This document discusses pilot plant design, operation, and scale up considerations for pharmaceutical manufacturing processes. It provides an overview of the need for pilot plants and scale up to transfer processes from the laboratory to production scale. Key sections include descriptions of pilot plant attributes, operational aspects like validation and training, scale up principles of similarity, and development milestones from formulation through clinical and commercial production. Process parameters that should be evaluated at various stages like mixing, drying, milling and compression are also outlined.

1. By,
Mr. Nitin M. Kadam
R&D (Formulation)
Micro Labs Limited.

2. Content
 Introduction
 Pilot plant design
 Pilot plant operation
 Requirements
 Scale up consideration
 Principles of similarity
 Development milestones

3. INTRODUCTIONINTRODUCTION

4. Pilot Scale and Scale-Up
Pilot Scale
Scale-Up
R & D
Large Scale
Production

5. Pilot Scale and Scale-Up Means ?
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)

6.  Ultimately facilitates the transfer of product from laboratory into production
 Bench studies (product characterization , purity)
 Animal studies (toxicology , pharmacokinetics-ADME , efficacy)
 Clinical studies
 Increasing compliance with regulations as product moves through testing and
evaluation
 Increasing knowledge about the product
 Increasing knowledge about the possible problems, snags, pitfalls with manufacturing,
processing, packing, storing (and installing) the product
Need of Pilot
Scale ?

7. Need of Scale-Up ? A well defined
process
A perfect product
in laboratory and
pilot plant
But may fail in
QA tests
Because
processes are
scale dependent
Processes
behave
differently on a
small scale and
on a large scale
Scale-Up is necessary to
determine the effect of scale
on product quality

8. Formulation related
Indentification and
control of critical
components and other
variables
Equipment related
Identification and
control of critical
parameters and operating
ranges
Production and
Process related
Evaluation, validation,
and finalization of
controls
Product related
Development and
validation of
reprocessing
procedures
Documentation
Records and reports according to cGMP

9.  Ability to withstand batch scale
 Process modification
 Compatibility of the equipment with the formulation
 Cost factor
 Physical space required
 Market requirement
 Layout of the related functions
 Availability of the raw materials meeting the specifications

10.  Should Adequately monitor the process
 To provide the assurance that the process is under control
 The product produced maintains the specified attributes
originally intended

12. Pilot Plant Design
Formulation and
Process Development
Technology evaluation,
Scale-Up and
Transfer
Clinical supply
manufacture

13. Attributes required …..
 cGMP Compliance
 A flexible highly trained staff
 Equipment to support multiple dosage form development
 Equipment at multiple scales based on similarly operating
principles to those in production (Intermediate sized and Full
scale equipment)
 Portable equipment
 Multipurpose rooms
 Restricted access , regulated personnel flow and material flow
 Low maintenance and operating costs

14. Pilot Plant OperationPilot Plant Operation

15. OperationalOperational
AspectsAspects
OperationalOperational
AspectsAspects
Validation
Training
Engineering
support
Maintenance and
Calibration
Inventory, Orders,
Labeling
Material control
Process &
Manufacturing
Activities
QA & QC

16. V
A
L
I
D
A
T
I
O
N
V
A
L
I
D
A
T
I
O
N
Design
specifications
Design
specifications
Installation
Qualification
Installation
Qualification
Operational
Qualification
Operational
Qualification
Performance
Qualification
Performance
Qualification
Compliance with cGMP and FDA standardsCompliance with cGMP and FDA standards

17. Compliance with
GMP
Safety and
environmental
responsibilities
Compliance with
SOPs
Technical skills
and knowledge
TrainingTraining

18. Engineering SupportEngineering Support
Design of facility
Construction
of facility
Co-ordination, scheduling,
direction of ongoing operations
Validation
of facility

19. To ensure data
integrity and
equipment reliability
To meet cGMPTo meet cGMP
normsnorms
Maintenance & CalibrationMaintenance & Calibration

20. Computerized SystemComputerized System
Material
control
Material
control
InventoryInventory
Orders
(FIFO)
Orders
(FIFO)
Labeling
(GMP-GLP)
Labeling
(GMP-GLP)

21. ProcessProcess
AndAnd
ManufacturingManufacturing
ActivitiesActivities
Formulation &Formulation &
Process DevelopmentProcess Development
studiesstudies
Technology evaluation,Technology evaluation,
Scale Up, & TransferScale Up, & Transfer
Clinical supplyClinical supply
manufacturemanufacture

22. Quality AssuranceQuality AssuranceQuality AssuranceQuality Assurance
 Auditing pilot plant
 Auditing and approval of component suppliers
 Reviewing, approval and maintaining batch records for clinical supplies
 Sampling and release of raw materials and components required for
clinical supplies
 Release of clinical supplies
 Maintaining and distributing facility and operating procedures (SOPs)
 Review and approval of validation and engineering documentation

23. QUALITY CONTROLQUALITY CONTROL
 Release Testing of finished product
 Physical, Chemical and Microbiological testing of finished
clinical products, components required for clinical supplies
 Testing for validation and revalidation programs
 QC in-process testing during development, Scale-Up and
 Technology transfer activities

25. 1. Personnel Requirements
2. Equipment Requirements
3. Space Requirements
4. Process Evaluation
5. Preparation of Master Manufacturing
Procedures
6. GMP Considerations

26. PERSONNEL
REQUIREMENTS
Theoretical Knowledge
of Pharmaceutics
Ability to
communicate
Practical
experience
in pharmaceutical
industry
Engineering
Capability
Knowledge of
electronics
and computers

27. Equipment selected based on processing characteristics
of product
Most economical, simplest and efficient
The size should be relevant to production sized batches
Ease of cleaning
Time of cleaning
EQUIPEMENT REQUIREMENT

28. Administration and Information Processing
Physical Testing Area
Standard Pilot Plant Equipment Floor Space
Storage Area
Separate for API and Excipients and further segregated into area for
approved and unapproved materials
In process materials, finished bulk products, retained samples, experimental
production batches, packaging materials
Controlled environment space for Stability Samples
SPACE REQUIREMENTS

29. Process parameters should be evaluated and optimized.
For example : Mixing
Order of addition
Mixing speed
Mixing time
Rate of addition etc.,
PROCESS EVALUATION

30. Chemical weigh sheet
Identify the chemicals
Its quantity
The order of using
The sampling directions
Process specifications
Should be in understandable language
In process and finished product specifications
Proper documentation required

31. Process Validation
Regular process review and revalidation
Relevant written Standard Operating Procedures
Equipment Qualification
Regularly scheduled preventive maintenance
contd…..
GMP CONSIDERATIONS

32. Validated cleaning procedures
An orderly arrangement of equipment so as to ease
material flow and prevent cross-contamination
A well defined technology transfer system
The use of competent, technically qualified personnel
Adequate provision for training of personnel

34. Material/Powder Handling
Two primary concerns : Achieving reliable flow and
maintaining blend uniformity.
Segregation leads to poor product uniformity.
Handling system :
- Must deliver the accurate amount of the
ingredient
- Material loss should be less
- There should be no cross contamination

35. Avoiding segregation …..
Modify the powder in a way to reduce its inherent tendency
to segregate
Change the particle size such that the active segregation
mechanism becomes less dominant
Change the cohesiveness of the powder such that the particles
in a bed of powder are less likely to move independent of
each other
Modify the equipment to reduce forces that act to segregate
the powder
Change the equipment to provide remixing

36. Dry Blending
Dry blend should take place in granulation vessel
Larger batch may be dry blended and then subdivided
into multiple sections for granulation.
All ingredients should be free of lumps otherwise it
causes flow problems.
Screening and/or milling of the ingredients prior to
blending usually makes the process more reliable
and reproducible.

37. GRANULATION
The weight of the material and the shear forces
generated by granulation equipment.
The use of multifunctional processors (significant in
terms of space and manpower requirements).
Viscosity of the granulating solution.

38. FLUIDISED BED GRANULATIONS
Process inlet air temperature
Atomization Air Pressure
Air Volume
Liquid Spray Rate
Nozzle Position and Number of Spray Heads
Product and Exhaust Air Temperature
Filter Porosity
Cleaning Frequency
Bowl Capacity

39. DRYING
HOT AIR OVEN
FLUIDIZED BED DRYER

40. Hot Air Oven
Air flow
Air Temperature
Depth of the granulation on the trays
Monitoring of the drying process by the use of moisture and
temperature probes
Drying times at specified temperatures and air flow
rates for each product

41. Fluidized Bed Dryer
Optimum Load
Air Flow Rate
Inlet Air Temperature
Humidity of the Incoming Air

42. PARTICLE SIZE REDUCTION
Sizing plays a key role in achieving uniformity.
There are two ways of sizing : Particle size separation
and Particle size reduction.
Major Factor – Feed rate of the material.
During scale up, overhead feeding equipment is
incorporated to mimic large scale production.

43. BLENDING
Blender loads
Blender size
Mixing speed
Mixing time
Bulk density of the raw material (considered in selecting
blender and in determining optimum load)
Characteristics of the material

44. SPECIALISED GRANULATION
PROCEDURES
Dry Blending and Direct Compression
Slugging (Dry Granulation)

45. Dry Blending and Direct Compression
The order of addition of components to the blender
The blender load
The mixing speed
The mixing time
The use of auxiliary dispersion equipment within the
mixer
The mixing action
Compression force

46. Slugging (Dry Granulation)
Forces used for slugging operation
The diameter of the punches
Subsequent sizing and screening operations

47. GRANULATION HANDLING AND
FEED SYSTEM
Evaluation of vacuum automated handling systems and
mechanical systems
Segregation : Due to static charges built up due to
vacuum can alter material flow property
The effect of above system on the content uniformity
of the drug and on the particle size

48. COMPRESSION
Press speed
Handling and compression characteristics (in the
selection of a tablet press)
Die filling rate
Flow rate of granules
Induced die feed systems (for high speed machines) –
speed of feed paddles
The clearance between the scraper blade and the die
table
Design and condition of the punches

49. TABLET COATING (FILM COATING)
Pan Coating
Fluidized Bed Coating

50. Pan and Fluidized Coating
Optimum tablet load
Operating tablet bed temperature
Drying airflow rate and temperature
The solution application rate
The size and shape of the nozzle aperture (for airless sprayer)
The atomizing air pressure and the liquid flow rate (for air
atomized sprayers)

51. Pan Coating
Fixed Operating
Parameters
Variable Operating
Parameters
Other Parameters
Pan Loading (kg)
Solid content of coating
suspension (%w/w)
Spray gun dynamics
Drying Air (cfm)
Inlet air temperature
( ْC )
Gun to tablet bed
distance
Coating System Spray rate (g min-1
)
Quantity of coating
applied (%w/w)
Atomizing air pressure (psi,
bar)
Air Pressure (psi, bar)
Pan speed
Number of spray guns

52. Fluidized Bed Coating
Batch size
Drying/fluidizing air volumes
Spray nozzle dynamics
Spray evaporation rate

54. SOLUTION
 Tank size (diameter)
 Impeller type
 Impeller diameter
 Rotational speed of the impeller
 Number of the impellers
 Number of baffles
 Mixing capability of impeller
 Clearance between impeller blades and wall of the mixing tank
 Contd…..

55. Height of the filled volume in the tank
Filtration equipment (should not remove active or
adjuvant ingredients)
Transfer system
Passivation of stainless steel (pre reacting the SS with
acetic acid or nitric acid solution to remove the surface
alkalinity of the SS)

56. SUSPENSION
 Addition and dispersion of suspending agents (Vibrating feed
system at production scale)
 Hydration/Wetting of suspending agent
 Time and temperature required for hydration of suspending
agent
 Mixing speeds (High speed lead to air entrapment)
 Selection of the equipment according to batch size
 Versator (to avoid air entrapment)
 Mesh size (should not filter out any of the active ingredients)

57. EMULSION
Temperature
Mixing Equipment
Homogenizing Equipment
In process or final product filters
Screens, pumps and filling equipment
Phase volumes
Phase viscosities
Phase densities

59.  Mixing equipment
 Motors (used to drive mixing system and must be sized to handle the product
at its most viscous stage)
 Mixing speed
 Component homogenization
 Heating and cooling process
 Addition of active ingredients
 Product transfer
 Working temperature range (critical to the quality of the final product)

60. Shear during handling and transfer from manufacturing to
holding tank to filling lines
Transfer pumps
While choosing size and type of pump :
Product viscosity
Pumping rate
Product compatibility with the pump surface
Pumping pressure required should be considered

62. PARENTERAL SOLUTION
It is liquid scale up task.
Mixing is one of the important process to be scaled up.
Large scale mixing -- Flow
Small scale mixing -- Shear
Geometric factors :-
-- Diameter of the impeller (D)
-- Diameter of the tank (T)
-- Height of the liquid in the vessel (Z)
-- Impeller speed

63.  Sterilization equipment
 Filtration equipment
 Pumps
 Packaging equipment
also have to be scaled up.

65.  The design and Scale-up of biological processes is very
challenging.
 Parameters to be considered for scale-up of biotechnology
products are :
1. Bioreactor Operation
2. Filtration Operation
3. Centrifugation
4. Chromatography
5. Viral Clearance

66. BIOREACTOR OPERATION
(STIRRED TANK)
Impeller rate
Aeration rate
Hydrostatic pressure
Agitation rate
Mixing time

67. FILTERATION OPERATION
Transmembrane pressure
Volume
Operating time
Temperature
Flux rate
Protein concentration
Solution viscosity
Retentate flow rate
Permeate flux

68. Other variables used in scale-up work for filteration are :
The length of the fibers (L)
The fiber diameter (D)
The number of fibers per cartridge (n)
The density of the culture (ρ)
The viscosity of the culture (μ)
From these variables, scale-up parameters such as wall shear rate
and its effect on flux are derived.

69. CHROMATOGRAPHY
 Gel Capacity
 Linear Velocity
 Buffer Volume
 Bed Height
 Temperature
 Cleanability
 Gel lifetime
 pH of the elution buffer
 Conductivity of the elution buffer

70. VIRAL CLEARANCE
It is very important part of the process design for
biotechnology product.
It is also to be scaled up.

72. PRINCIPLES OF SIMILARITY
GEOMETRIC
SIMILARITY
MECHANICAL
SIMILARITY
THERMAL
SIMILARITY
CHEMICAL
SIMILARITY
STATIC
SIMILARITY
KINEMATIC
SIMILARITY
DYNAMIC
SIMILARITY

73.  Similarity with respect to geometrical factors
i.e. shape, height, thickness, breadth, etc.,
 Small scale and large scale equipments must be
in scale ratio of 1:2, 1:5, 1:20 etc.,

74. MECHANICAL SIMILARITY
Concerned with application of force to a stationary or moving
system.
Static similarity – It is the deformation of one body or
structure to that of an other under constant stress.
Kinematic similarity – Corresponding moving particles take
similar path in the corresponding time interval.
Dynamic similarity – Forces which accelerate or retard the
motion of materials.
Moving systems are dynamically similar when the ratio of
all forces is equal.
It is useful in the prediction of pressure drops, power
consumption.

75. NOTE

76. THERMAL SIMILARITY
It is concerned with flow of heat (by radiation,
conduction, convection, or the bulk transfer of
material).
Geometrically similar systems are thermally similar
when temperature difference bears constant ratio and
in moving systems it must have Kinematic similarity.

77. CHEMICAL SIMILARITY
It is concerned with the variation in chemical
composition from point to point as a function of
time.
It is related to existence of comparable concentration
gradients.
It is dependent upon both thermal and Kinematic
similarity.

79. Marketing Formulation
Defined
Process Development
Identify critical process
and packaging parameters
Pilot scale studies
Scale-Up/Stability/
Clinical Supply batches
Site Selection
Initial large scale process
qualification studies
Development Report

80. Scale-Up Report
NDA Submission
Manufacture Validation
Batches
Large scale process qualification
studies
Product transfer document issued
Product acceptance by manufacturing
Validation protocol written
Pre approval inspection by FDA
Manufacturing site preparation
Validation Report

81. NDA Approval
Production Start Up
FDA Approval to
market product
Product Launch

82. CONCLUSION

83. 1. What is the difference between Pilot Scale and Scale-Up?
2. Outline the Pilot Plant Operation and give brief note on
each .
3. Enumerate the parameters that should be considered
during the scale up of Tablet Coating ?
4. Give a brief note on Scale-Up of Biotechnology-Derived
Products and Parenteral Solutions .
5. What are the steps involved in transfer of a formulation
right from F&D to Production Facility ?

84. The Theory and Practice of Industrial Pharmacy : Leon Lachman,
Herbert A Lieberman , Joseph L Kanig : Section IV : Chapter 23 : Pilot
Plant Scale-Up Techniques : Page No . 681 – 710 .
Encyclopedia of Pharmaceutical Technology : James Swarbrick , James
C Boylan : Volume 12 : Pilot Plant Design : Page No . 171 – 186 .
Pilot Plant Operation : Page No . 187 – 208 .
Drugs and The Pharmaceutical Sciences : Pharmaceutical Process
Scale-Up : Marcel Dekker series : Michael Levin : Volume 118
Parenteral Drug Scale-Up : Page No. 43 – 56 .
Scale-Up Considerations for Biotechnology-Derived Products :
Page No. 95 – 114
Powder Handling : Page No. 133 – 150 .
Scale-Up of Film Coating : Page No. 259 – 310 .
REFERENCES

85. Believe In ‘ApplicationBelieve In ‘Application
Of Knowledge’ RatherOf Knowledge’ Rather
Than The ‘Knowledge’Than The ‘Knowledge’
It Self.It Self.
- Mr. Nitin KadamMr. Nitin Kadam
Thank You.