The dosage form may also be
variously described as soft elastic (gelatin) capsules, soft gels or
(one-piece) liquid-filled capsules. Compared with tablet or powder-in-capsule
solid dosage forms, soft capsules tend to utilize excipients that are mostly
(non-water-based) liquid in nature or dissolved in liquid, and the materials
tend to be different from the materials that are used to create solid dosage
forms.
The soft capsule is a
hermetically sealed, one-piece capsule shell with a liquid, gel or semisolid
fill without a bubble of air or gas. The shape can be anything not too complex
with a plane of symmetry but typically oval or rounded oblong.
The shell is composed, at a
minimum, of polymer, plasticizer and water. The content of water in the
finished dried product is rather low and, being mostly bound to the shell
polymer, inactive. Typically, the shell polymer consists entirely of natural
gelatin as described in the original invention.
In the original process gelatin
is dissolved in water as part of the manufacturing process. After
encapsulation, the residual water needs to be dried out in order to provide a
robust and stable finished dosage form. The manufacturing steps require precise
control of room conditions (both temperature and humidity), with the most
significant infrastructure and energy needed for drying.
For any new soft capsule product,
there are a range of parameters for which a variety of information will need to
be collected, in order to determine the appropriate risk (of failure) and to
develop mitigation or control strategies. In order to minimize risk, it is
better to select a fill and a shell formulation that are already used
successfully in commercial products (with several year's data showing process
capability).
Process Development
Process development may include
selection of the appropriate equipment, and processing sequence. Fill mixing is
typically a batch process where order of addition, temperature and mixing/shear
speeds are most important. For a solution, it may be critical to prove that all
of the API is in solution at the end of the process. The fill needs to be
entirely free of air to ensure filling uniformity. The gel preparation is also
typically a batch process where a homogenous solution free of air is required,
but it may be difficult to identify any other process issues that are critical.
There has been a lot of debate on the most important process parameters for
soft capsule encapsulation, but casting drum temperature is typically on every
short list as this controls the structure of the gel ribbon, which has a direct
effect on encapsulation.
Critical Parameters
The critical ‘operation’ in the manufacture of soft capsules, is the encapsulation step where the capsules are formed, filled and sealed. Unlike a two-piece hard capsule, the filling and sealing of soft capsules occurs in one single process. Where include fill preparation; gel preparation; encapsulation; drying (tray and/or tumble); finishing; packaging (bulk and or primary).
In-process testing parameters
Fill weight, shell weight and
seal quality are recorded based on batch size, confidence in the stability of
the process and need to collect data. Other parameters are recorded in order to
be able to correlate process conditions with output capsule quality, and to
support trend analysis, typically machine speed, casting drum temperature,
wedge temperature, gel temperature and others as considered appropriate based
on the actual process employed. If there is high confidence that the process is
under control, it may be appropriate to perform a reduced number of in-process
tests (testing only two or three pockets across the wedge instead of all of
them), provided that these are sufficient to perform a useful trend analysis,
as part of a well-considered testing strategy.
Finished product testing parameters
Once the soft capsules have
completed all steps in the process, the lot may be inspected and sampled for
the final product release. The finished product specification for an active
product will usually include appearance, identity of actives, assay, related
substances, fill weight, dissolution or disintegration, content uniformity and
microbial testing, but the actual test may depend on monograph or regulatory
requirements.
Advantages and Disadvantages of Soft Gelatin Capsules
Advantages
- Improved oral bioavailability
- Excellent dose uniformity
- Enhanced drug stability
- Superior patient compliance/consumer preference
- Product differentiation
Disadvantages
-
Specialized manufacturing equipment and facilities with high start-up costs
Raw material quality/stability/variability
Formulation complexity
