16 Pharmaceutical Technology REGULATORY SOURCEBOOK DECEMBER 2019 P h a r mTe c h . c o m
use of PAT and DoE much earlier in the process.
Within the past five years, high-throughput min-
iature bioreactors, which were previously used in
pre-clinical screening, have been replacing bench-
scale bioreactors in scale-down exercises. Scale-
down is an important step in scaling up processes
for current good manufacturing practices manu-
facturing in late-stage clinical development.
The devices eliminate the problems found with
microtiter plates, spin tubes, and shake f lasks,
which can be difficult to automate (1), and allow
more than 24 bioreactors to be run in parallel.
They are also fitted with analytics that can take
continuous readings on such crucial variables as
pH, dissolved oxygen, and pressure for each of
many samples.
Although developers have not yet filed new drug
applications (NDAs) with FDA mentioning this
technology, more companies including Genentech,
Merck, Biogen, Lonza, and FujiFilm are working
on this approach to scale-down (2). Developers are
using devices such as Sartorius Stedim's ambr 15
and 250 bioreactors (3). Starting in 2015, Sarto-
rius Stedim Biotech has integrated Umetrics' DoE
software with its ambr 15 and 250 high throughput
minibioreactors, later incorporated Nova Biomedi-
cal's BioProfile FLEX2 automated cell culture ana-
lyzer, to simplify PAT and QbD work, and make
scaleup and process optimization more efficient
(4). The approach is also being evaluated for use
in gene and cell therapy development.
If anything, these developments show the du-
rability and importance of DoE as a way to make
drug development (whether for small molecules or
biopharmaceuticals) more systematic. Equipment
and software evolution promises to make these
techniques, as well as QbD approaches, easier to
apply in the future.
References
1. M. Lourdes Velez-Suberbie et al, Biotechnology Progress, 31(1)
2018, pp 58-68,www.ncbi.nlm.nih.gov/pmc/articles/
PMC5836883/
2. F. Slingsby and S. Dewar, "Use of the ambr 250 in Conjunction
with High Throughput Design and Analysis Tools for Rapid,
Scaleable USP development," Fujifilm White Paper, January 15,
2015.
3. V. Sandner et al, "Scale-Down Model Development in Ambr
Systems: An Industrial Perspective," https://fujifilmdiosynth.
com/assets/Scale-Down-Model-Development-in-ambr-systems-
An-industrial-Perspective.pdf.
4. Sartorius-Stedim Biotechnology, Product Brochure, 2019.
PT
Design of Experiments
Scale-down is an important
step in scaling up
processes for current good
manufacturing practices
manufacturing in late-stage
clinical development.
Visit PharmTech.com to read the following articles about quality and process
development:
• AQbD, the Evolution of Pharmacopoeial Standards?
www.PharmTech.com/aqbd-evolution-pharmacopoeial-standards
• QbD Takes Shape for Topical Pharmaceuticals
www.PharmTech.com/qbd-takes-shape-topical-pharmaceuticals
• Design Space Characterization and
Risk Assessment Through Mechanistic Modeling
www.PharmTech.com/design-space-characterization-
and-risk-assessment-through-mechanistic-modeling
• QbD and API Process Development:
A Marriage of Chemistry and Engineering
www.PharmTech.com/qbd-and-api-process-
development-marriage-chemistry-and-engineering
• Simple by Design
www.PharmTech.com/simple-design
• QbD: Improving Pharmaceutical Development and
Manufacturing Workflows to Deliver Better Patient Outcomes
www.PharmTech.com/qbd-improving-pharmaceutical-
development-and-manufacturing-workflows-
deliver-better-patient-outcomes
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