Pharmaceutical Outsourcing Q3 2023 - 29

CONTRACT MANUFACTURING
SECTION TITLE
drug and matrix or excipient form a complex that not only improves
the dissolution and bioavailability of poorly soluble APIs through a
low association constant, but also enhances the stability of the drug
product. With inclusion complexes, stability is improved as the API is
either partially or fully encapsulated within a hydrophobic cavity or
segment of the host molecule.
Recent Developments in
Solubilization Techniques
As the water insolubility of drug molecules has increased, the need for
effective solubilization techniques has increased too. With traditional
additives struggling to keep pace with the demand for improved
solubility, novel excipients offer great potential for solubilization as
well as offering additional formulatory and commercial benefits.
Recently, novel excipients have been shown to increase the solubility
of water insoluble APIs 50,000-fold where commonly used excipients
have previously failed.3
These formulants provide additional
solubilization routes as one size does not fit all, increasing the overall
chance of achieving the target product profile. Additionally, there is
plenty of patent life remaining for novel excipients, resulting in more
exclusivity in future drug design projects.
Over recent years, the sterile pharmaceutical market has expanded
significantly, mainly driven by the COVID-19 pandemic. With this
growth expected to continue, formulators are presented with not only
the challenge of solubilizing poorly soluble APIs, but also producing
sterile dosage forms for parenteral, ophthalmic, optic, and inhaled
routes, as per FDA requirements.
Sterile medicines must have careful control over the levels of
microorganisms, which can cause life-threatening conditions, such
as sepsis, if released into the bloodstream.3
However, the common
approach of terminal sterilization is often incompatible with
solubilization techniques. For example, very few nanosuspensions
are amenable to terminal sterilization. An important development
has been the aseptic nanomilling process, where contamination is
controlled throughout the manufacturing process. The sterile API is
combined with sterile excipients and milled in a fully closed sterile
equipment
train. The sterile drug product intermediate is then
aseptically filled and finished, affording sterile products that are safe
for injectables and other sterile dosage forms.
Key Challenges in Solubilization
With a plethora of techniques available for increasing drug solubility,
the first challenge is knowing where to start in the development and
formulation process. Having several options - ideally orthogonal
approaches that can be run in parallel - will enable the highest
chance of success, as some techniques are more likely to work with
certain routes of administration. For example, ASDs are ideal for oral
dosage forms, but not so for other routes of administration.4
By identifying the physicochemical characteristics of the API and the
target product profile, formulators can decide which solubilization
methods are most likely to yield success. However, this requires
experience and expertise, and may also call for specialized equipment
not currently available in-house.
Reproducibility and reliability are key pillars in pharmaceutical
development, and this is especially true when formulating APIs with
poor solubility. To ensure the drug product is consistent throughout,
suitable analytical methods must be used to adequately characterize
the drug product, as well as to identify and correlate relevant critical
quality attributes (CQAs) to biological performance and drug
product stability. Pharmaceutical manufacturing that incorporates
solubility enhancement often involves complex processes, which
can make it difficult to ensure that operations are progressing as
intended. As a result, maintenance and calibration may need to be
more frequent to ensure the equipment is working as intended,
leading to increased costs.
Another important consideration is the scalability of the process.
Some systems, such as microfluidics processing, are very effective
but struggle when the time comes to scale up for commercial
manufacture. Traditionally, the solution would be to run the
technique in parallel to afford larger quantities - but this can lead to
an engineering headache when trying to scale up processes that are
not designed for large throughput.
When new equipment is brought into the process, additional time
and cost must be expended not only for design, installation, and
qualification, but also to train staff to GMP standards on the new
technologies. Additionally, the inclusion of automation adds further
complexity and, given that the system will need to be compliant
with the FDA's 21 CFR Part 11 data expectations, more resources will
be required during the set-up process, potentially setting back the
project and further increasing the costs.
In summary, where solubilization techniques are required, drug
developers may see extended timelines and increased overall
development costs of a drug product, due to the need for specialized
equipment, as well as the appropriate expertise.
Leveraging CDMOs to Reduce Cost and
Accelerate Time to Market
Many of the challenges associated with developing and manufacturing
drug products with poorly soluble APIs can be mitigated by leveraging
external resources. Outsourcing to a CDMO has many advantages -
ultimately saving time and expense, with the bonus of working with
a team that is experienced in multiple techniques. This allows for a
better evaluation of compatible drug delivery systems and helps to
sidestep potential roadblocks in development and scale up.
Qualified contract developers will work in close collaboration with
their clients to fully understand the API and the desired drug product,
including communicating efficiently to define the target product
profile. Using a wealth of knowledge and experience, potential drug
delivery systems and bioavailability enhancement techniques can be
evaluated through feasibility studies. These are inexpensive and rapid
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Pharmaceutical Outsourcing Q3 2023

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