In our final webinar of the MDC Connects Series 2021 | A Guide to Complex Medicines. This slide deck takes a closer look at overcoming the challenges of scaling up a complex medicine. Graham Worrall and Emily Port, CPI

1. Copyright © 2019 Centre for Process Innovation Limited trading as CPI. All rights reserved.
Overcoming the challenges of
scaling up a complex medicine
Graham Worrall and Emily Port
Complex Medicines, Formulation

2. At CPI we help companies to
develop, prove, scale up and
commercialize new products and
processes
As part of the UK’s
High Value
Manufacturing
Catapult….. we
support growth in
advanced
manufacturing

3. Nanomedicines: formulation and manufacturing challenges
Interactions with biological systems (safety/efficacy) are highly dependent on
Nanomaterial characteristics – Manufacturing is critical to clinical success
Manufacturing
Process and In-
Process
Controls
Critical Quality
Attributes
Biological
Performance

4. System self-assembly
Combination of 2 streams to form nanoparticles
using a mixing device
Can combine use of in-line dilution to improve
stability of particles
Scale-up considerations
Step 1: run small scale development work to
understand system
Step 2: transfer to scale-up
Step 3: implement any development at scale to fine
tune parameters
Parameter Small scale Large scale
Volume 20 mL 10 L
Flow rate 12 mL/min 115 mL/min
Flow rate ratio Constant
Inputs Constant
Throughout scale-up, success is defined by consistent characterisation results, including
particle size, PDI, zeta potential and loading

5. Downstream processing
Allows clean up of product to:
• Remove impurities and unwanted solvent
• Exchange for final solvent system
• Concentrate to final volume
Scale-up considerations
Need to understand effects of:
• Shear rate, to ensure no damage to product
• Pressure in system and flux rate, to retain
filtration efficiency
Parameter Small scale Large scale
Volume 20 mL 10 L
Flow rate 50 mL/min 1 L/min
Filter surface area 100 cm2 5000 cm2
Filter pore size Constant
Throughout scale-up, success is defined by consistent characterisation results, including
particle size, PDI, zeta potential and loading

6. Additional scale-up considerations
Pre-experiment
Safety assessment, including
potent APIs and ATEX
requirements
During experiment
How to handle large volumes of
liquid, e.g. additional mixing
considerations for feeds
End of experiment
Clean down to avoid cross-
contamination
Waste disposal of large
volumes
Post-experiment
Environmental monitoring

7. Advancing complex medicines production
Accelerating the development of
complex medicines
Advancing the use of nanomedicines as targeted drugs to maximise
efficacy and minimise side effects, for example in the treatment of
cancer, or for use in vaccines.
OUTCOMES AND IMPACT
• Developing a unique test facility to support the microfluidic scale-up
of difficult-to-produce nanomedicines
2 years £765,372
Collaborative R&D
Purification
Manufacturing process Isolation In-vitro and in-vivo testing Characterisation

8. Advancing complex medicines production
Accelerating the
development of
complex medicines
Developing a continuous pilot line with in-line
purification via TFF and at-line analysis.
Permeate
9mL / min
Precision
Nanosystems
Blaze
10mL / min
Retentate
1mL / min
Diluent
9mL / min
Permeate
9mL / min
Retentate
1mL / min
Permeate
9mL / min
Diluent
9mL / min
Retentate
1mL / min
Diluent
9mL / min
10mL / min
At-line
particle sizing
Malvern Panalytical
Zetasizer AT
At-line particle sizing
Custom-built TFF
In-line product filtration
Precision
Nanosystems Blaze
Microfluidic production
Reproducible product
Organic phase Aqueous phase
Peristaltic
pumps
Pressure
sensors
Purification
Manufacturing process Isolation In-vitro and in-vivo testing Characterisation

9. Advancing complex medicines production
“This rapidly emerging technology has the potential to deliver drugs more
effectively and in a kinder way to patients. Together, we have
manufactured clinical grade gold nanoparticle treatments that are now
being investigated in clinical trials.”
Areitio Junquera, Project Co-ordinator
Midatech Pharma
Accelerating the development of
nano-pharmaceuticals
Developing new manufacturing methods and improving supply chain
co-ordination for Nano-pharmaceuticals, to advance treatments for rare
cancers, autoimmune diseases and viral infections.
OUTCOMES AND IMPACT
• Enabled treatments using nano-
pharmaceuticals to be advanced
into clinical settings
• Establishment of an open access
pilot line for the process
development, scale-up and
production of nano-pharmaceuticals
in both batch and continuous modes
4 years £6.3 million
Purification
Manufacturing process Isolation In-vitro and in-vivo testing Characterisation
Collaborative R&D
VALUE
• Production, formulation and final
production purification of both gold
nanoparticles with linkers, and of
active pharmaceuticals in support of
drug development

10. Advancing complex medicines production
Accelerating the development of
nano-pharmaceuticals
Developing new manufacturing methods and improving supply chain
co-ordination for nano-pharmaceuticals, to advance treatments for rare
cancers, autoimmune diseases and viral infections.
4 years £6.3 million
Collaborative R&D
Precursors and pumps Micro-mixing Clean and isolate
Purification
Manufacturing process Isolation In-vitro and in-vivo testing Characterisation

11. Emily Port
Team Leader – Nanopharmaceuticals
emily.port@uk-cpi.com