APR January/February 2022 - 42

» MANUFACTURING
»
susceptible than small molecules to degradation by agitation, sheer
stress, and prolonged exposure to high room temperatures or more
direct heat sources.
In cases where the active pharmaceutical ingredient is a large molecule,
the filling process itself is a factor in the behavior and stability of the
product. Because large molecules are inherently more fragile, using
the wrong protocol can hamper the effectiveness of the finished
product. And because small batch sizes require the same amount of
QC testing as large batches, smaller batches can be more expensive to
produce, on a per-unit basis.
The shearing forces from rotary piston pumps used to fill vials can also
damage large molecules. Furthermore, because large molecules can
create a more viscous product, inconsistent filling is not uncommon.
As the viscosity of the product increases, sterile filtering becomes
more difficult.
To guard against instability or degradation of the product, large
molecule solutions must be handled gently, under carefully
controlled temperatures. Unless the sterile fill process is approved
for large molecule products, just going through the pump and
fill line may be enough to compromise the product's potency or
structural integrity.
These are not inherently obvious problems. A lot of knowledge and
experience is involved. Manufacturers need to understand as much as
possible about protein physiology and the ways in which production
processes can adversely affect molecular structures - and the function
and stability of the finished product.
Finding a CDMO partner
As may be clear by now, there are many moving parts to the challenge
of sterile fill/finish, not just for companies working with large
molecules, but especially for companies manufacturing such products
in small batches. Coordinating all those moving parts and levels of
experience is difficult, and thus identifying a CDMO partner that can
assist in development of formulations, and appreciates the challenges
described above, is critical.
Finding the right partner can be its own challenge, though. Many
sterile fill labs focus on large batch sizes, so they may lack the skill
set to meet the needs of smaller manufacturers. What's more, larger
companies occupy much of the already-scarce space available in
sterile fill CDMOs, making smaller companies - for example, makers
of cell and gene therapies - scramble for what's left over. That's why
a CDMO specializing in small batch manufacturing would also be the
ideal partner for producing large molecule drug products.
So, how should a company go about selecting an aseptic CDMO? The
right partner should have a solid relationship with the local FDA/DEA
District Office, along with a positive reputation for their overall Quality
System Program, managed and run by technicians with appropriate
demonstrated experience.
Is the CDMO's equipment suited to fill product in the desired
configurations (vials, syringes, cartridges, etc.)? Does the CDMO have
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the proper certifications to manufacture and support the product in
its current phase? Can they meet the turnaround timetable required to
manufacture and release the product for human testing?
The CDMO must have experience with working with large molecules.
The filling of large molecule therapeutics uses a much smaller and
different scale and unit than small molecules.
A CDMO with experience in large molecules will make designing the
sterile fill process that much easier. They will innately understand the
necessary pump and fill rates, the size of tubing required for larger viral
particles or cells, and the different methods of sterilization demanded
by the operation, for example.
Perhaps the bandwidth shortage among large batch CDMOs is
actually opening up a new market for companies focused on serving
small batch developers. As personalized medicine starts taking up
more market share, more companies catering to small batch fill-finish
will need to emerge.
For now, it's incumbent on the developer to ensure they work with
a CDMO that is experienced in small batch skills and techniques -
and has the available time to devote to the particular needs of small
batch producers. That is the best way to ensure that products are safe,
pure, effective, and fit for intended use, and stay that way from the
manufacturing plant through their use by patients.
Author Biographies
Alex Garner's experience extends from Chemistry and Manufacturing
Controls (CMC) development, process and formulation development,
clinical trial batch manufacturing, through packaging and
documentation. His background provides a wealth of knowledge and
comprehensive support to biopharmaceutical clients whose product
portfolios include small and large molecule development.
Frank Manella's expertise extends to the design, construction, and
operation of contract manufacturing facilities (CMOs) capable of filling
potent and non-potent sterile compounds. The growth of several aseptic
CDMO businesses, as well as the successful licensing of various new
chemical entities and ANDA and NDA filings, have been accelerated
as a result of his technical background and deep understanding of the
pharmaceutical, biotechnology, and IVD/medical device industries.
Khanh Ngo Courtney's experience extends from R&D to analytical
method development, validation, implementation, method transfer,
and optimization of test methods for the cGMP setting per USP and
ICH guidelines. These skills provide her with the foundation for effective
authorship of INDs, BLAs and MAAs for biological therapeutic molecules,
as well as responses to requests and questions from the FDA, EMA,
and PMDA. Khanh holds a PhD in Biochemistry from the University of
Wisconsin-Madison.

APR January/February 2022

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