PRESENTED BY:

KALPESH K. MEHTA
DEPARTMENT OF INDUSTRIAL PHARMACY
S.K.PATEL COLLEGE OF PHARMACEUTICAL
EDUCATION & RESEARCH
GANPAT UNIVERSITY
KHERVA-MEHSANA
Pilot Scale and Scale-Up
Pilot Scale
Scale-Up
R & D
Large Scale
Production
at Do Pilot Scale and Scale-
Up Mean ?
INTERMEDIATE
BATCH SCALE
MANUFACTURES DRUG
PRODUCT BY A PROCEDURE
FULLY REPRESRNTATIVE OF AND
SIMULATORY TO THAT OF
MANUFACTURING SCALE
PILOT SCALE SCALE-UP
NEXT TO
PILOT SCALE
PROCESS OF INCREASING
THE BATCH SIZE (MIXING) /
PROCEDURE FOR APPLYING
THE SAME PROCESS TO
DIFFERENT OUTPUT VOLUMES
(TABLETTING)
Benc 8tudie8 (product caracterization , purity)
Animal 8tudie8 (toxicology , parmacokinetic8-ADME ,
eIIicacy)
Clinical 8tudie8
Increa8ing compliance wit regulation8 a8 product move8
troug te8ting and evaluation
Increa8ing knowledge about te product
Increa8ing knowledge about te po88ible problem8, 8nag8,
pitIall8 wit manuIacturing, proce88ing, packing, 8toring
(and in8talling) te product
Ultimately Iacilitate8 te tran8Ier oI product Irom
laboratory into production
y Pilot Scale ?
y Scale-Up ?
A well deIined
proce88
But may Iail in
QA te8t8
Becau8e
proce88e8 are
8cale dependent
Scale-Up is necessary to
determine the effect of scale
on product quality
Formulation related
IndentiIication and
control oI critical
component8 and oter
variable8
Equipment related
IdentiIication and
control oI critical
parameter8 and operating
range8
Production and
Process related
Evaluation, validation,
and Iinalization oI
control8
Product related
Development and
validation oI
reproce88ing
procedure8
Documentation
Record8 and report8 according to cGMP
Ability to
wit8tand
batc 8cale
Compatibility oI
te equipment
wit te Iormulation
Layout oI
te related
Iunction8
Market
requirement
Availability oI
te raw material8
meeting te
8peciIication8
Co8t Iactor
Py8ical 8pace
required
Proce88
modiIication
Sould Adequately
monitor te proce88
To provide te a88urance tat
te proce88 i8 under control
Te product produced maintain8
te 8peciIied attribute8 originally
intended
Pilot Plant De8ign
Formulation and
Proce88 Development
Tecnology evaluation,
Scale-Up and
Tran8Ier
Clinical 8upply
manuIacture
Attribute8 required ...
cGMP Compliance
A Ilexible igly trained 8taII
Equipment to 8upport multiple do8age Iorm development
Equipment at multiple 8cale8 ba8ed on 8imilarly operating
principle8 to to8e in production (Intermediate 8ized and
Full 8cale equipment)
Portable equipment
Multipurpo8e room8
Re8tricted acce88 , regulated per8onnel Ilow and material
Ilow
Low maintenance and operating co8t8
Operational
A8pect8
Validation
Training
Engineering 8upport
Maintenance and
Calibration
Inventory, Order8,
Labeling
Material control
Proce88 &
ManuIacturing
Activitie8
QA & QC

l
l
0

1
l
0
8
De8ign
8peciIication8
In8tallation
QualiIication
Operational
QualiIication
PerIormance
QualiIication
Compliance wit
cGMPand
FDA 8tandard8
Compliance wit
GMP
SaIety and
environmental
re8pon8ibilitie8
Compliance wit
SOP8
Tecnical 8kill8
and knowledge
18l8l86
l86l8ll8l86 $0FF081
De8ign oI Iacility
Con8truction
oI Iacility
Co-ordination, 8ceduling,
direction oI ongoing operation8
Validation
oI Iacility
To en8ure data
integrity and
equipment reliability
To meet cGMP
norm8
N8ll0800 8 08ll0f8ll0
00M00l0flI08 898l0M
Material
control
Inventory
Order8
(FIFO)
Labeling
(GMP-GLP)
F800l$$
80
N80f0108l86
01ll1ll$
Formulation &
Proce88 Development
8tudie8
Tecnology evaluation,
ScaleUp, & Tran8Ier
Clinical 8upply
manuIacture
QUALITY ASSURANCE QUALITY ASSURANCE
Auditing pilot plant
Auditing and approval oI component 8upplier8
Reviewing, approval and maintaining batc record8 Ior
clinical 8upplie8
Sampling and relea8e oI raw material8 and component8
required Ior clinical 8upplie8
Relea8e oI clinical 8upplie8
Maintaining and di8tributing Iacility and operating procedure8
(SOP8)
Review and approval oI validation and engineering
documentation
QUALITY CONTROL QUALITY CONTROL
Relea8e Te8ting oI Iini8ed product
Py8ical, Cemical and Microbiological te8ting oI Iini8ed
clinical product8, component8 required Ior clinical 8upplie8
Te8ting Ior validation and revalidation program8
QC in-proce88 te8ting during development, Scale-Up and
Tecnology tran8Ier activitie8
Per8onnel Requirement8
Equipment Requirement8
Space Requirement8
Proce88 Evaluation
Preparation oI Ma8ter ManuIacturing Procedure8
GMP Con8ideration8
Fl8$088ll
8l00l8lNl81$
Teoretical Knowledge
oI Parmaceutic8
Ability to
communicate
Practical experience
in parmaceutical
indu8try
Engineering
Capability
Knowledge oI electronic8
and computer8
l00lFNl81 8l00l8lNl81$ l00lFNl81 8l00l8lNl81$
Equipment 8elected ba8ed on proce88ing caracteri8tic8
oI product
Mo8t economical, 8imple8t and eIIicient
Te 8ize 8ould be relevant to production 8ized batce8
Ea8e oI cleaning
Time oI cleaning
$F0l 8l00l8lNl81$
Admini8tration and InIormation Proce88ing
Py8ical Te8ting Area
Standard Pilot Plant Equipment Floor Space
Storage Area
Separate Ior API and Excipient8 and Iurter 8egregated into area Ior
approved and unapproved material8
Inproce88 material8, Iini8ed bulk product8, retained 8ample8, experimental
production batce8, packaging material8
Controlled enviornment 8pace Ior Stability Sample8
Proce88 parameter8 8ould be evaluated and
optimized.
For example : Mixing
Order oI addition
Mixing 8peed
Mixing time
Rate oI addition etc.,
F800l$$ ll01l08
Cemical weig 8eet
IdentiIy te cemical8
It8 quanitity
Te order oI u8ing
Te 8ampling direction8
Proce88 8peciIication8
Sould be in under8tandable language
In proce88 and Iini8ed product 8peciIication8
Proper documentation required
Proce88 Validation
Regular proce88 review and revalidation
Relevant written Standard Operating Procedure8
Equipment QualiIication
Regularly 8ceduled preventive maintenance
contd...
6NF 008$l0l81l08$
Validated cleaning procedure8
An orderly arrangement oI equipment 8o a8 to ea8e
material Ilow and prevent cro88-contamination
A well deIined tecnology tran8Ier 8y8tem
Te u8e oI competent, tecnically qualiIied per8onnel
Adequate provi8ion Ior training oI per8onnel
MATEPIAL/POWDEP HAMDLIM0
Two primary concern8 : Acieving reliable Ilow
and maintaining blend uniIormity.
Segregation lead8 to poor product uniIormity.
Handling 8y8tem :
- Mu8t deliver te accurate amount oI te
ingredient
- Material lo88 8ould be le88
- Tere 8ould be no cro88 contamination
Avoiding 8egregation ...
ModiIy te powder in a way to reduce it8 inerent tendency to
8egregate
Cange te particle 8ize 8uc tat te active 8egregation
mecani8m become8 le88 dominant
Cange te coe8ivene88 oI te powder 8uc tat te particle8 in a
bed oI powder are le88 likely to move independent oI eac oter
ModiIy te equipment to reduce Iorce8 tat act to 8egregate te
powder
Cange te equipment to provide remixing
DPY 8LEMDIM0
Dry blend 8ould take place in granulation ve88el
Larger batc may be dry blended and ten 8ubdivided
into multiple 8ection8 Ior granulation.
All ingredient8 8ould be Iree oI lump8 oterwi8e it
cau8e8 Ilow problem8.
Screening and/or milling oI te ingredient8 prior to
blending u8ually make8 te proce88 more reliable and
reproducible.
0PAMULATIOM
Te weigt oI te material and te 8ear Iorce8
generated by granulation equipment.
Te u8e oI multiIunctional proce88or8
(8igniIicant in term8 oI 8pace and manpower
requirement8).
Vi8co8ity oI te granulating 8olution.
LUIDISED 8ED 0PAMULATIOMS
Proce88 inlet air temperature
Atomization Air Pre88ure
Air Volume
Liquid Spray Rate
Nozzle Po8ition and Number oI Spray Head8
Product and Exau8t Air Temperature
Filter Poro8ity
Cleaning Frequency
Bowl Capacity
DPYIM0
HOT AIR OVEN
FLUIDIZED BED DRYER
Hot Air Oven
Air Ilow
Air Temperature
Dept oI te granulation on te tray8
Monitoring oI te drying proce88 by te u8e oI moi8ture
and temperature probe8
Drying time8 at 8peciIied temperature8 and air Ilow
rate8 Ior eac product
Fluidized Bed Dryer
Optimum Load
Air Flow Rate
Inlet Air Temperature
Humidity oI te Incoming Air
PAPTICLE SIZE PEDUCTIOM
Sizing play8 a key role in acieving uniIormity.
Tere are two way8 oI 8izing : Particle 8ize
8eparation and Particle 8ize reduction.
Maior Factor Feed rate oI te material.
A8 te Ieed rate i8 increa8ed 8o i8 re8idence time
wit in te camber oI te equipment wic in
turn re8ult8 in Iiner di8tribution.
During 8cale up, overead Ieeding equipment i8
incorporated to mimic large 8cale production.
8LEMDIM0
o Blender load8
o Blender 8ize
o Mixing 8peed
o Mixing time
o Bulk den8ity oI te raw material (con8idered in
8electing blender and in determining optimum
load)
o Caracteri8tic8 oI te material
SPECIALISED 0PAMULATIOM
PPOCEDUPES
Dry Blending and Direct Compre88ion
Slugging (Dry Granulation)
Dry 8Iendinq ond Direcf Compression
Te order oI addition oI component8 to te blender
Te blender load
Te mixing 8peed
Te mixing time
Te u8e oI auxiliary di8per8ion equipment witin te mixer
Te mixing action
Compre88ion Iorce
SIuqqinq (Dry 0ronuIofion)
Force8 u8ed Ior 8lugging operation
Te diameter oI te punce8
Sub8equent 8izing and 8creening operation8
0PAMULATIOM HAMDLIM0
AMD EED SYSTEM
Evaluation oI vacuum automated andling
8y8tem8 and mecanical 8y8tem8
Segregation : Due to 8tatic carge8 built up due to
vacuum can alter material Ilow property
Te eIIect oI above 8y8tem on te content
uniIormity oI te drug and on te particle 8ize
COMPPESSIOM
Pre88 8peed
Handling and compre88ion caracteri8tic8 (in
te 8election oI a tablet pre88)
Die Iilling rate
Flow rate oI granule8
Induced die Ieed 8y8tem8 (Ior ig 8peed
macine8) 8peed oI Ieed paddle8
Te clearance between te 8craper blade and te
die table
De8ign and condition oI te punce8
TA8LET COATIM0 (ILM COATIM0)
Pan Coating
Fluidized Bed Coating
Pon ond Iuidized Coofinq
Optimum tablet load
Operating tablet bed temperature
Drying airIlow rate and temperature
Te 8olution application rate
Te 8ize and 8ape oI te nozzle aperture (Ior airle88
8prayer)
Te atomizing air pre88ure and te liquid Ilow rate (Ior
air atomized 8prayer8)
Pon Coofinq
Fixed Operating
Parameters
Variable Operating
Parameters
Other
Parameters
Pan Loading (kg)
Solid content oI coating
8u8pen8ion (w/w)
Spray gun dynamic8
Drying Air (cIm)
Inlet air temperature
( C )
Gun to tablet bed
di8tance
Coating Sy8tem Spray rate (g min
-1
)
Quantity oI coating
applied (w/w)
Atomizing air pre88ure (p8i,
bar)
Air Pre88ure (p8i, bar)
Pan 8peed
Number oI 8pray gun8
Iuidized 8ed Coofinq
Batc 8ize
Drying/Iluidizing air volume8
Spray nozzle dynamic8
Spray evaporation rate
SOLUTIOM
Tank 8ize (diameter)
Impeller type
Impeller diameter
Rotational 8peed oI te impeller
Number oI te impeller8
Number oI baIIle8
Mixing capability oI impeller
Clearance between impeller blade8 and wall oI te mixing tank
Contd...
Heigt oI te Iilled volume in te tank
Filteration equipment (8ould not remove active or
adiuvant ingredient8)
Tran8Ier 8y8tem
Pa88ivation oI 8tainle88 8teel (pre reacting te SS wit
acetic acid or nitric acid 8olution to remove te
8urIace alkalinity oI te SS)
SUSPEMSIOM
Addition and di8per8ion oI 8u8pending agent8 (Vibrating
Ieed 8y8tem at production 8cale)
Hydration/etting oI 8u8pending agent
Time and temperature required Ior ydration oI
8u8pending agent
Mixing 8peed8 (Hig 8peed lead to air entrapment)
Selection oI te equipment according to batc 8ize
Ver8ator (to avoid air entrapment)
Me8 8ize (8ould not Iilter out any oI te active
ingredient8)
EMULSIOM
Temperature
Mixing Equipment
Homogenizing Equipment
In proce88 or Iinal product Iilter8
Screen8, pump8 and Iilling equipment
Pa8e volume8
Pa8e vi8co8itie8
Pa8e den8itie8
Mixing equipment
Motor8 (u8ed to drive mixing 8y8tem and mu8t be 8ized to andle
te product at it8 mo8t vi8cou8 8tage)
Mixing 8peed
Component omogenization
Heating and cooling proce88
Addition oI active ingredient8
Product tran8Ier
orking temperature range (critical to te quality oI te Iinal
product)
Sear during andling and tran8Ier Irom
manuIacturing to olding tank to Iilling line8
Tran8Ier pump8
ile coo8ing 8ize and type oI pump :
Product vi8co8ity
Pumping rate
Product compatibility wit te pump 8urIace
Pumping pre88ure
required 8ould be con8idered
PAPEMTEPAL SOLUTIOM
It i8 liquid 8cale up ta8k
Mixing i8 one oI te important proce88 to be
8caled up
Large 8cale mixing -- Flow
Small 8cale mixing -- Sear
Geometric Iactor8 :-
-- Diameter oI te impeller (D)
-- Diameter oI te tank (T)
-- Heigt oI te liquid in te ve88el (Z)
-- Impeller 8peed
Sterilization equipment
Filteration equipment
Pump8
Packaging equipment
al8o ave to be 8caled up.
Te de8ign and Scale-up oI biological proce88e8 i8 very
callenging.
Parameter8 to be con8idered Ior 8cale-up oI
biotecnology product8 are :
Bioreactor Operation
Filteration Operation
CentriIugation
Cromatograpy
Viral Clearance
8IOPEACTOP OPEPATIOM
(STIPPED TAMI)
Impeller rate
Aeration rate
Hydro8tatic pre88ure
Agitation rate
Mixing time
ILTEPATIOM OPEPATIOM
Tran8membrane pre88ure
Volume
Operating time
Temperature
Flux rate
Protein concentration
Solution vi8co8ity
Retentate Ilow rate
Permeate Ilux
Oter variable8 u8ed in 8cale-up work Ior Iilteration
are :
Te lengt oI te Iiber8 (L)
Te Iiber diameter (D)
Te number oI Iiber8 per cartridge (n)
Te den8ity oI te culture (p)
Te vi8co8ity oI te culture ()
From te8e variable8, 8cale-up parameter8 8uc a8
wall 8ear rate and it8 eIIect on Ilux are derived.
CHPOMATO0PAPHY
Gel Capacity
Linear Velocity
BuIIer Volume
Bed Heigt
Temperature
Cleanability
Gel liIetime
pH oI te elution buIIer
Conductivity oI te elution buIIer
'IPAL CLEAPAMCE
It i8 very important part oI te proce88 de8ign
Ior biotecnology product.
It i8 al8o to be 8caled up.
PRINCIPLES OF SIMILARITY
GEOMETRIC
SIMILARITY
MECHANICAL
SIMILARITY
THERMAL
SIMILARITY
CHEMICAL
SIMILARITY
STATIC
SIMILARITY
KINEMATIC
SIMILARITY
DYNAMIC
SIMILARITY
0EOMETPIC SIMILAPITY
Similarity wit re8pect to geometrical Iactor8
i.e. 8ape, eigt, tickne88, breadt, etc.,
Small 8cale and large 8cale equipment8 mu8t be
in 8cale ratio oI 1:2, 1:5, 1:20 etc.,
MECHAMICAL SIMILAPITY
Concerned wit application oI Iorce to a 8tationary or moving
8y8tem.
Static 8imilarity It i8 te deIormation oI one body or
8tructure to tat oI an oter under con8tant 8tre88.
Kinematic 8imilarity Corre8ponding moving particle8 take
8imilar pat in te corre8ponding time interval.
Dynamic 8imilarity Force8 wic accelerate or retard te
motion oI material8.
Moving 8y8tem8 are dynamically 8imilar wen te ratio oI all
Iorce8 i8 equal.
It i8 u8eIul in te prediction oI pre88ure drop8, power
con8umption.
NOTE
Sy8tem8 exibit mecanical
8imilarity only iI tey are
geometrically 8imilar
THEPMAL SIMILAPITY
It i8 concerned wit Ilow oI eat (by radiation,
conduction, convection, or te bulk tran8Ier oI
material).
Geometrically 8imilar 8y8tem8 are termally
8imilar wen temperature diIIerence bear8
con8tant ratio and in moving 8y8tem8 it mu8t
ave kinematic 8imilarity.
CHEMICAL SIMILAPITY
It i8 concerned wit te variation in cemical
compo8ition Irom point to point a8 a Iunction oI
time.
It i8 related to exi8tence oI comparable concentration
gradient8.
It i8 dependent upon bot termal and kinematic
8imilarity.
Marketing Formulation
DeIined
Proce88 Development
IdentiIy critical proce88
and packaging parameter8
Pilot 8cale 8tudie8
Scale-Up/Stability/
Clinical Supply batce8
Site Selection
Initial large 8cale proce88
qualiIication 8tudie8
Development Report
Scale-Up Report
NDA Submi88ion
ManuIacture Validation
Batce8
Large 8cale proce88 qualiIication
8tudie8
Product tran8Ier document i88ued
Product acceptance by manuIacturing
Validation protocol written
Pre approval in8pection by FDA
ManuIacturing 8ite preparation
Validation Report
NDA Approval
Production Start Up
FDA Approval to
market product
Product Launc
A toroug under8tanding oI te integration oI
8cale Iactor8, Iacility de8ign, equipment de8ign
and proce88 perIormance i8 nece88ary Ior 8cale-
up and proce88 tran8Ier.
CONCLUSION
at i8 te diIIerence between Pilot Scale and Scale-Up?
| 1 mark |
Outline te Pilot Plant Operation and give brieI note on
eac . | 5 mark8 |
Enumerate te parameter8 tat 8ould be con8idered
during te 8cale up oI Tablet Coating ? | 2 mark8 |
Give a brieI note on Scale-Up oI Biotecnology-Derived
Product8 and Parenteral Solution8 . | 5 mark8 |
at are te 8tep8 involved in tran8Ier oI a Iormulation
rigt Irom F&D to Production Facility ? | 5 mark8 |
The Theory and Practice of Industrial Pharmacy : Leon Lacman,
Herbert A Lieberman , Jo8ep L Kanig : Section IV : Capter 23 : Pilot
Plant Scale-Up Tecnique8 : Page No . 681 710 .
Encylopedia of Pharmaceutical Technology : Jame8 Swarbrick , Jame8 C Boylan
: Volume 12 : Pilot Plant De8ign : Page No . 171 186 .
Pilot Plant Operation : Page No . 187 208 .
Drugs and The Pharmaceutical Sciences : Pharmaceutical Process Scale-Up :
Marcel Dekker 8erie8 : Micael Levin : Volume 118
Parenteral Drug Scale-Up : Page No. 43 56 .
Scale-Up Con8ideration8 Ior Biotecnology-Derived Product8 :
Page No. 95 114
Powder Handling : Page No. 133 150 .
Scale-Up oI Film Coating : Page No. 259 310 .
REFERENCES