This presentation contains general scale-up challenges and solutions.

1. Scale-up of Nano-products:
Challenges and solutions
Presented By:
Shubham Bhise MS-Pharmaceutics
NIPER

2. Introduction
Preparation techniques
for Nano-products
Challenges to scale-up of
manufacturing for Nano-
products
Case
study
Conclusio
ns
2

3. “Scale up with respect to pharmaceutical manufacturing process is a translation involving the
transformation from microscopic (molecular) lab level to macroscopic (bulk) industrial commercial
level production”
Introduction to Scale-up
 Operationally scale up ratio is defined as follows:
“Scale up ratio= large scale production rate/small scale production rate”
 However, in literal sense, scale up is a process which could not be detailed by such a simple ratio.
 The design and development of scale up is emphasized because there is no framed algorithm which can
help the formulators predict the large scale performance of a product based on its small scale behaviour.
3
Levin M. Pharmaceutical process scale-up: CRC Press; 2001.

4. R&D Pilot-scale Scale-up
Large scale
production
Process of scale-up4

5. What do pilot scale and scale-up mean ?
Pilot-scale Scale-up
Intermediate
Batch scale
Next to
Pilot scale
Manufactures drug
product by a procedure
fully representative of and
simulatory to that of
manufacturing scale
Process of increasing
the batch size /
procedure for applying
the same process to
different output volumes
5

6. Challenges in manufacturing scale-up
Analytical characterization & quality control
challenges
Pharmacological & safety challenges
Regulatory challenges
Challenges associated with successful translation of
Nano products into commercial products
6
Agrahari V, et al. Challenges associated and approaches for successful translation of nanomedicines into commercial
products. Future Medicine; 2017.

7. Bottom-up process
Processes where the particles are created
from the molecular level up to
nanoparticle scale.
Top-down process
Processes where objects initially of the
millimetre or micrometre size are reduced to
the Nano-objects scale.
Preparation techniques for Nano products
Depending on the particle characteristics and sterility requirements,
different processing techniques are used
7
Nakach M, et al. Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations. Pharmaceutical
Nanotechnology: Innovation and Production, 2 Volumes. 2016.

8. Bottom-up process
Used for the manufacturing of
• Nanocrystalline,
• Nanoamorphous,
• Nanopolymeric suspension
The control of the particle growth/crystal growth using this technique is often very challenging.
Needs removal of the traces of the remaining solvent which is a difficult process
Thus scaling up of this process is difficult.
8
Nakach M, et al. Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations.
Pharmaceutical Nanotechnology: Innovation and Production, 2 Volumes. 2016.

9. Top-down process
Based on comminution technology: Bead mill or a high-pressure homogenizer
Used for
Solid nanoparticles,
Liposomes
9
Nakach M, et al. Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations.
Pharmaceutical Nanotechnology: Innovation and Production, 2 Volumes. 2016.

10. The top-down process has several advantages compared to the
bottom-up process
• Free from organic solvent
• Poorly soluble API can be processed
• Less number of manufacturing steps (four versus six)
• The target particle size of the suspension is more easily
obtained and controlled
• It is possible to process highly concentrated suspensions (up
to 40 wt%)
Advantages of Top-down process10

11. REPRODUCIBILITY
PHYSICAL
STABILITY
STERILITY
ENVIRONMENTAL
SAFETY
Challenges to scale up of
manufacturing for Nano products
11
Kraft JC, et al. Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery
systems. Journal of pharmaceutical sciences. 2014;103(1):29-52.

12. Reproducibility
 Minute changes in operating conditions can have pronounced effects on nanoparticles.
 Change in scale needs changes in process variables like time, flow, speed, agitation rate, equipment used
etc.
12
Kaur IP,et al. Issues and concerns in nanotech product development and its commercialization. Journal of Controlled
Release. 2014;193:51-62.
Alter the
product
characterist
ics
Alteration
in size
Altered
crystallinit
y
Change in
drug
entrapment
and release
characters
Developm
ent of
surface
charge
Drug
loading

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Implementation of a robust quality
control (QC) system and in-process
testing
Incorporating a quality by
design approach
Identification of the
product’s critical quality
attributes
Identification of process parameters that can be
deleterious for the product to ensure batch-to-batch
reproducibility.
Solutions to address reproducibility issues
Ragelle H,et al. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures.
Expert opinion on drug delivery. 2017;14(7):851-64.

14. Environmental
conditions(temperature, pH,
pressure),
Formulation parameters (raw
materials, ratio between the
different components, solvents
used)
Formulation operations (time,
speed, flow conditions)
Equipment used in the process
Critical
process
parameters
14

15. Physical Stability
Integrity Size distribution
Composition Intrinsic properties
Physical stability determined by following product characteristics:
15
Desai N. Challenges in development of nanoparticle-based therapeutics. The AAPS journal. 2012;14(2):282-95.

16. 16
Large scale
equipment
consumes more time
when compared to
lab equipment.
Long processing
times
Adverse conditions
Adsorption,
precipitation,
viscosity alterations
Processing temperature
may alter the physical
properties of drug.

17. Solutions to address physical stability
Critical manufacturing parameters
should be identified and evaluated
during development stage
Scale,
Shear force and
Temperature etc.
A robust formulation to retain the
stability of the product all through
its shelf life
Incorporating proper
choice of stabilizers
and redispersants
17

18. 18
Stability studies
To determine the stability of
the product and to predict
its shelf life.
Characterization of process
For filtering the processing
parameters
The design of
equipment should be
done according to
different scales of
study

19. Sterility
Nano products that are given
to by parenteral route
Sterilization is most important
step during production
Methods for
sterilization for
Nano products
Membra
ne
filtration
Autoclavin
g
Gamma
radiation
High
hydrostat
ic
pressure
Ethelyne
oxide
19
Vauthier C, Bouchemal K. Methods for the preparation and manufacture of polymeric nanoparticles.
Pharmaceutical research. 2009;26(5):1025-58.

20. Membrane
filtration
Loss of active
ingredient if size
is more than
220nm
Autoclaving
Particles
aggregation and
degradation due
to heat
Challenges associated with sterilisation process20

21. 21
Chemical
sterilization
with ethylene
oxide
Lead to toxic
residues
Difficulty in
redispersion of
Nano product
after
sterilization
High
hydrostatic
pressure
technique
Maintains the
integrity of
Nano product
More
complicated
and expensive
At large scale all
methods are not feasible
and each method is
associate with a
challenge

22. Solutions to address sterilization related problems
Selection of method of sterilization at large scale depends on type of Nano-product
to be produced
Gamma radiation seems to be most promising technique which does not alter
nanoparticles physicochemical characteristics ensuring sterility of injectable
nanoparticles
• Particle size,
• Yield,
• Zeta potential,
• Drug loading and
• In vitro release
22
Aseptic
manufacturing is
always an option.

23. Environmental safety
Large scale
production of
nanoparticles
Airborne
nanoparticles
distribute as
aerosols
Solvents used
during
preparation of
Nano products
Lung deposition
of such
nanoparticles
Pulmonary
Toxicities
23
Desai N. Challenges in development of nanoparticle-based therapeutics. The AAPS journal. 2012;14(2):282-95.

24. 24 Solutions to address environmental safety
 Nanoparticles that are created entirely within a liquid environment may have
significantly lower environmental impact.
 Proper disposal of solvents.

25. 25
Emulsification–diffusion
Scale-up production for emulsion-based methods was carried out
by increasing 20-fold the volume of the laboratory batches.
When increasing the stirring rate, the NP mean size clearly shifted
to smaller diameters.
The break-up phenomenon increased with batch size, leading to
smaller droplets in larger stirred tank.
Involves preparation of nanoparticles by three methods:
 Emulsification–diffusion
 Salting-out
 Nanoprecipitation

26. 26
Nanoparticle characteristics Lab scale Pilot scale
Mean diameter(nm) 293 287
Polydispersity index(0-1) 0.082 0.116
Ibuprofen loading (%) 7.7 5.5
Entrapment efficiency(%) 86 62
Residual PVAL(%) 4.8 5.0
Scanning electron micrographs of nanoparticles prepared at
laboratory and pilot scales by emulsification-diffusion
Comparison of the nanoparticles prepared at the laboratory and pilot scales

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Conclusions
Not much attention has been paid for the issues related to the scale-up process.
The success of any product, including nanomedicines, relies on its large-scale industrial production and
commercialization.
Therefore, the scientific community should pay more attention to the large-scale industrial production
after their successful development of the laboratory scale.
To face the challenges posed by the scale-up of nanomedicines, practical experimental designs could provide
efficient solutions. Once scale-up is achieved, nanomedicines will be made better available in the market for
the treatment of a myriad of diseases.

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1. Levin M. Pharmaceutical process scale-up: CRC Press; 2001.
2. Agrahari V, et al. Challenges associated and approaches for successful translation of nanomedicines into
commercial products. Future Medicine; 2017.
3. Nakach M, et al. Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical
Investigations. Pharmaceutical Nanotechnology: Innovation and Production, 2 Volumes. 2016.
4. Kraft JC, et al. Emerging research and clinical development trends of liposome and lipid nanoparticle drug
delivery systems. Journal of pharmaceutical sciences. 2014;103(1):29-52.
5. Kaur IP,et al. Issues and concerns in nanotech product development and its commercialization. Journal of
Controlled Release. 2014;193:51-62.
6. Ragelle H,et al. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field
matures. Expert opinion on drug delivery. 2017;14(7):851-64.
7. Desai N. Challenges in development of nanoparticle-based therapeutics. The AAPS journal. 2012;14(2):282-
95.
8. Srivalli KMR, et al. Drug nanocrystals: a way toward scale-up. Saudi Pharmaceutical Journal.
2016;24(4):386-404.
9. Galindo-Rodríguez SA, et al. Comparative scale-up of three methods for producing ibuprofen-loaded
nanoparticles. European journal of pharmaceutical sciences. 2005;25(4):357-67.
10. Vauthier C, et al. Methods for the preparation and manufacture of polymeric nanoparticles. Pharmaceutical
research. 2009;26(5):1025-58.
References

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