Implementing Fundamental Pharmaceutical

Science and Materials/Engineer Expertise

in Scale-up
2nd FDA/PQRI Conference on Advancing Product Quality
Session: The Science of Tech Transfer/Scale-up
North Bethesda, Maryland, October 05-07, 2015

Ecevit Bilgili
(E-mail: bilgece@njit.edu, Phone: 973-596-2998)
Associate Professor & Associate Chair
Department of Chemical, Biological, & Pharmaceutical Engineering
New Jersey Institute of Technology
Newark, NJ
 Outline
A chemical engineering perspective to unit ops. scale-up
Art or science/engineering or maybe both?
Scale-up or down? What to scale-up?
Fundamental, first-principle-based models (DEM/PBM/CFD)
Criticality of understanding the key physical transformations, measuring
relevant response variables and using scale-up rules/heuristics &
PAT/simulators

Case Study with Fluidized Bed Granulation (FBG) Scale-up

Brief intro to FBG
Demonstration of scale-up
Do scaling rules/PAT/surrogate tools work?

Conclusions and Outlook

The Concept of (FBG) Scale-up in Batch Processes

(~100 g)
(10-15 kg) (100-150 kg)

Product volume, batch size, and capacity increase with scale.

 Elements of a QbD Program
D. Ventura, American Association of Pharmaceutical Scientists Workshop, Sept. 2006

Robust Product

Formulation & Equipment

Materials

Process

The same elements are needed for successful scale-up! Scale-up/down is an

integral part of product (process/formulation) development.
 Fact: Scale-up still entails a marriage between
science/engineering and the art of making!
Unit ops. scale-up has evolved from traditional trial-error approach to
a creative activity involving scientific/engineering principles
More use of scale-up rules based on fundamental dimensionless #s and
empirical studies
More use of first-principle-based models based on continuum theories or
discrete particle interactions (DEM/PBM/CFD/FEM) & their combination
More use of PAT and data-driven process models

But the art of making/manufacturing did not disappear:

Scale-up: a creative process also requiring skills based on experience
(personal skills, company internal knowhow/culture) and observation of
process, equipment, and operational aspects as well as economics
Upon more use of scientific/engineering principles, the involvement of
the art component will be less significant.
 Scale-up or down? What to scale-up?
Scale-up is an integral part of product development. Process
development at small/pilot scale equipment must consider eventual
scale-up. In the selection of smaller scale equipment/process, we use
Scale-up rules for approximate scale-down
In-house experience/expertise, equipment knowledge, etc.
Retrospective studies of prior development activities
We cannot perform DOEs at every scale. Hence, understanding the
key physical transformations and considering equipment-
independent, “key response variables” for scale-up/down is critical.
Design space grows automatically if extensive process variables vs.
dimensionless or key response variables are used.

Scale-up Commercial Scale

Lab Scale Pilot Scale

 On Various Process Modeling Approaches
DEM Simulation: a
milling ball on
particles

CFD Simulation of Multiphase Flow in an FBG:

Volume fraction of powder
DEM-PBM Multi-Scale Modeling Approach for Dry Milling (Capece et al., 2015, Chem. Eng. Sci.)
Case Study: Scale-up of Fluidized
Bed Granulation (FBG) Process
ABC of FBG
 What is Fluid Bed Granulation?
Definition: A wet granulation process in which API(s)
and excipient powders, which are set in fluidization by
a heated gas, are bound together by binder droplets
originating from a two-fluid nozzle
Objective: Form granules that allow or improve
successful down-stream processing of pharmaceutical
materials (from blending to tabletting)

Materials: API(s), excipients, binder (usually dissolved

in a solvent prior to atomization)

Equipment: An FBG processer equipped with an air

handling unit (AHU), two-fluid atomizing nozzle, and
spray pump
 How does FBG Work?
Exhaust Air

Exhaust Fan

Police Filters

Filter Bags Expansion Chamber

Conical binder spray (droplets)

Two-fluid Nozzle Assembly
Product Bowl
Powder Bed
Air Ambient Air
Pump
Handling Sucked In
Unit
(AHU)
Binder Solution Inlet Plenum

Air Filters
 Fluid Bed Granulation Parameters
Equipment
Gas Distributor Plate:
type, nominal & open Area
Bowl-Expansion Chamber:
diameter, height, cone angle
Two-fluid Nozzle:
location on the column
number of nozzle heads
liquid tip, air cap size
relative position of tip/air cap
Air Handling Unit (AHU)
Filter Bag/Cartridge:
type, pore size, permeability
one-side vs. two-side shake,
Pulsation pressure
Process
Hydrodynamic Behavior:
Inlet air flow rate
Binder Soln. Dispersion &
Droplet Size Distribution:
dimensionless flux number,
spray rate, atomization
air pressure and flow rate
Product Bed Moisture Content
& Temperature:
Spray rate, excess air velocity,
inlet air flow rate, temperature,
and humidity
Bed height: batch size
Fines Incorporation:
shake duration & frequency,
inlet air flowrate
Formulation
Particle:
Density, size, shape,
surface characteristics,
porosity, friction, terminal
velocity, initial moisture,
dissolution, hydrophilicity,
wettability, mechanical
properties
Bulk/Powder:
Bulk/tap density, cohesion,
minimum fluidization and
bubbling velocity
Binder and Binder Solution:
Level, concentration,
viscosity, surface tension
11
 What is Fluidization? Fundamentals (I)
Fluidization Regimes as Determined by Superficial Air Velocity &
Material Characteristics

Vigorous bubbling/turbulent fluidization is key to a successful FBG process.

Schematic from a Lecture by Prof. J. Werther, 5th World Cong. on Particle Technol. 2006
 What is Fluidization? Fundamentals (II)
Geldart’s Classification of Powders

Lecture by Prof. J. Werther, 5th World Cong. on Particle Technol. 2006

Case Study: Scale-up of Fluidized
Bed Granulation Process
Scale-up to Ensure Key Response
Variables Remain Scale-Invariant
 Process Scale-up (I): What to Maintain?
Scaling rules based on
theory/modeling/heuristics/
Key Input experiments are needed!!!
Variables
Air Flow Rate, Q Key Response
Distributor Plate (Output) Variables
Area, A
Hydrodynamic Product
Spray Rate, S
Behavior
Characteristics
Inlet Air
Bed moisture and PSD
Temperature/RH
temperature
Atomization Air Drying-end-point
Droplet size moisture
Pressure, P
distribution
Number of nozzle Granule
Binder/saturation Morphology
heads, N
distribution
Spray foot-print Granule porosity
area, Af
 Process Scale-up (II): Scaling Rules for FBG
Key Input Scaling Rules
Variables (Connecting Input
to Response) Key Response
Air Flow Rate, Q
(Output) Variables
Distributor Plate Area,
A Q Hydrodynamic
ue = u − umf = − umf
A Behavior
Spray Rate, S
S Bed moisture and
Inlet Air Temperature , Tin , RH temperature
Q
and Humidity, Tin&RH
Atomization Air Flow Mehta (1988), S or S Droplet size
Rambali (2003) NM a2 NP 2
distribution
or Pressure, Ma or Pa a

3S Dimensionless Spray
Number of nozzle ψ=
heads, N 2 Pxd Flux (Litster, 2001) or
 ρ p ue A f  Akkermans Flux #,
Spray foot-print area, FN = log10   FN (1988)
 S 
Af
 Granule PSD upon Scale-up
100

Cumulative Mass Percent Retained (%)

Peak
LOD
80 45 L, 0219151:0042, 2.1%
45 L, 0219151:0043, 5.2%
45 L, 0219151:0044, 1.3%
420 L Scale Batch A, 1.6%
60 420 L Scale Batch B, 2.2%

40

20

0
0 200 400 600 800 1000

Sieve Opening Size (µm)

Similar granule PSD achieved at 420L scale in Batch B, after

slightly adjusting the spray rate from that in Batch A (Basis for
scale-up: Batch 0042 at 45 L scale).
 Conclusions & Outlook
More science/engineering vs. the art
More scale-up rules and modeling for process scale-up; no more
trial-error
A fundamental understanding of the underlying physical
transformations as opposed to “black-box” treatment of processes
To DesignOE or not to DesignOE upon scale-up? Too expensive,
impractical, …Not needed with establishment of good process
understanding at smal/pilot scales.
Design space in terms of scale-independent parameters
May provide regulatory flexibility for tech transfer
Instead of reestablishing the design space at each scale,
confirm the “relatively fixed design” space at larger scales