PRESENTED BY:

DIMENDRA PATEL

DEPARTMENT OF PHARMACEUTICSBARODA COLLEGE OF PHARMACY

LIMDA-VADODARA

INTRODUCTIONINTRODUCTION

Pilot Scale and Scale-Up

Pilot Scale

Scale-Up

R & D

Large Scale Production

What Do Pilot Scale and Scale-Up Mean ?

INTERMEDIATEBATCH 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)

Bench studies (product characterization , purity)Animal studies (toxicology , pharmacokinetics-ADME , efficacy)Clinical studiesIncreasing compliance with regulations as product moves through testing and evaluationIncreasing knowledge about the productIncreasing knowledge about the possible problems, snags, pitfalls with manufacturing, processing, packing, storing (and installing) the productUltimately facilitates the transfer of product from laboratory into production

Why Pilot Scale ?

Why 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

Formulation relatedIndentification and control of critical components and othervariables

Equipment relatedIdentification and control of critical parameters and operating ranges

Production and Process relatedEvaluation, validation,and finalization of controls

Product relatedDevelopment and validation of reprocessing procedures

DocumentationRecords and reports according to cGMP

Ability to withstand batch scale

Compatibility of the equipment

with the formulation

Layout of the related functions

Market requirement

Availability ofthe raw materials

meeting the specifications

Cost factor

Physical spacerequired

Processmodification

Should Adequatelymonitor the process

To provide the assurance thatthe process is under control

The product produced maintainsthe specified attributes originally

intended

PILOT PLANT DESIGNPILOT PLANT DESIGN

Pilot Plant Design

Formulation andProcess Development

Technology evaluation,Scale-Up and

Transfer

Clinical supply manufacture

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

PILOT PLANT OPERATIONPILOT PLANT OPERATION

OperationalAspects

Validation

Training

Engineering support

Maintenance and Calibration

Inventory, Orders, Labeling

Material control

Process & Manufacturing Activities

QA & QC

VALIDATION

Design specifications

InstallationQualification

Operational Qualification

PerformanceQualification

Compliance with cGMPand

FDA standards

Compliance withGMP

Safety andenvironmentalresponsibilities

Compliance withSOPs

Technical skillsand knowledge TRAINING

ENGINEERING SUPPORT

Design of facility

Construction of facility

Co-ordination, scheduling, direction of ongoing operations

Validation of facility

To ensure dataintegrity and

equipment reliability

To meet cGMP norms

Maintenance & Calibration

Computerized system

Material control

Inventory

Orders (FIFO)

Labeling(GMP-GLP)

PROCESSAND

MANUFACTURING ACTIVITIES

Formulation &Process Development

studies

Technology evaluation, ScaleUp, & Transfer

Clinical supplymanufacture

QUALITY 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

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

REQUIREMENTS REQUIREMENTS

Personnel Requirements

Equipment Requirements

Space Requirements

Process Evaluation

Preparation of Master Manufacturing Procedures

GMP Considerations

PERSONNEL REQUIREMENTS

Theoretical Knowledge of Pharmaceutics

Ability to communicate

Practical experiencein pharmaceutical

industry

Engineering Capability

Knowledge of electronicsand computers

EQUIPMENT REQUIREMENTS

EQUIPMENT REQUIREMENTS

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

SPACE REQUIREMENTS

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 Inprocess materials, finished bulk products, retained samples, experimental

production batches, packaging materials Controlled enviornment space for Stability Samples

Process parameters should be evaluated and optimized.

For example : MixingOrder of addition

Mixing speed

Mixing time

Rate of addition etc.,

PROCESS EVALUATION

Chemical weigh sheetIdentify the chemicalsIts quanitityThe order of using

The sampling directions

Process specifications

Should be in understandable language

In process and finished product specifications

Proper documentation required

• Process Validation

• Regular process review and revalidation

• Relevant written Standard Operating Procedures

• Equipment Qualification

• Regularly scheduled preventive maintenance

contd…..

GMP CONSIDERATIONS

• 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

SCALE-UP CONSIDERATIONS FOR TABLETSSCALE-UP CONSIDERATIONS FOR TABLETS

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

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

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.

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.

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

DRYING

• HOT AIR OVEN

• FLUIDIZED BED DRYER

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

Fluidized Bed Dryer Optimum Load

Air Flow Rate

Inlet Air Temperature

Humidity of the Incoming Air

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. As the feed rate is increased so is residence time

with in the chamber of the equipment which in turn results in finer distribution.

During scale up, overhead feeding equipment is incorporated to mimic large scale production.

BLENDINGo Blender loads

o Blender size

o Mixing speed

o Mixing time

o Bulk density of the raw material (considered in selecting blender and in determining optimum load)

o Characteristics of the material

SPECIALISED GRANULATION PROCEDURES

• Dry Blending and Direct Compression

• Slugging (Dry Granulation)

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

Slugging (Dry Granulation)

Forces used for slugging operation

The diameter of the punches

Subsequent sizing and screening operations

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

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

TABLET COATING (FILM COATING)

Pan Coating

Fluidized Bed Coating

Pan and Fluidized CoatingOptimum 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)

Pan CoatingFixed Operating

ParametersVariable Operating

ParametersOther

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

Fluidized Bed Coating

Batch size

Drying/fluidizing air volumes

Spray nozzle dynamics

Spray evaporation rate

LIQUID DOSAGE FORMSLIQUID DOSAGE FORMS

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…..

Height of the filled volume in the tank

Filteration 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)

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)

EMULSION Temperature

Mixing Equipment

Homogenizing Equipment

In process or final product filters

Screens, pumps and filling equipment

Phase volumes

Phase viscosities

Phase densities

SEMISOLID PRODUCTSSEMISOLID PRODUCTS

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)

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

PARENTERAL PRODUCTSPARENTERAL PRODUCTS

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

Sterilization equipment

Filteration equipment

Pumps

Packaging equipment

also have to be scaled up.

BIOTECHNOLOGY DERIVED PRODUCTSBIOTECHNOLOGY DERIVED PRODUCTS

The design and Scale-up of biological processes is very challenging.

Parameters to be considered for scale-up of biotechnology products are :

Bioreactor Operation

Filteration Operation

Centrifugation

Chromatography

Viral Clearance

BIOREACTOR OPERATION(STIRRED TANK)

Impeller rate

Aeration rate

Hydrostatic pressure

Agitation rate

Mixing time

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

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.

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

VIRAL CLEARANCE

It is very important part of the process design for biotechnology product.

It is also to be scaled up.

PRINCIPLES OF SIMILARITYPRINCIPLES OF SIMILARITY

PRINCIPLES OF SIMILARITYPRINCIPLES OF SIMILARITY

GEOMETRIC SIMILARITY

GEOMETRIC SIMILARITY

MECHANICAL SIMILARITY

MECHANICAL SIMILARITY

THERMAL SIMILARITY

THERMAL SIMILARITY

CHEMICAL SIMILARITY

CHEMICAL SIMILARITY

STATIC SIMILARITY

STATIC SIMILARITY KINEMATIC

SIMILARITY

KINEMATIC SIMILARITY DYNAMIC

SIMILARITY

DYNAMIC SIMILARITY

GEOMETRIC SIMILARITY 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.,

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.

NOTE

Systems exhibit mechanical similarity only if they are

geometrically similar

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.

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.

DEVELOPMENT MILESTONESDEVELOPMENT MILESTONES

Marketing FormulationDefined

Process DevelopmentIdentify critical process

and packaging parameters Pilot scale studies

Scale-Up/Stability/Clinical Supply batches

Site SelectionInitial large scale process

qualification studies

Development Report

Scale-Up Report

NDA Submission

Manufacture ValidationBatches

Large scale process qualification studies

Product transfer document issuedProduct acceptance by manufacturing

Validation protocol writtenPre approval inspection by FDAManufacturing site preparation

Validation Report

NDA Approval

Production Start Up

FDA Approval to market product

Product Launch

A thorough understanding of the integration of scale factors, facility design, equipment design and process performance is necessary for scale-up and process transfer.

CONCLUSION

What is the difference between Pilot Scale and Scale-Up? [ 1 mark ]

Outline the Pilot Plant Operation and give brief note on each . [ 5 marks ]

Enumerate the parameters that should be considered during the scale up of Tablet Coating ? [ 2 marks ]

Give a brief note on Scale-Up of Biotechnology-Derived Products and Parenteral Solutions . [ 5 marks ]

What are the steps involved in transfer of a formulation right from F&D to Production Facility ? [ 5 marks ]

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 .

Encylopedia 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