the polymer solutions eliminate the need for cleaning and are substantially less expensive.

• To avoid the need for operator intervention when monitoring metal check operating by manually inserting test tablets, Pharma Technology has developed a unique automatic testing system for metal detector. Integrated into Ceia or Lock brand metal detectors, our patented Auto-Check automatically inserts the three test balls (stainless steel, ferrous, and non-ferrous) into a separate chamber through the metal check at regular pre-set interval. This exclusive solution eliminates any risk of containment breaches by automatically shutting down the deduster and tablet press if the detection test fails.

• Automated pinch valves are used on inlet and outlet ports that, typically, do not require frequent disconnection. They contain the API inside the equipment’s contaminated area and can only be disconnected after a Wash In Place (WIP) cycle has been performed on the machine. This type of solution is often supplemented by interlocked pressure decay tests, which create a vacuum inside the machine for a specified duration of time prior to startup to check all valves and connections are correctly attached and positioned. This helps make sure there will be no leak from the process equipment prior to introducing the API onto it and starting the manufacturing process.
• Closed tight-fitting silicone connections between tablet presses and ancillary dedusters, metal detectors or diverters help ensure securely contained transfer of tablets also the production line and must be cleaned via WIP system prior to opening to prevent operator exposure. Usually, they are secured at either end by retaining clips.
• For metal detectors specifically, closed round silicone chutes help ensure contained transfer throughout the inspection process. Most metal detectors come with two-part Perspex chutes that cannot be closed easily for containment purposes. By contrast, Pharma Technology has specifically designed a one-piece closed chute connected in a containment manner at both ends, facilitating containment by avoiding tri-clover clamp connections and additional seals.

• Airtight seals on a metal detector’s reject assembly window also helps ensure containment. These seals are generally compressed into grooves in the stainless-steel portion of the reject assembly and are glued in place inside a groove on the window. This is so they cannot be lost and do not require refitting with each assembly.
• Rejected or sampled tablets are then collected into a continuous liner instead of a bottle. The liner is coiled onto a polymer stump underneath the metal detector reject assembly, where a collection bottle would normally be placed. The liner can be pulled down to a suitable length and is either clipped or heat sealed before starting production, providing an airtight bag that securely collects rejected tablets. At the end of a batch, the liner gets clipped, or heat sealed again, creating a contained bag with tablets inside.

• Operating equipment under negative pressure inside the processing chamber helps ensure that no API escapes. Here, continuous negative pressure monitoring by a sensor inside the process chamber is used to automatically close valves should any internal positive pressure be detected. For additional safety, the split valves on a deduster’s air inlet ports can be supplemented by a two-way Hepa filter. Automated pressure decay testing may be considered after equipment assembly, to ensure containment before potent drug manufacturing. This well-known testing method takes only a few minutes and guarantees operator safety and document traceability.

• A Wash In Place (WIP) system with all connections for cleaning media already piped in and connected helps run a complete wash cycle at the push of a button at a batch’s conclusion. Even if the wash does not remove 100% of the residual API inside the tablet press or deduster, any residual material will be wet and can therefore be safely cleaned away by the operator without having to wear PPI.

Following a WIP cycle, the equipment still needs to be opened, wiped down with alcohol in some areas and then air dried before it can be swabbed. Clean In Place cycles have received attention in the pharma industry, but have never been truly achieved on tablet presses and dedusters due to an inherent limitation; namely, this type of process would restrict drying as the equipment would never be opened.

• Isolators allow placement of a complete piece of process equipment inside an airtight box, which is rated for a certain level of containment with access via strategically placed glove boxes and Rapid Transfer Ports (RTPs). The isolator is a complete barrier enclosure and is usually maintained under negative pressure by means of a dedicated vacuum dust collection unit.
• Dedicated vacuum dust collection units for high containment are usually placed in the process room to ensure that API residual material is collected where it has been processed – in other words, that it does not migrate. Dust collected via this process does not travel to a central dust extraction system that collects powder for the whole plant or area. Rather, these dedicated vacuum units typically come with Hepa filtration, bag in-bag out systems for filter change and contained double bag systems for powder collection.

Amazingly, this is only a partial list of possible containment components and solutions. With so much to consider, it’s important to stay focused on an overarching principle: It’s a big game of keep away. The fewer potential touchpoints between operator and API, the safer – and, by definition, the more automated – the production process.

Conclusion

Fortunately, containment features on process equipment are becoming increasingly modular and are no longer mere clunky afterthoughts that get bolted on. Some of these features can be added to or upgraded on existing equipment. Other features get integrated into the design of the equipment from the beginning.

Some tablet dedusters, for example, can be supplied as standard dust tight units that can be upgraded at any point in the future to OEB 3 or even OEB5 containment levels. The fully enclosed design of the standard version keeps the API inside regardless of requirement level. This is achieved by adding pre-determined modules onto a base machine already prepared and designed with high containment in mind – such as a set of high containment inlet or outlet valves, or a WIP cart – that directs all water distribution inside the machine, including cleaning media supply, flooding and spraying, and drainage upon wash cycle completion.

Running a WIP cycle on a tablet press or deduster, however, means that some manual intervention is still needed to finish off the cleaning process. Typically, tablet presses or dedusters must be opened after a WIP cycle to be dried and swab tested. Again, the benefit of the WIP cycle is that it normally removes most of the API to which operators should not be exposed and wet any residual API to the point that it cannot become airborne. With such a WIP system, operators no longer need PPE or respirators when performing final cleaning operations.  Going one step further, when using other process equipment such as fluid bed driers or pan coaters, it is possible to run a complete CIP cycle that includes drying and swabbing of product contact surface areas inside. Limiting operator exposure is not simply a question of using physical barriers between the product and the operator, it is also rethinking the process to reduce or remove operator intervention. If the equipment can be automated to run and be cleaned remotely without operator intervention in the room, then any potential for exposure is de facto reduced and the equipment can be used for continuous manufacturing.