Filling equipment for the pharmaceutical industry.
Erik Swain, Senior Editor
|Service Industries's upper manifold designed for slat fillers has fewer pieces to clean due to the reduced component count.|
Accuracy is crucial for filling equipment in the pharmaceutical industry. For liquids, overfills can cause some drugs to become too strong or too toxic, while underfills can compromise some drugs' effectiveness. For tablets and capsules, undercounts can unexpectedly deprive patients of medication, while broken pills can lead to inadequate dosages.
It is therefore incumbent on the manufacturers of filling equipment to provide the best accuracy possible. In recent years, many have risen to the challenge, thanks to improvements in sensors and other aspects of motion control, and better design of systems and their parts. At the same time, many of these improvements have also brought other positive developments, such as fewer change parts. Nonetheless, before proceeding with a purchase of filling equipment, pharmaceutical firms need to make sure that the accuracy claims for these new systems are statistically sound.
There are three main ways to ensure liquid fill accuracy, and all have been refined in recent years: volumetric filling, time/pressure dosing, and net weight filling.
The new breed of volumetric pumps can dose ±0.25% absolute of nominal fill weight and may provide the most accuracy attainable, says Oliver Bausch, vice president of Bausch + Stroebel Machine Company, Inc. (Clinton, CT). "Because volumetric pumps are valveless and sealless, they have been very successful in handling and accuracy," he says. "The dosing pump, because it is separate from the drive system, can be easily exchanged on the machine."
While maybe not quite as accurate, time/pressure dosing systems have their advantages too, he says. "A big advantage of the time-pressure dosing system is that it does not contain any mechanical moving parts in the product stream," he says. "The product is driven by pressure from nitrogen or sterile air. No pumping mechanism is involved. When the fill target is reached, the filling hose is pinched by a special pinching mechanism."
Nonetheless, there have been breakthroughs in the accuracy of time/pressure dosing systems, too, says Bill Arden, marketing manager at Bosch Packaging Technology (Minneapolis).
"The biggest improvement has been to bring the technology of time/ pressure filling under control. With advancements in software and microprocessors to close the feedback loop, we are now able to correct temperature and pressure in something like real time and with minimal product contact parts. This is more accurate than the alternative, which is peristaltic pumps. Lower cost is one advantage of having no pumps (either diaphragms or pistons). Also, instead of cleaning or sterilizing the product contact parts, it is easier to replace them, in which case the old parts are removed and disposed of, often by burning. The simpler the product path, the better."
Bausch notes, however, that "the issue with time/pressure is that you don't have positive control of the flow. Fill volume is based on a calculation using time, pressure, and temperature; no actual flow is measured. It's based on calculations, and you're more or less going on an assumption of what falls into the vial. Therefore, we recommend an in-process control station. It allows easy setup and operation of the filling system to reach the targeted fill volume, with verification of the actual fill."
Net-weight systems are less common and tend to be used for expensive products. But they are coming into favor with products that have inconsistent densities, says Brian Baker, president of AMS Filling Systems Inc. (Honey Brook, PA).
"Standard auger fillers dispense a certain amount of product by volume, but what if there are variations in bulk density?" he asks. "When you fill by weight, a scale sends a signal back to the servo, and as it approaches the target weight, it slows down the rpm of the motor and stops the fill on target. It can make up for variations in bulk density and can improve accuracy ±1% to ±0.1%."
Another advantage, Bausch says, is that net-weight systems "allow 100% checking of each individual vial and full traceability of all filling weights."
Advancements in motion control through use of servomotors have enhanced the accuracy of all types of equipment, Baker notes.
"You can now gain very precise motor control out of the drive mechanism," he says. "Old systems could control motion to 1/200 of a revolution. With servo, you can break the motion cycle down into 4000 parts, which makes for more precise control. Another area where servomotors have helped is the coast or drift on the auger. To get a precise fill, the auger should start and stop at the same point every time. But on smaller fills, the pistons can't open and close fast enough to allow it to start and stop at the same place. At 600 rpm, the auger wouldn't stop consistently in the same place. But with a servomotor, the pinpoint accuracy will stop it every time in the exact same spot. It will give you precisely two revolutions if that is what you want. There is no overdrift or coast."
|AMS's Servo scale machine helps achieve high levels of accuracy through motion control capabilities and the integration of the scale to fill by weight.|
Servomotors are also becoming popular in tube-filling applications, says Fredrik Nilsson, sales manager at Norden Inc. (Branchburg, NJ). "Once you get them behind the pump, they can greatly increase accuracy," he says. "If the accuracy is 0.01% to 0.05% when cam-driven, it will be basically dead-on every time if you add a servo. If you need to change the time and pressure, you can punch in numbers, and it's perfect every time."
Another factor in improving accuracy is the material choices and design of the parts for the filling system.
"A major development has been the use of ceramic pistons and cylinders," says Garrett Geary, regional sales manager, Marchesini Packaging Machinery Inc. (West Caldwell, NJ). "There is much higher tolerance than pistons that are made out of materials other than ceramics."
John Erdner, product managerliquid division, IMA North America Inc. (Bristol, PA), agrees. "Ceramic pumps are more durable and take up less space," he says. "They are very accurate—the same as, if not more so, than a rolling diaphragm, with the advantage that you can use them over and over again, whereas you have to throw away the rolling diaphragm each time so you don't have to do cleaning validation. And you need individual adjustments on each filling head to account for the thickness of the diaphragm. However, if you work with special enzymes for cleaning, there are no functional problems with rolling diaphragms. There are no sliding seals, which can be a problem with the piston style. We use them for microfills and in some applications for nasal sprays."
Decisions on how to set up a filling system can also have an effect on its accuracy, Nilsson says.
"With a fixed filling head, you can lift the tube holder up and don't have to move the whole filling nozzle," he says. "That ensures better accuracy, because if you have flexible hoses, it is impossible to control the flow of the product."
Also, he notes, if "there is as short a distance as possible between the hopper and the filling nozzle, there is less of a chance of variances that way."
The filling of solid-dose drugs such as tablets and capsules brings a different set of challenges. Individual units must be controlled and arranged in a way that facilitates counting. But at high speeds, accuracy is not easy to maintain.
"Bottles with 100% fill accuracy is the goal for every bottle-filling application," says Ralph Nelson, manager of the bottle-filling business unit at Service Industries LLC (Rolling Meadows, IL). "However, accuracy can be speed-sensitive. At high production speeds, getting the tablets to behave as expected while in the bottle-filling machine is the major challenge. In the case of slat fillers, a slat cavity design is only as good as the operation of the slat-filling machine. In other words, you need a well-maintained and properly operated piece of equipment combined with a cavity design that fills and empties as quickly as possible without overfilling and or abusing the tablets during filling to get maximum accuracy."
One trend in recent years, says Joel Gray, president of Service Industries, is the increased use of positive tablet ejectors. "Slats and machines with provisions for positive tablet ejection ensure that all slat cavities are empty after the tablet drop point."
As with liquid fillers, improvements in sensor technology are contributing to better accuracy of tablet fillers. One example is the electronic counter employed on the tablet fillers made by Aylward Enterprises Inc. (New Bern, NC). "Usually electronic counters were for low-speed operations," says Matt Neumann, vice president of sales and marketing. "Now we can use them at high speed. We guarantee the correct count at 300 to 400 bottles per minute."
"It counts each individual tablet through a window sensor just before the tablet drops into the bottle," he says. "It controls the advance and movement of each individual counting wheel. Holding one tablet in each pocket, it fills the pockets with tablets and releases them from the pockets. The tablets free-fall into the bottle. It still has time to stop the wheel once it reaches the correct count. The counter is a tablet-by-tablet positive count, and if there are broken tablets or chips, it can detect that and reject the bottle."
A significant advantage of the system, he says, is its ability to change the tablet count electronically without any change parts. "If you want to run seven tablets for a physician sample, set it to seven," he says. "If you want to fill a 225-tablet bottle, set it to 225."
Even capsule fillers in the nutritional industry, not known for having the high quality standards of the pharmaceutical industry, have made strides in accuracy recently, says Clint Draney, senior install technician at Tradimex International (Orem, UT). "We have changed to high-compression springs, which wear more consistently," he says. "Traditional springs would wear unevenly, leading to inconsistent fill weights, which are not accepted anymore."
WHAT IS ACCURACY, ANYWAY?
Regardless of what filling technology a drug company uses, suppliers say, it is important that its engineers understand the product well enough to discern what level of accuracy is crucial and understand the different measurement systems well enough to compare the claims of different vendors.
As one possibility, Bosch suggests using the process capability index, Cpk, which is accepted in the aerospace industry. It takes into account the upper and lower specification limits, and measures overall performance of a system (both accuracy and precision) with respect to specification. Another alternative, Arden says, is a method defined in ISO 3207: "Statistical interpretation of data—determination of a statistical tolerance interval," which calculates upper and lower tolerance limits using the mean and standard deviation of the sample while factoring in sample size.
"There is going to be a measurement issue," predicts Arden. "What exactly does 0.1% accuracy mean? We run into it all the time in specification battles. For example, does it mean ±3 standard deviations, or ±1? There is no standard measurement for it. Something needs to be done, because our customers are going to start caring, and FDA is going to start caring [about what these measurements really mean]."