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To ensure an effective treatment, a patient often must take equal doses of an active pharmaceutical ingredient (API) at regular intervals.
To ensure an effective treatment, a patient often must take equal doses of an active pharmaceutical ingredient (API) at regular intervals. Powder-in-capsule dosage forms must maintain a consistent ratio of API to excipients as well as a consistent amount of each ingredient. Pharmaceutical manufacturers must therefore achieve content and fill-weight uniformity.
Producers of powder-in-capsule dosage forms face several obstacles to reaching these goals, however. One major challenge is filling capsules with powders having poor flow properties or that are highly cohesive. Karl-Heinz Seyfang, division leader of pharmaceutical services at Harro Höfliger Packaging Systems (Allmersbach im Tal, Germany), says that filling capsules with those kinds of powders is particularly challenging at fill weights of less than 10 mg. The challenge results from the variance introduced by the confinement step, which separates the dose from the bulk powder. To overcome this problem, Harro Höfliger equips its capsule-filling machines with a vacuum-drum filling system. This system doses powders at low fill weights by using a vacuum to draw the powder from a small hopper into bores on the drum.
Reuben Zielinski, senior director of technical operations at Catalent Pharma Solutions (Somerset, NJ), remarks that his greatest challenge is ensuring smooth material flow at high encapsulation-machine speeds. Zielinski says maintaining good flow requires vibratory action, but notes that this technique can reduce capsules’ content uniformity. “For this reason, we run our encapsulation machines only as fast as the gravity feed will allow,” he explains.
Another potential threat to content uniformity is powder segregation, Seyfang observes. To be certain that segregation has not occurred, a capsule-filling machine “must be equipped with process analytical technology devices such as a near-infrared spectrometer, a UV–vis spectrometer, or other technologies to verify API content.” Zielinski says Catalent takes samples throughout the capsule-filling process, according to company testing protocols, to monitor content uniformity.
A powder’s physical properties are not the only influences on content and fill-weight uniformity, however. Zielinski points out that manufacturers must consider the properties of their production machinery. He names the thickness of the encapsulator’s dosing disk as an example.
“We have found that the machined tolerances on dosing disks can affect the fill-weight accuracy,” he explains. Because the diameters of the disk’s through-holes accommodate standard capsule sizes, the dosing disk’s thickness determines the accuracy of capsule fill weights.
After they are filled, capsules must be checked. In addition to having the proper dosing system, Seyfang notes, a capsule-filling machine “must include an appropriate tare and gross check-weighing system to neutralize capsule-shell weight variance.” He recommends encapsulators that weigh capsules both before and after filling.
Yet weight-checker data should not necessarily be taken at face value. Zielinski cautions that a manufacturing plant’s inherent vibrations affect the location of the weight-checker. “These vibrations cause displacements that in turn can cause an abnormal amount of rejected capsules because of the sensitivity of the load cells,” he says.
Manufacturers achieve content and fill-weight uniformity by taking into account several factors. Filling equipment must operate precisely at high speeds and must also be validated to ensure that capsules meet label claim specifications. Also, facilities produce dosage forms of consistent quality when equipment operators are well trained and experienced. The facility environment must be monitored, as well: temperatures must be kept within 15–25 °C and relative humidities should be maintained within 35–55% to enable good powder flow. Attention to critical details such as these helps produce uniform and effective products for end users.