Battling Off-Weight Tablets

Consumers of pharmaceutical tablets are protected by regulations and agencies that set stringent guidelines to assure that the products are safe and effective. Manufacturers themselves, however, must take the initiative for ensuring product quality, not only to protect those using the product but also themselves. The negative fallout related to a poor-quality product reaching store shelves is too great to ignore. At a minimum it will result in a loss of goodwill attached to the manufacturer’s name. In more extreme cases it can result in harm to the consumer, related legal ramifications, and the real potential of having one’s doors closed.

A crucial parameter of any finished tablet, regardless of its intended use, is weight. Other important parameters include thickness, which can determine how effectively the tablet moves through downstream equipment such as a packaging line, and hardness, which is correlated with whether or not a tablet can withstand the trip through such related equipment, as well as how effectively and rapidly the product dissolves in the body of the person taking it. Cosmetic considerations also play an undeniable role in a product’s marketability. But of all the most commonly referenced tablet characteristics, weight is the most closely correlated with overall quality because of its close relationship to the target quantity of active material found in the final tablet. It is no surprise, then, that in the last several years there have been close to 50 product recalls directly related to tablet-weight issues (1).

While it is easy to argue that overweight tablets are more of an issue than their underweight counterparts, both represent potential issues. Overweight tablets can result in too much of an ingredient which, in many cases, can lead to a harmful effect. But tablets that are too light are also problematic, given the fact they may not offer enough of a particular ingredient to bring about an intended therapeutic benefit. A manufacturer’s goal should be two-fold: do not produce off-weight tablets in the first place, and catch and reject them, accurately and reliably, if they are produced.

Causes of off-weight tablets
There are many potential causes for producing off-weight tablets. Problems caused by equipment design, set-up, calibration, or maintenance include:

• Feeder configuration not optimized to match product characteristics

• Incorrect or suboptimal weight-related machine settings, such as filling depth

• Poor or inconsistent filling of dies

• Inappropriately sized fill cams (in most cases too large, leading to too much “back-dosing”)

• Suboptimal punch-penetration settings

• Improperly set (or missing) recirculation components

• Tablet back-up at the take-off, where rogue tablets may jump the bar and potentially re-enter a feeder

• No rejection of start-up material or improper settings related to start-up

• Absent or faulty low product-level sensors

• Poor dust extraction system or improper settings

• Worn parts, including scrapers, cams, and feeder and punch seals

• Poor, worn tooling, with inconsistent working lengths

• The use of non-original-equipment-manufacturer replacement parts that are manufactured without reference to the originally engineered specifications.

In some cases, excipients with poor or inconsistent flow characteristics can be a problem. For products with poor flow attributes, vendors sometimes offer special cams, such as “deep fill” filling cams, which can improve die filling by creating a small amount of vacuum under the cavity. In addition, operators must recognize that product “recipes” need to be tweaked to account for batch-to-batch variability in flow and compression characteristics.

Although materials may cause challenges, blaming the formulation is generally a dead-end street. It is equally fruitless, however, for anyone to simply state that if the machine made the bad tablet, then the machine is at fault. The operator must take responsibility. Causes of off-weight tablets related to operator training include:

• Inadequate training on the machine’s mechanical, electrical, or computer-related capabilities and features

• Unqualified operator making adjustments while logged in under the password of a qualified operator

• Blind reliance on automated systems

• Improper feeder manipulation by operator

• Lack of attention to operational standard operating procedures (SOPs) or no SOPs at all.

Potential remedies
The best ways to prevent the manufacturing of off-weight tablets begin before product is loaded into the hopper--through comprehensive operator training, diligent and rigorous preventive maintenance, and regularly scheduled calibration of the press and its subassemblies. The most effective, first line of defense is training on both press and process. Operators should be tested regularly to ascertain and reconfirm their proficiency with making a tablet in the absence of automation (i.e., “Tableting 101”) and with making tablets using the specific equipment their company employs as part of the manufacturing process.

Training. The importance of training cannot be overstated. Training should cover the prevention of virtually all the factors listed in the previous section. Companies should have SOPs and ensure that operators follow the SOPs. A tablet-press vendor should be able to demonstrate and confer comprehensive knowledge of their technology and of how it can be used to manufacture tablets of optimal quality. A press vendor can provide training specific to understanding the feeder and optimizing its use, because the feeder has a direct correlation to maintaining acceptable tablet weights. Users should also understand and use the relationship between feeder speeds and consistent die filling. A press vendor can also recommend how to manipulate the feeder-paddle style and configuration; different paddles offer different spoke designs that can have discernibly variable effects from one product to the next (see Figure 1). When possible, a tablet-press vendor should directly assist during execution of product qualification runs. Their expertise can prove valuable when creating a new product recipe for the first time and can help streamline the process before mistakes can be made.

Maintenance and calibration. Thorough preventive maintenance and regular inspection and calibration should be conducted on the entire tablet press. In particular, users should maintain calibration of devices controlling filling depth regulation on a press. Tooling and cams should be consistently and carefully inspected. Cam-wear indicators should be used whenever possible. A guideline for what constitutes a worn tool should be established, and it should serve as a prompt for timely replacement.

A force-based relative standard deviation should be used as an indicator of consistent tablet weights. This statistic allows an operator to determine how consistently they are compressing tablets. Many modern presses calculate this figure for the user, which streamlines the ability to quickly analyze results in real time.

Seek outside help. Companies should solicit the help of third-party experts such as tablet-press vendors, reputable consultants, or specialists in overall equipment effectiveness. Third-party assessments can immediately uncover multiple inadequacies in the process, machine, and/or user. The engagement of these individuals or organizations is especially valuable because they generally view the situation through a different lens, rather than being focused on getting product out the door. For particularly problematic products, a company may consider scheduling a test at the tablet press vendor’s facility on the same model of press owned by the tablet manufacturer.

Rejecting out-of-specification tablets
Because presses manufacture tablets at high speeds, it would be too idealistic to assume that one could ever achieve a state where a press simply does not ever manufacture a single tablet not meeting batch-specific definitions for what is acceptable. Rejection mechanisms (see Figure 2) are thus used, except on very old machines, to prevent bad tablets from entering the good product stream. The mechanisms employed vary from manufacturer to manufacturer, but most are triggered by a signal representing the measurement of an off-specification tablet. The signal is often force-based, as measured by a load cell or comparable device. Subsequently the suspect tablet is diverted into a “bad” channel or outlet. Both vendor and press user must place significant emphasis on training specific to the set-up, operation and maintenance of these devices, which may be electromechanical, pneumatic, or some combination thereof. These mechanisms warrant great attention because they must be accurate at high speeds. The mechanisms should be challenged frequently and their constituent parts should be maintained and calibrated regularly. Above all, the operator must understand the purpose of the rejection mechanism. A lack of understanding or a failure to properly use a rejection assembly can greatly diminish the capability that modern presses have for ensuring high quality.

Prevention is the goal
A thorough understanding of a tablet press, be it older or cutting-edge, must serve as the first assurance of manufacturing quality tablets. An equipment supplier should offer training for set-up, operation, and calibration of all pertinent machine features, most notably feeding, filling depth, and rejection mechanisms. Off-weight tablets warrant serious attention, and, through collaborative efforts, excessive production of off-weight tablets can be prevented.

Reference
1. IPQ, “An upsurge in recalls of overweight tablets and a recent FDA warning letter show industry’s process understanding shortcomings,” (IPQ Website), Mar. 5, 2012, www.ipqpubs.com, accessed Dec. 6, 2013.