www.biopharminternational.com February 2020 BioPharm International eBook 19
results in a minimum-time robust
cycle, which will reduce manufac-
turing cost, produce consistently
pharmaceutically acceptable prod-
uct, and provide assurance that
the cycle is well within the capac-
ity of equipment failure points.
"The outcome of a design space
approach is a safe-zone of opera-
tion. During production activities,
the knowledge gained to develop
the safe-zone of operation can
facilitate the handling of any devi-
ations, resulting in reduced risks of
batch failure," she says.
TECHNICAL CHALLENGES
In addition to specialized knowl-
edge and skills, CDMO partners
will also need to have constructive
approaches to dealing with techni-
cal challenges that lyophilization
presents. There are a number of
factors that can impact the perfor-
mace of the freeze-dryer, for exam-
ple, including variables related to
equipment capability, such as shelf
cooling and heating rates, shelf
temperature uniformity and vac-
uum control, and the maximum
capacity of the condenser, Saffell-
Clemmer points out.
In addition, the geometry of the
glass vial has an impact on the
heat transfer from the lyophilizer
shelf to the product vial, and the
product formulation will impact
the rate at which water is removed.
"The desig n space approach to
cycle development results in an
understanding of how changes in
the variables in process or product
can impact the acceptability of the
cycle and ultimately the quality of
the final product. Without this sci-
entific knowledge, a lyophilization
service provider will not know how
to handle the inevitable deviations
that occur during manufacturing
and will discard acceptable prod-
uct unnecessarily," explains Saffell-
Clemmer.
OTHER CHALLENGES
Having the right partner for lyo-
philization can go a long way in
helping to tackle other biophar-
maceutical challenges for the pro-
cess. One such industry challenge
is that the development of process
monitoring tools for lyophiliza-
tion has lagged behind other man-
ufacturing unit operations, says
Saffell-Clemmer. Process monitor-
ing tools for lyophilization are typ-
ically limited to the monitoring of
shelf temperature and comparative
pressure monitoring, such as by
Pirani and capacitance manometer
gauges, which are used to deter-
mine the endpoint of sublimation,
she emphasizes.
"The implementation of pro -
cess monitor ing tools, such as
t u nable- d iode laser absor pt ion
sp e c t roscopy ( T DL A S), du r i ng
d e ve lop me nt a nd s c a le - up of
manufacturing can further aid in
determining the appropriate end-
point of primary drying," Saffell-
Clemmer says. She also explains
that the high cost of biologic drugs
and emerging therapies increases
the focus on yield, which can be
improved through non-destr uc-
t ive, on-l i ne pro duc t te st i ng.
"Techniques such as near infra-
red spectroscopy (NIR) can be used
to measure water content and, in
many cases, could be used as an
identity test of the product the vial
contains. Visual inspection of lyo-
philized cakes for visible particle
detection is challenging, and sam-
pling is required so that the prod-
uct can be reconstituted for further
visual examination," she adds.
Futhermore, innovation in X-ray
and other visible and sub-visible
imaging could eliminate the need
for sampling and allow for 100%
non-destructive automated inspec-
tion, Saffell- Clemmer explains.
With the increasing drug develop-
ment of gene therapies, in partic-
ular, the industry must focus on
developing innovations for gene
therapy product potency and sta-
bility that will catalyze develop-
ment of product formulations and
manufacturing processes to sup-
port the unique needs of biologics,
she concludes.
REFERENCES
1. Research and Markets, Lyophilization
Services for Biopharmaceuticals, 2017-
2027, ResearchandMarkets.com, April
2017.
2. FDA, "Novel Drug Approvals for 2017,"
FDA.gov, accessed Feb. 7, 2020.
3. FDA, "Novel Drug Approvals for 2018,"
FDA.gov, accessed Feb. 7, 2020.
4. FDA, "Novel Drug Approvals for 2019,"
FDA.gov, accessed Feb. 7, 2020.
5. NIIMBLE, Gene Therapy Roadmap
(NIIMBLE/BioPhorum Operations
Group, 2017).
6. Baxter, "Best Practices in Formulation
and Lyophilization Development:
Proteins, mAbs, and ADCs," Baxter
BioPharma Solutions White Paper,
accessed Jan. 20, 2019.
7. N. DiFranco, "Lyophilization of
Pharmaceuticals: An Overview,"
LubrizolCDMO.com, Oct. 8, 2019.
8. C. Challener, BioPharm International 30
(1) 32–35 (2017).
9. L. Wegiel and G. Sacha,
"Considerations for Development
of a Lyophilized Biosimilar," Baxter
BioPharma Solutions Case Studies,
2018. BP
Partnerships for Outsourcing Manufacturing
In addition to
specialized knowledge
and skills, CDMO
partners will also need
to have constructive
approaches to
dealing with
technical challenges
that lyophilization
presents.
