Filling pharmaceutical bottles, vials, syringes, blisters, and other containers accurately is a key process requirement. Fill volumes must match those stated in labeling and should align with dosing regimens, not only for regulatory compliance but also for patient safety and convenience.
And given today’s new pharma products, which can be potent, sensitive, and expensive, hitting tight filling tolerances is ever more critical. “Since the advent of new biopharmaceutical products, which are often expensive to produce, the focus of filling and closing processes has increasingly been on optimal product yield,” explains Matthias Poslovski, technical sales director at Optima Pharma GmbH. “Obviously, the number of rejected units due to underfills should be minimized. Overfilling is just as undesirable, since the sum of all overfills outside of normal tolerances could have been used to fill other saleable units. In either case, underfilling or undesired overfilling should be mitigated to maintain high product quality, patient safety, and economic gain.”
|Image courtesy OPTIMA|
In the pharmaceutical industry, “volumetric filling is typically used, and tight tolerances of ±½% must be maintained for accuracy,” reports Dennis Martin, technical regional sales manager for Cozzoli. Of all the available filling methods, piston cylinder and peristaltic filling are most used.
So what leads to overfills, underfills, and misfills? PMP News asked filling equipment manufacturers for common causes and potential solutions.
SUPPLY TANK ISSUES
Supply tank positioning and levels could present challenges in both piston cylinder and peristaltic filling processes. “Supply tanks may not be at the correct level,” explains Martin. “And if levels are too low, there won’t be the right amount of head pressure, especially for viscous products.
“Ultrasonic sensors are used for proper tank level, instead of a float-type sensor,” says Martin.
“In order to achieve ±½% in accuracy or better, the supply tank height and correct sensor has to be used,” he says.
Unlike piston cylinder filling, in which the piston syringe can be used for very long runs, peristaltic pumps, depending on run time and speed, can cause the silicon tubing to stretch and therefore lose accuracy,” explains Martin. “It is good to have a continuous run with no stoppages, otherwise the first one or two vials after filling resumes can have low fill volumes until the stoppage clears.”
In addition, filling equipment operators should be sure to use the correct diameter for specific formulations, ranging from aqueous to viscous products. “Product can build up in a tube, just like cholesterol can build up in an artery,” says Martin.
High fills could also be caused by temperature changes in the formulation, he adds. “Most standard operating procedures require an operator to check processes every 15 minutes to ensure fill levels are adequate,” Martin says.
|Image courtesy Cozzoli|
WEAR AND TEAR
In piston filling processes, piston cylinder wear and tear could lead to filling inconsistencies, says Martin. “After approximately three million cycles, wear could lead to leakage, and therefore lower accuracy,” he says.
Solutions include refurbishing or replacing pistons, he says.
In addition, “sporadic fills could be caused by leakages at points where air is allowed through a connection,” says Martin. “All air leaks should be corrected and tested."
Laminar air flow within the machine cabin can also falsify weighing results, explains Poslovski. “Studies have shown that an air flow of 0.45 m/s result in measured median weights 1-2 g higher than the control. The measured error in the signal (with software filter) was ±1 mg. The same test carried out with an air flow of 0.6 m/s resulted in a median value 10-12 g higher than the control. The measured error was ±5 mg. A constant laminar air flow speed and direction (vertically perpendicular to the weigh cell) must therefore also be ensured to obtain optimum measurement accuracy.”
According to Poslovski, vibration of the weigh cells must be eliminated. “Mechanical design provides the solution, with an independent support base for the weigh scales. The weighing system is physically isolated from the machine(s) whilst remaining integrated within the functional processes of the line and the sequence of operation,” he says.
Vibration from the floor as well as movement of liquid within the vial can also negatively affect the weighing accuracy of scales, Poslovski says. “To minimize movement of liquid in the vial, OPTIMA pharma uses a patented transport system which reduces oscillation of liquid, and thereby greatly improves the weighing accuracy. Other vibrations are compensated for via a software filter,” he says.
Weigh cells can also be affected by electrostatic charge on products. “Studies with neutrally charged products show, as expected, that measured values remain constant over time,” says Poslovski. “Products which have an electrostatic charge returned steadily decreasing weight measurements over time, thereby creating unreliable values. Technical solutions eliminate the offending static charge; ionization of the containers prior to tare weighing.”
When feeding solid dose products into bottles, a common issue is the effect that uncoated, dusty product has on fill accuracy and efficiencies, explains Ralf Klotz, regional sales manager for Uhlmann Packaging Systems. “We equip our format independent electronic counters with integrated vacuum ports for maximum dust extraction. These ports are routed internally on each counter, which allows for easy cleaning at changeover. In the case of multiple counters there is a common vacuum connection point channeled to all counters making a cleaner and more efficient utility connection.”
Both Martin and Poslovski urge filling line operators to consider in-line inspection.
“Once the above possible sources of error have been dealt with, a 100% in-process control (IPC) using weigh scales significantly increases the dosing accuracy,” says Poslovski. “The use of IPC halves the standard deviation (srel) versus periodic sampling.”
“A checkweighing system for 100% in-line inspection can check bottles for gross weight,” says Martin. If inaccuracies are detected, operators can make corrections right then and there,” he says. “If you are working with expensive or critical products, you may want to consider it.”
Once a 100% IPC is being used, “a re-dosing station can be installed to eliminate rejects due to underfilling,” says Poslovski. “Units that have been underfilled by the primary dosing station are identified by the weigh cells, and the re-dosing station takes over, exactly topping up the fill to the required level. “
In addition, “100% IPC allows for the implementation of special priming and run-empty cycles,” he continues. “During the priming of the dosing system in conventional filling, vials are only partially filled or even overfilled while the dosing and weighing systems are being primed and calibrated. To counter this loss of product, priming of the dosing system takes place on the weigh cell; the first container which enters and leaves the line is properly filled. The same procedure can be used at the end of a batch, ensuring that all possible product from the batch tank is fully utilized. Without 100% IPC, filling would have to stop much earlier to prevent underfilled units from leaving the line.”
Poslovski also suggests using “redundant processing stations. In normal processing, a correctly filled container which would otherwise be sent to the reject for a missing or high stopper can likewise be re-stoppered, turning a reject into a saleable unit. This station only activates when needed.”
Martin suggests the “suck-back feature” available on many Cozzoli models. “The suck-back or draw-back device ensures that no extra droplet enters a vial at the end of a filling cycle,” he says.
Klotz adds that when feeding solid dose products into product cavities on blister lines, the goal is to maximize efficiencies and minimize waste.
“We achieve this with our SimTap family of feeders, which automatically places individual products into each blister cavity at fill rates exceeding 99%,” he explains. "We also have the ability to disengage the feeder as necessary thus ensuring we are not filling blisters that are flagged for rejection due to previous quality checks; the presence of splice tap for example. Not only does this achieve maximum output, but in some cases it has also allowed a reduction in the number of personnel on the line, as the
SimTap feeding systems are fully automatic.”
Visit Uhlmann Packaging Systems at Booth #3339 at Pharmapack North America June 10-12 in New York City.
By Daphne Allen
Editor, Pharmaceutical & Medical Packaging News