In-process controls (IPC) for soft capsules
While the release tests for solid dosage forms and softgel capsules are typically well-defined in the pharmacopeias, IPC testing is rarely discussed. This article gives an overview of the most common IPC testing methods for each step of softgel manufacture.
1. IPC tests for gelatin mass preparation
As the characteristics of the gelatin mass may impact the processability, appearance, and physical stability of the capsules, appropriate IPC testing includes the following:
Appearance (visual): the mass should be uniform and free of bubbles
Homogeneity (visual): the mass should be homogeneous, and the gelatin dissolved
Color (visual): in the case of colored gel mass, the match with the target color should be confirmed
Processability: while the viscosity of the gel mass can impact its processability, this is a notoriously hard parameter to test reproducibly, e.g. due to the processing at elevated temperatures and artifacts that may occur during testing. The test is therefore not always applied.
2. Fill mass preparation
The IPC tests for the fill mass should reflect the individual characteristics of the product and vary significantly between products. For example, a solution may be checked for the appearance and absence of crystals, while a suspension has to be controlled for its particle size. As large particles may position themselves in the capsule seam, the particle size distribution (PSD) of the suspension has to be below the typical seam thickness.
Some formulations that have varying API content may require also assay analysis as an IPC test. Further tests may include assay, refractive index, or even degradation products.
3. IPC tests for encapsulation
The rotary-die encapsulation process is a standard, continuous manufacturing process, and therefore standard controls are typically employed for all products. In all products, the encapsulation process settings may impact the capsule integrity and dissolution/disintegration characteristics by the thickness of the capsule seam, assay, and content uniformity. The following IPC tests are therefore typically performed:
Seam thickness (measurement under a microscope)
Wall thickness ( measurement under a microscope)
Fill mass (weighing)
Shell mass (weighing)
The limits for the seam and wall thickness are defined based on the used encapsulation tooling, while the fill and shell mass limits typically vary between +/- 3 and. +/- 5%. Defining the fill mass limits below the pharmacopeial mass variation limits for the given capsule size is recommended here.
4. IPC tests for drying of softgel capsules
During drying, the excess water required for processing is removed. The most appropriate end-point indicator for capsule drying should be defined during development. For this purpose, the conduction of extensive drying kinetic studies involving testing of capsule mass, hardness, and water content e.g. is also advised.
As the main objective of this process step is to reach the physical stability of the capsules, typically capsule hardness is tested utilizing specific equipment. The target capsule hardness is defined for each product and may range between 5-12 N.
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Tumble drying of softgel capsules
5. IPC tests for coating of softgel capsules
In case the capsules are coated, typically with a functional coat, the main IPC test is the capsule mass to establish whether the pre-defined weight gain is reached.
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