Jan Vogeleer

The main challenge for tablet manufacturers processing highly potent APIs (HPAPIs) is to protect equipment operators from the inhalation of airborne particles and prevent skin contact with the product during the entire production process: dispensing, granulation, tablet compression, coating and packaging.  

One of the earliest solutions was the use of air suits, but these are not at all ergonomic and protect only the operator. A tremendous amount of cleaning is also still required; all process equipment is contaminated, as are the processing rooms and corridors. Furthermore, in most Western countries, health and safety laws only allow personal protective equipment as a last resort. 

To that end, isolators were introduced, which got the operator out of the air suit and reduced the amount of cleaning work. Operations, from dispensing to packaging, were integrated into large, sophisticated and highly contained isolators. However, as well as requiring large amounts of space and being impractical in terms of cleaning and product changeover, this solution quickly proved to be very expensive. WIP and CIP capabilities were integrated as much as possible, but this made installations even more complex. Moreover, in many cases, such isolator technology proved to be excessive in relation to HPAPI containment and the concentrations being processed.  

One newer, more cost-effective and practical approach is to design inherently closed process equipment using 'containment at the source'. With this technique, the section of the machine in contact with the product is small and carefully isolated from both the electromechanical part of the machine and the environment. Additionally, it is easy to clean without breaching containment.  

A more rational approach can also be adopted towards containment requirements in the various production stages. Indeed, the containment level required of equipment used at the dispensing stage (where the material handled is pure HPAPI in powder phase) is different from that needed in tablet coating (where the HPAPI is diluted and compressed into a tablet). The concentration of airborne API particles also varies during the different operational steps of the tablet production process. The only correct way to assess risk and determine the appropriate containment level for the various process steps/equipment is to calculate real daily intake (RDI) and compare this with the allowable daily intake (ADI).  

Tablet presses for highly potent drugs need to have a compression zone that: 					

 is highly isolated from the remainder of the machine

contains the smallest possible number of mechanical components (in no case should it contain the cam tracks or compression rollers)

features automatic underpressure monitoring and control

is easily removable from the machine for fast product change-over

can be washed down off-line without breaking containment. 			

These requirements also apply to downstream equipment, including the tablet deduster, metal detector and the automatic tablet sampler (and tester).			

The feeding of powder into the tablet press and the collection of tablets into drums or intermediate bulk containers (IBCs) also need to be conducted in a contained way. I recommend split butterfly valves as a solution to achieve this because such valves offer the requisite containment level, and allow for reliable and fast connection and disconnection, while maintaining  containment. In view of this, a highly integrated solution is preferable from powder in-feed to tablet collection, with high-containment interfaces and connections between them. 

With a growing number of increasingly potent new APIs often targeted at specific niche therapeutic applications, the pharma industry will need flexible medium- to small-scale, highcontainment tablet presses that enable swift product changeover with no risk of product cross-contamination. It follows that future design improvements for potent tablet manufacturing equipment will focus on these trends.  

Articles

The main challenge for tablet manufacturers processing highly potent APIs (HPAPIs) is to protect equipment operators from the inhalation of airborne particles and prevent skin contact with the product during the entire production process: dispensing, granulation, tablet compression, coating and packaging.

Ensuring Tabletting Safety For High Potency APIs

The market for tablet compression technology and the demands placed on equipment manufacturers have changed quite significantly in recent years. This has been driven by a number of factors. Firstly, the pharmaceutical industry has seen a significant shift of investments in solid dosage production equipment towards generics and contract manufacturing. As the companies in this segment of the market are, by nature, strongly focused on cost reduction, a big emphasis is placed on productivity, flexibility and process yield (i.e., minimal product loss). Equipment cost and reliability, as well as fast on-site assistance have also become key selection criteria. research and development based companies have also been forced to follow this cost reduction trend.

Secondly, the meteoric growth of new pharmaceutical markets in the Middle East and the Far East (e.g., India, China, South Korea) has led investments in solid dosage equipment in these regions to surpass the investments made in North America and Europe. This puts an increased pressure on equipment price and has resulted in several Western based companies moving the design, manufacture and assembly of their equipment to Asia.    

 Jan Vogeleer. Managing Director at GEA Courtoy.

Finally, with the increased potency of new APIs, there is a growing need for better protection of the operator against the effects of pharmaceutical product processing. Operator exposure can be reduced either through the use of Personal Protective Equipment (PPE) or by making the equipment highly contained. The latter approach is the preferred solution, primarily for ergonomic reasons and because it offers a more efficient way of protecting the environment in general, as well as the facility and other personnel. 

Although the operating principle and fundamental design of the rotary tablet press have not changed for decades, multiple machine design improvements have been developed and implemented by various suppliers to reduce cost and lead time, and more importantly, to increase productivity, flexibility and safety performance.

The initial emphasis of innovation was on reducing the amount of time required for machine cleaning and product changeover. The first significant change was the “exchangeable turret”, introduced to the market by Fette in the early 1990s and now available from nearly all suppliers. While this machine feature offers great flexibility with regard to the tooling types that can be used on the same machine, the time saved for cleaning and format changeover is limited; after removal of the turret, the complex inside of the tablet press still needs to be cleaned. Therefore, openness of structure and accessibility were further improved (e.g., the XL range by Korsch). Taking a different approach to the challenge, IMA came up with a revolutionary design without exchangeable turret, but with centrifugal die filling and Clean-In-Place capability. Whilst in early 2000, GEA Courtoy introduced the “Exchangeable Compression Module", a concept that made extremely fast product changeover possible thanks to off-line cleaning, and also offered n increased level of dust containment compared with conventional removable turret machines. 

In more recent years, various improvements in machine designs have been made to increase the instantaneous output of tablet presses. To achieve this, it was necessary to enhance the efficiency of the forced paddle feeders to guarantee uniform die filling — and consequently tablet weight stability — at these higher outputs. The next step was to increase the number of punch stations on the turret (e.g., die plate segments by Fette; exchangeable die disc with die shells by GEA Courtoy) and/or to increase the rotation speed of the turret. When increasing the rpm of the turret, the compression dwell time for each individual tablet shortens, often resulting in insufficient hardness, capping or lamination. Methods that have now been developed to maintain a longer dwell time include air compensation and, to a lesser extent, larger compression rollers and punches with special head design. 

The last 10 years have also seen a significant effort to design complete tablet production lines to handle potent and toxic drugs. As the powder in‑feed, tablet handling, sampling and tablet collection all have to be performed under “high containment” conditions, it became imperative to design complete lines integrating the peripheral equipment, such as powder discharge station, tablet de-duster, metal detector, dust extractor and tablet analyser. Initially, the most common technique was to build isolators around the equipment and provide wash-in-place capability. However, the latest design trend is toward containment at the source and off-line washing, as these concepts allow equipment to be smaller, easier to install and operate, and lower priced. 

The main shortcoming of modern tablet presses is their lack of advanced process control. Most tablet presses are equipped with only one feedback control loop, which is based on main compression force measurement as an indirect estimation of tablet weight. Re-correction of this loop is achieved through tablet sampling: 20 tablets every 15 to 30 min are sampled while the machine runs at 200000 tablets/h. This naturally calls into question the statistical relevance and accuracy of this method. Only very few new methods of process control and new types of sensors are being offered for on-line monitoring and controlling of other tablet CQAs, such as hardness, API content and dissolution time. 

In its continuous quest for cost reduction, the pharmaceutical industry will continue to push for a further increase in operational efficiency. This can be accomplished through higher speeds, faster cleaning and product changeover, and fully automatic unmanned operation. Flexibility will also be developed further as the complexity of tablets increases, with the emergence of special tablets, such as multiple-layer tablets and core-coated tablets. 

But most of all, future developments should focus on advanced process control to guarantee improved and constant tablet quality. This is one of the basic requirements to help realise two crucially important new concepts, which will shape the future of solid dosage production: continuous processing and real-time release. The implementation of new control strategies and the implementation of new types of sensors into tablet presses are vital means to this end. With the advent of promising new devices such as NIR sensors, progress is being made, but these are just the early stages of the new developments that are required. 

The market for tablet compression technology and the demands placed on equipment manufacturers have changed quite significantly in recent years. This has been driven by a number of factors.

Tablet compression: changing trends, more demands

Intense pressure from governments regarding health care costs, increasing competition from generics manufacturers, and escalating research and development (R&D) expenses are forcing pharmaceutical companies to review and significantly reduce their costs. Consequently, the industry is witnessing continuous merger and acquisition (M&A) activity,1 aimed at consolidating the enormous R&D costs, and increasing efficiency in the manufacture and distribution of pharmaceutical products.	

As part of corporate cost-cutting measures, some tabletting facilities have closed and tablet production is now concentrated at a limited number of plants. Striving for ultimate efficiency, these remaining facilities must be able to handle greater volumes of more varied and more potent products in smaller batch sizes; at the same time, stocks (products in production and finished goods) and lead time must decrease, whereas flexibility to market demands must increase. These issues can be grouped into three areas:	

total cost of ownership (TCO) of the production plant; that is, the total cost per produced unit

flexibility, allowing quick reaction to external factors such as sudden market changes

containment of potent drugs for maximum operator safety and environmental protection

The TCO approach is being increasingly used by pharmaceutical manufacturers when selecting new equipment because it takes into account the real total cost of operating process equipment per unit of production. This total unit cost is the only true basis for comparison. Not only does it consider the capital investment of the equipment, but also:

its overall productivity, based on the downtime of the machine for cleaning, product changeover, maintenance and repair

the space required for installation and operation

the staff required to operate the equipment

The cost of equipment such as air conditioning, cleaning and clean rooms, is often underestimated and manufacturers should, therefore, consider fewer or smaller pieces of equipment.

Considering each of the three issues listed previously; for minimal TCO, a machine with a high instantaneous output and minimal downtime (high reliability and quick cleaning) is required. To achieve maximum flexibility, a machine that can changeover from one product to another easily and quickly with minimal risk of cross-contamination is required. For maximum containment, a machine that is completely isolated and sealed, ensuring operator and environment safety, is required.	

 Figure 1:  A Courtoy MODUL rotary tablet press.				

The concept of the exchangeable functional module (EFM) came to fruition after searching for a single solution to all three issues. An EFM can be described as part of a piece of process equipment that 	

contains all product-specific format parts

contains all parts in contact with the product

can be isolated from the remainder of the equipment

can be easily and quickly installed or removed

Using multiple EFMs, it is possible to simultaneously achieve quick product changeover in a completely contained way. The use of product-dedicated EFMs even eliminates the risk of cross-contamination. Removing all product-contaminated parts from the equipment eliminates the cleaning operation, which can then be performed off-line without impacting on downtime in a dedicated area.		

  Figure 2:  The ECM inside the tablet press.

The EFM concept has been developed and integrated into a rotary tablet press (Figure 1). This was relatively simple because on a rotary press all product-contact parts and product-format parts (upper and lower punches, and the dies) are situated around the central area of the machine; that is, the turret or die table.					

In a turret, the punches and dies, powder feeder, scraper and ejection finger, dust extraction nozzles and tablet chute can all be integrated in one isolated box, called an exchangeable compression module (ECM). The ECM can be removed from the equipment as a complete, isolated unit in less then 15 min; installation also takes 15 min, resulting in a complete machine changeover time of 30 min. The entire ECM exchange procedure can be performed by one operator because most operations are performed by the machine's control system, minimizing human errors. Furthermore, using an isolated ECM eliminates the need for covers inside the machine to prevent dust from entering, thereby significantly improving visibility, accessibility and maintainability of the equipment (Figures 2 and 3).			

   Figure 3:  The ECM removed from the press.	

Applying EFM technology to a tablet press brings advantages to productivity, flexibility and containment. However, the full potential of EFM technology can only be appreciated when the peripheral equipment of the tablet press (such as tablet dedusters and metal detection systems), also has extremely fast changeover, flexibility and containment. As long as standard peripheral equipment is used, the time required to clean these peripherals, as well as the clean room, will still determine the total downtime. There are three alternative solutions to this problem:				

Alternative 1. This method involves duplicating the peripherals in two separate clean rooms (Figure 4). Standard peripheral equipment is set up in two separate clean rooms and at product changeover, the ECM of the tablet press is disconnected from the tablet deduster, integrated with a metal checker, and, eventually, the tablet distribution system. It is then disconnected from the sampling unit for online tablet analysis and the dust extraction unit. Finally, it is removed from the press. The clean ECM is then installed and connected to the peripherals located in the adjacent room. The tabletting process can restart, after which the equipment in the first room can be cleaned. The tablet press can be located in a grey zone, allowing one (large) clean room to be replaced by two smaller ones.	

 Figure 4:  The tablet press in a grey zone with peripheral equipment duplicated in clean rooms.	

Alternative 2. Integrating the peripheral equipment in an isolated box (Figure 5). Again, there are two sets of peripherals, but they are now integrated in a dust-tight transparent box. The isolation level of this box depends on the required level of containment, which can range from a dust-tight box up to a high containment isolator. Although the peripheral equipment becomes more complex, tabletting is now fully isolated, eliminating the need for a clean room. The complete tablet production operation can take place in a grey zone.	

Alternative 3. Applying EFM to peripheral equipment (Figure 6). In this solution, only the EFM parts of the peripheral units need to be duplicated, saving space and equipment compared with the previous solutions. Moreover, the EFM concept is easily applicable to the metal detector and tablet diverter gate. With the metal detector, the product travels through a closed tube running through a magnetic field; removing and exchanging this tube in an isolated way is simple. Applying EFM technology to a tablet deduster is more complicated, but is simple compared with the ECM on the tablet press. The EFM of the tablet deduster has five external connections:		

  Figure 5:  Peripheral equipment integrated in an isolator.	

Only the drive axis is between the EFM and the machine base, making the interface and connect/disconnect design straightforward. Alternatives 2 and 3 allow tablets to be produced in grey zones, eliminating the need for clean rooms and representing a significant cost saving.

When using a variety of equipment simultaneously, each using EFM technology, an important issue is to guarantee product containment. A high level of containment is important for processing high-potency drugs and when working in a grey zone environment. Product containment must be maintained, not only during production but also when disconnecting and removing different EFMs. Currently, there are a number of solutions available that allow a contained disconnection; that is, a disconnection with minimal product loss.			

  Figure 6:  The EFM concept applied to peripheral equipment.				

Split valve technology. A split butterfly valve, split ball valve or split piston valve consists of two separate halves, each having a mating part. The two halves are connected together so the surfaces of the mating parts that would otherwise be open to the atmosphere are sealed, preventing the surfaces becoming contaminated by the product while the valve is open. The valve is opened by turning or sliding the connected mating parts; when the valve is closed again, the two mating parts can be disconnected, exposing the sealed non-contaminated surfaces to the environment.	

Rapid transfer or alpha-beta ports. This system uses the same concept as the split valve, but is typically bigger. This type of valve is primarily used for the transfer of parts rather than product feed.	

Heat sealing and cutting. When plastic tubing such as polyethylene or PVC is used, heat sealing with electrical resistance threads or RF welding can be used to close the tube. By cutting across the seal, or between two seals close to each other, a contained disconnection is possible.	

Strapping and cutting. When flexible tubing is used, a variety of systems, such as plastic cable ties, steel bands, twisted wires or adhesive tape, can be used to close the tube. Cutting across the strap or between two straps close to each other allows contained disconnection. The optimal technology depends on the required level of containment. 	

A number of solutions do exist, but the solution of choice depends on the required level of containment. It should be clear that the effective operator exposure level (OEL) will also depend on the product characteristics and the standard operating procedures (SOPs).				

 Figure 8:  The ECM equipped with spray nozzles and a drain for WIP.	

Modern tablet production facilities are faced with two increasingly important, yet contradictory, demands - being able to handle more potent drugs and, at the same time, reduce costs. Additionally, batch sizes must become smaller and production planning more flexible. Until recently, these issues could only be dealt with individually and not as a whole; however, the exchangeable functional module (EFM) may provide a solution to this problem, as this article describes.