Has Tablet Manufacture Reached Its Peak?

The Panel

Robert Sedlock, Director of Technical Training & Development at Natoli Engineering. Natoli offers a full line of products and services to assist at all stages of the tablet and encapsulation production process.

Scott Koehler, Vice President, Sales & Marketing at Elizabeth Companies. Elizabeth started as a six-man machine shop in 1954 and has grown into a global provider of punches and dies, tablet presses, parts and services.

Matt Bundenthal, Director Sales and Marketing at Fette Compacting America. Fette has installed more than 5000 machines across the globe and specializes in tableting and capsule machinery.

Some would say that the tableting process hasn’t changed significantly over the years. What are your thoughts?

Robert Sedlock: I would say that the overall tableting process has remained the same; the core principles of compression and the basics of how tablet presses operate are largely unchanged. However, significant improvements have been made in the control systems and safety features of tablet presses. Adjustments to tablet weight or thickness are no longer made by mechanical handwheels but are now controlled through touchscreen human-machine interfaces (HMIs) and servo motors, for example.

Scott Koehler: I believe that is a fair comment from a fundamental perspective. It is both testimony to the longevity of a stable process technology, and the cost-effective nature of compressing solid dose products. It is also compelling that similar technology can apply across a wide variety of products and industries beyond pharmaceuticals. Though the basic process is common, the nuances are significant, which challenges both tablet manufacturers, who need to ensure their formulations have the right properties to work well in the equipment, and equipment manufacturers who are designing machines to be as flexible as possible.

Matt Bundenthal: Although the core process has not changed all that much, manufacturers are using increasingly creative approaches in terms of the form taken by finished tablets. This, in some cases, is prompted by marketing-driven initiatives, but can also be based on requirements for optimized bio-availability, or making a controlled substance more resistant to abuse, for example.

Like virtually everything else today, speed has become a driving force in tableting. While not every formulation lends itself to being compressed at high speeds, most end users would like their presses to compress their products as quickly as possible. And given the increasing prevalence of potent compounds, modern presses have to run quickly and maintain control more tightly than ever before.

Another significant change to the compression process is the degree to which electronic and computer controls have facilitated the attainment of this balance between speed and control. Results must be validatable, and repeatable, to the highest degree – something not practically attainable with the “manual” presses of old.

What new innovations and trends are emerging?

Robert: I am excited by the advances in materials science and coating technology – there are now a variety of different steel types and coatings available to help address tableting issues, such as sticking and picking, abrasion and corrosion control, or any combination of common tableting issues. Frequently, a change of material or application of a specialized coating can resolve tablet defects and/or significantly improve tooling service life.

Scott: For me, industry adoption of continuous manufacturing techniques – although still in its infancy – portends powerful shifts in terms of factory processes and the wider business landscape of the pharma industry; continuous manufacturing should lead to more cost-effective and efficient processes. For continuous processing, the basic tableting process is not so different, but the compression department must adapt to more agile and fluid production flow. Apparatus within the compression activity, consequently, must compliment the new paradigm and be robust from short to long product runs.

Matt: Over the last 5–10 years, I’ve seen an increasing focus on potent compounds. Technologies specific to high-containment applications (for example, wash-in-place features, glove ports, door interlocks, and rapid transfer ports) have been developed to greatly mitigate the risk of operator exposure, mostly in the form of accidental inhalation. High-containment presses are therefore increasingly popular in the pharmaceutical realm. High-containment applications necessitate not only effective means for ensuring that potent products remain inside the tablet press, but they also must allow an operator to periodically gain access to the interior of the machine during a campaign (to check a suspect punch, for example, or to change a fill cam) without breaching containment. Hence, the use of rapid transfer port technology, glove ports and integrated spray and vacuum wands within the compression zone.

More recently, there is a trend towards continuous manufacturing, as Scott mentioned. The tablet press is only one component in an integrated equipment train that allows the user to avoid the “hold” phases between conventional manufacturing steps, and thus streamline their overall process. Given the need for the different pieces of equipment, such as mixers, blenders and presses, to communicate in an unencumbered fashion, these applications have also driven improvements in controls integration and ease of use.

What kind of requests are you receiving from the industry?

Scott: Often we are asked about transitioning tablet production to multi-tip tooling in support of cost reduction initiatives or efficient scaling of factory output. Another cost-motivated trend is the adoption of direct compression powder batches in lieu of wet granulation. Direct compression powder blends are often less forgiving within the tableting process than wet granulation and require intelligent press and tooling choices to reach reliable volume production.

Also, there are many opportunities in pediatric medicines, which are accelerating the need for smaller, low-dose tablets. Production of such small tablets is often being considered with multi-tip tooling; the design of such tooling and the tablet press set-up become critical to robust production.

Robert: Mini-tablets are a growing market for our customers. This dosage form is compelling because it can address many compliance issues – certainly in the pediatric space, but also geriatric patient populations who may have trouble swallowing conventional tablets. As well as being easier to swallow, mini-tablets are able to deliver precise dosages with ease; delivering an exact dose to children is far more difficult than the average adult, as weight and height can vary significantly even within the same age range.

Matt: As Scott and Robert say, mini- and micro-tablets have become more common, as some manufacturers are essentially combining the compression and encapsulation processes (in other words, mini- or micro-tabs can be fed into empty capsules after being compressed). An advantage to mini-tabs is the fact that, if any surface defect exists on an individual small tablet, there is a very low risk of compromising the product’s therapeutic band. A surface defect on a more conventional, larger tablet, like an unseen crack, however, can lead to all of the API being released too soon in the intestinal tract, thereby potentially ruining the intended therapeutic effect.

Double-layer tablets remain the most common of the “uncommon” tablet dosage forms, though some of the technology involved in their processing – such as mechanisms for higher-speed, more accurate first-layer sampling – have improved by leaps and bounds.

Another infrequently used but interesting tablet type meters, or “pumps” its active product at a controlled rate through a tiny aperture – typically created with a laser-based drill.

How are these trends affecting innovation in tableting equipment?

Scott: These trends require more thoughtful consideration of the dynamics between tablet press and tooling as compared with traditional single-tip, heavier tablets. Optimization of press cam tracks and tooling head forms enable volume production at acceptable compression forces. As tips are added to punches, there is a corresponding increase in the tablet press compression forces needed to generate the higher volume of acceptable tablets. As compression tooling multi-tip assemblies become more complex, a more critical view is necessary to ensure reliable operation within the tablet press, while avoiding large escalation in tooling cost.

Robert: The size of mini-tablets and the rather delicate nature of the tooling pose a different set of challenges compared with typical tablets. When you have 20 or more tips on a single punch, downstream equipment must be able to process the drastically increased number of tablets; for quick and efficient removal, air-assisted tablet take-offs can be helpful. Other press features, such as lower punch retainers and shallow fill cams can also help maintain the mechanical integrity of the tooling.

The flow properties and particle size distribution of a formulation intended for mini-tablets is also incredibly important. Not only do you need to achieve equal and consistent fill in all the die bores, but you must also have a product that flows well into the smaller, more restrictive die openings. As noted, mini-tablet punch tips are delicate – and, therefore, more prone to bending or experiencing other forms of damage if over-compressed. Presses with finite controls and instrumentation that is sensitive enough for the collection of compression analytics enable tablet manufacturers to report on data that is precise and accurate in order to alleviate the chances of tooling damage.

Matt: In the past, double-layer tablets presented challenges (typically running much slower than mono-layer tablets, with high loss and low yields). Today, their increasing popularity has driven a host of new features that i) prevent cross-contamination between layers, ii) decrease the likelihood of transitional rejected tablets, and iii) allow for compression force control of each individual layer, rather than just the final, complete tablet. It is also far easier with modern presses to rapidly change from mono-layer to bi-layer mode – and back again – than it was in the past.

It is also common nowadays to hear of tablet manufacturers moving from larger, sustained runs to more numerous, smaller ones. To remain commercially viable, such companies require tablet presses that allow transition from “Product A” to “Product B” in the shortest possible changeover time. To that end, removal of parts has to be as easy as possible – as does re-assembly – and the fewer tools needed the better. Easily removable turret assemblies, and now “segmented” turrets, which dramatically reduce changeover times by eliminating the need for individual dies, have revolutionized changeover procedures and led to greatly increased press utilization levels.

What aspects of formulation should companies be considering?

Scott: Fundamentally, the granulation or powder must be compressible. Sometimes the mix simply is not – regardless of what tableting equipment is used. You must also consider the ratio of fine granules (< 0.2 micron) within the formulation. A formulation with a high percentage of “fines” can cause segregation, which leads to an inability to form a cohesive bonding of particles. A high percentage of fine granules can result in low yields due to product flow-by, imperfections on the tablet (such as flashing), and capping issues.

Matt: The two primary product characteristics that will affect how well a product may behave on a tablet press are flow and, unsurprisingly, compressibility. All high-speed tablet presses use some form of hopper to bring product to the feeder, and once in the feeder the product must flow well enough to make its way into individual die cavities. The smaller the cavities, the greater the challenge.

Filling the cavities efficaciously is half the battle. If you can’t form a tablet that holds together under compression, with the target weight, thickness and hardness, then you’re back to square one. Improving flow and compressibility is a topic that warrants its own article! In brief, improving flow generally takes one of two early paths: a more effective flowing agent or the selection of a main filler with a higher degree of coarse particles – silicon dioxide, for example. A good first step for improving compressibility is to check the deformation profile of the product. There should be a high enough degree of plastic deformation under compression, without damaging particles. If the profile is too low, it can often be improved by increasing the concentration of an excipient with a profile more conducive to compression, such as microcrystalline cellulose.

Robert: As Matt and Scott say, there are a number of formulation factors that must be taken into account. I also believe that being able to simulate the compression behavior of a formulation on a small-scale R&D press can be invaluable, as it helps you predict and resolve potential issues prior to full-scale production. Additional tooling features, such as reduced head flats, can simulate the dwell times of large production presses to better anticipate any issues that might arise during scale-up.

In what ways can companies improve efficiency and production in their tableting operations?

Scott: As with most mechanical devices, proper care and maintenance make a huge difference in asset life and the quality of products produced. Properly maintained tablet tooling and rotary presses can last for decades. A simple adage to determine end-of-life of tablet tooling is: “Does the tooling still make good tablets?” If not, it is likely time to replace. By nature, tablet tooling does wear, so when it comes to some aspects of maintenance, especially polishing, “less is more.” It’s disappointing to see short-lived tooling because of over and improper polishing of the cup face. In the case of rotary tablet presses, most damage often starts in transients during start-up or shut-down of the press. When a press stops under load and is restarted without first relieving the pressure rolls, it causes the highest stress and wear on press and tooling (and can sometimes be catastrophic to the tooling). Thoroughly documented start-up/shut-down procedures, and well-trained personnel are the lifeblood of tableting equipment longevity.

Robert: One of the most prevalent causes of tablet press failure comes as a result of inadequate or irregular tooling and press maintenance. Here, training is key. With proper and frequent training of press set-up technicians, operators, and tooling technicians, costly mistakes can be avoided, which increases productivity and reduces downtime. Some companies cross-train and frequently move their personnel around to different areas of production. However, because of the high-level of technical expertise that is required for each process, it is more beneficial to keep them well-trained (and well-paid) on one process to ensure your operation runs more efficiently. It is also important to establish performance indicators that can be used to compare productivity over time. Without a baseline on which to measure success, you will be unable to effectively evaluate areas of potential improvement.

Matt: Comprehensive training should precede all else. It represents the cornerstone of protecting one’s operators and the tablet press itself (a huge capital investment for any company) – and it ensures that the press always operates and performs at the levels for which it was designed. Training can take many forms, but if an equipment manufacturer offers any type of certification program, the opportunity should be seized with gusto. There is no better way to ensure maximal production results than to learn the ropes from those who designed the press in the first place. It is astounding how small deviations from the original equipment manufacturer’s recommended practices can quickly lead to a loss of efficiency.

Though most vendors would like to sell new equipment as frequently as possible, the truth is many of the leading companies manufacture presses that can easily offer useful lives of two decades or more. Having said that, there are some signs that a press may require refurbishment or, in more terminal cases, replacement. Some of the warning signals can include:

• erratic compression forces
• poor or inconsistent weight control caused by various issues, such as bad punch seals, worn dosing station gearboxes, worn/damaged cams
• low yields
• noisy compression stations
• product found in places where it should not be; worn seals are a common culprit
• excessive wear on parts that should not ordinarily wear out (for example, compression rolls, feeder tables)
• excessive vibration

One of the most common drivers for replacing a press with a new unit, if it is not purely capacity-driven, is the phenomenon of electronic and control obsolescence. There does come a time when certain components – often computer-related – simply become unavailable and, in those cases, an end user may find their hand forced.

Can you share your top tips for maintaining tableting machinery?

Scott: Properly functioning lubrication throughout the tablet press, as well as cam track and pressure roll inspections for irregular fit and wear. Once damage occurs, it only snowballs. It is imperative to monitor the turret condition. Punch guides, die table surface and seals should be checked regularly for cleanliness and wear. Improper turret maintenance leads to a host of downstream issues, such as improper tool alignment, excessive cam wear, yield loss, and poor tablet quality.

Finally, properly set-up tooling with good alignment. Three basic tips that should cover all tableting machinery are  keep compression pressure as low as possible, clean and lubricate the machine properly, and keep punches and dies in good condition.

Matt: The number one tip is to establish a preventive maintenance program; make it an official part of your internal standard operating procedures, and enforce its consistent implementation without fail.  The more critical items to regularly keep an eye on with a modern tablet press include the following:

• compression rolls
• cams (fill, ejection, dosing)
• punch seals and restraining mechanisms
• scrapers
• turret assemblies
• lubricant levels
• gearboxes
• force feeders

Ask your OEM press vendor for all documentation to augment your own procedures.

Robert: Establishing a standard operating procedure for regular inspection helps keep the tooling and equipment in good working order. Also, the operator should be reminded when it is time to replace tooling or a wear part – before press downtime and productivity loss can ever occur. Prevention is always the best approach!