Pilot plant

This is very useful presentation for UG and PG students of Pharmacy

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CONTENTS
Definition
Significance
GeneralConsiderations
GMPConsiderations
ProductConsiderations
Advantages
Disadvantages
References
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Plant:-Itisaplacewherethe3M’sthatareMan,
MaterialandMoneyarebroughttogetherforthe
manufacturingofproducts.
PilotPlant:-Itisthepartofthepharmaceuticalindustry
wherealabscaleformulaistransformedintoaviable
productbydevelopmentofliablepracticalprocedureof
manufacturing.
Scale-up:-Theartfordesigningofprototypeusingthe
dataobtainedfromthepilotplantmodel.
DEFINITIONS
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SIGNIFICANCE
Permitscloseexaminationofformulaetodetermineits
abilitytowithstandbatchscaleandprocess
modification.
ReviewofEquipment-mostcompatiblewiththe
formulation&mosteconomical,simpleandreliablein
producingproduct.
Rawmaterials-consistentlymeetthespecifications
requiredtoproducetheproductcanbedetermined.
Productionrateadjustmentafterconsideringmarketing
requirements.
Giveroughideaaboutphysicalspacerequiredandof
relatedfunctions.
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Appropriaterecordsandreportsareissuedtosupport
goodmanufacturingpractices.
Procedurecanbedevelopedandvalidated.
Cont….
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GENERAL
CONSIDERATIONS
1.ReportingResponsibility:-
R & D group
with separate
staffing
The formulator who developed the
product can take into the production
and can provide support even after
transition into production has been
completed
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*Scientistswithexperiencein
pilotplantoperationsaswell
asinactualproductionarea
arethemostpreferable.
*Astheyhavetounderstand
theintentoftheformulatoras
wellasunderstandthe
perspectiveoftheproduction
personnel.
*Engineeringprinciples
*Knowledgeofcomputers&
electronics
2.Personnel Requirement:-
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3. SpaceRequirements:-
Administration
and information
processing
Physical
testing area
Standard
equipment
floor space
Storage
area
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Adequateofficeanddeskspaceshouldbeprovidedfor
bothscientistandtechnicians.
Thespaceshouldbeadjacenttotheworkingarea.
Computers.
3.1 Administration And Information Process:-
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3.2PhysicalTestingArea:-
Thisareashouldprovidepermanentbenchtopspaceforroutinely
usedphysical-testingequipment.
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Discreetpilotplantspace,wheretheequipmentneededfor
manufacturingalltypesofdosageformislocated.
Intermediate–sizedandfullscaleproductionequipment
isessentialinevaluatingtheeffectsofscale-upofresearch
formulationsandprocesses.
Equipmentsusedshouldbemadeportablewhereever
possible.Sothatafteruseitcanbestoredinthesmall
storeroom.
Spaceforcleaningoftheequipmentshouldbealso
provided.
3.3 Standard Pilot-plant Equipment Floor Space :-
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Itshouldhavetwoareas,
1.Approvedareaand
2.Unapprovedareaforactive
ingredientaswellasexcipient.
Differentareasshouldprovidedfor
thestorageofthein-process
materials,finishedbulkproducts
fromthepilot-plant&materials
fromtheexperimentalscale-up
batchesmadeintheproduction.
Storageareaforthepackaging
materialshouldalsobeprovided.
3.4 Storage Area:-
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Athoroughreviewoftheeachaspectofformulationis
important.
Thepurposeofeachingredientandit’scontributionto
thefinalproductmanufacturedonthesmall-scale
laboratoryequipmentshouldbeunderstood.
Thentheeffectofscale-upusingequipmentthatmay
subjecttheproducttostressesofdifferenttypesand
degreescanmorereadilybepredictedorrecognized.
4. Review of the formula:-
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Onepurpose/responsibilityofthepilot-plantisthe
approval&validationoftheactiveingredient&
excipientsrawmaterials.
Rawmaterialsusedinthesmallscaleproductioncannot
necessarilybetherepresentativeforthelargescale
production.
Ingredientsmaychangeinparticlesize,shapeor
morphologywhichresultindifferencesinbulkdensity,
staticcharges,rateofsolubility,flowproperties,color,
etc.
5. Raw materials :-
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6.Equipment:-
Themosteconomical,simplest&efficientequipment
whicharecapableofproducingproductwithinthe
proposedspecificationsareused.
Thesizeoftheequipmentshouldbesuchthatthe
experimentaltrialsrunshouldberelevanttothe
productionsizedbatches.
Iftoosmalltheprocessdevelopedwillnotscaleup.
Iftoobigthenthewastageoftheexpensiveactive
ingredients.
Easeofcleaning
Timeofcleaning
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Theimmediateaswellasthefuturemarkettrends/
requirementsareconsideredwhiledeterminingthe
productionrates.
7. Production Rates:-
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PARAMETERS
Order of mixing of
components Mixing
speed
Mixing
time
Rate of addition of
granulating agents,
solvents,
solutions of drug etc.
Heating and cooling
Rates
Filters size
(liquids)
Screen size
(solids)
Drying temp.
And drying time
8. Process Evaluation:-
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Thethreeimportantaspects
Weight sheetProcessing &
Sampling
directions
Manufacturing
procedure
9. Master Manufacturing Procedures:-
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Theweightsheetshouldclearlyidentifythechemicals
requiredinabatch.Topreventconfusionthenamesand
identifyingnumbersfortheingredientsshouldbeusedon
batchrecords.
Theprocessdirectionsshouldbepreciseandexplicit.
Amanufacturingprocedureshouldbewrittenbythe
actualoperator.
Variousspecificationslikeadditionrates,mixingtime,
mixingspeed,heating,andcoolingrates,temperature,
storingofthefinishedproductsamplesshouldbe
mentionedinthebatchrecorddirections.
Cont….
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Duringthescale-upofanewproduct,theanalytictest
methodsdevelopedinresearchmustbetransferredtothe
qualityassurancedepartment.
Earlyinthetransferprocess,thequalityassurancestaff
shouldreviewtheprocesstomakesurethattheproper
analyticinstrumentationisavailableandthatpersonnelare
trainedtoperformthetests.
Transfer of Analytical Method to
Quality Assurance
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Theprimaryobjectiveofthepilotplantisthephysicalas
wellaschemicalstabilityoftheproducts.
Henceeachpilotbatchrepresentingthefinalformulation
andmanufacturingprocedureshouldbestudiedfor
stability.
Stabilitystudiesshouldbecarriedoutinfinishedpackages
aswell.
10. Product Stability And Uniformity:-
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GMP CONSIDERATION
Equipmentqualification
Processvalidation
Regularlyprocessreview&revalidation
Relevantwrittenstandardoperatingprocedures
Theuseofcompetenttechnicallyqualifiedpersonnel
Adequateprovisionfortrainingofpersonnel
Awell-definedtechnologytransfersystem
Validatedcleaningprocedures
Anorderlyarrangementofequipmentsoastoease
materialflow&preventcross-contamination
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ADVANTAGES
Membersoftheproductionandqualitycontroldivisions
canreadilyobservescaleupruns.
Suppliesofexcipients&drugs,clearedbythequality
controldivision,canbedrawnfromthemorespacious
areasprovidedtotheproductiondivision.
Accesstoengineeringdepartmentpersonnelisprovided
forequipmentinstallation,maintenanceandrepair.
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DISADVANTAGES
Thefrequencyofdirectinteractionoftheformulator
withtheproductionpersonnelinthemanufacturingarea
willbereduced.
Anyprobleminmanufacturingwillbedirectedtowards
it’sownpilot-plantpersonnel.
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SOLID DOSAGE FORM
1. Material Handling
Laboratory Scale
Deliver accurate amount to the destination
Large Scale
* Lifting drums
* More Sophisticated Methods
-Vacuum Loading System
-Metering Pumps
Prevent Cross Contamination by Validation Cleaning
Procedures.
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2. Dry Blending
Powdersshouldbeusedforencapsulationortobe
granulatedpriortotablettingmustbewellblendto
ensuregooddrugdistribution.
Inadequateblendingcouldresultindrugcontent
uniformityvariation,especiallywhenthetabletorcapsule
issmall&thedrugconcentrationisrelativelylow.
Ingredientsshouldbelumpsfree,otherwiseitcouldcause
flowproblems.
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3. Granulations
Reasons :-
* To improve the flow properties.
* To increase the apparent density of the powder.
* To change the particle size distribution so that the
binding properties on compaction can be improved.
Types :-
a) Wet Granulation
b) Dry Granulation
c) Direct Compression Method
A small amount potent active ingredient can be dispersed
most effectively in a carrier granulation, when the drug is
dissolved in granulating solution and added during the
granulating process.
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Wet granulation has been carried out by using,
-Sigma Blades
-Heavy-duty planetary mixture
-Tumble Blenders
-High Speed Chopper Blades used in mixing of light
powders.
Multifunctional Processors,
dry blending, wet granulation, drying, sizing &
lubricating.
Effect of Binding Agent.
Cont….
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4. Drying
Hot Air Oven
* air temperature
* rate of air flow
* depth of granulation on the trays
Fluidized Bed Dryer
* optimum loads
* rate of airflow
* inlet air temperature
* humidity
Data used for small scale batches(1-5 kg) cannot be
extrapolate processing conditions for intermediated scale
(100 kg) or large batches.
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5. Reduction In Particle Size
Particle size to particle size distribution is important to
the compression characteristics of a granulation.
Compression factors that may affected by the particle
size distribution are flow ability, compressibility,
uniformity of tablet weight, content uniformity, tablet
hardness, tablet color uniformity.
Equipments :-
* oscillating granulator a mechanical sieving device
* a hammer mill
* screening device
If too large particle size :-
* weight variation
* mottling
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If too fines particle size,
* weight variation
* capping
Both oversized and undersized granulation can adversely
affect tablet content uniformity.
Lubricants & Gildants are added at final blend
Cont….
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6. Blending
Consequent attention should be paid to scale up of the
right design is used and blender loads, mixing speeds,
mixing timing are properly established.
In any blending operation segregation and mixing occurs
simultaneously, both processes are a function a particle
size, shape, hardness, density and dynamics of the mixing
action.
Low dose active ingredients –directly compressed.
Equipments :-
* Planetory type mixer
* Twin shell mixture
* Cone type
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Over loading in blender –
* retards the free flow of granules
* reduce the efficiency
* cause content un-uniformity
If the load is to small –
* powder blend slides rather than roll in blender
* improper mixing
Cont….
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7. Slugging
A dry powder blend that can not be directly compressed
because of poor flow properties may in some instances be
processed using a slugging operation.
Instruments :-
* Tablet press –which operates at pressure of 15 tons,
compared with a normal tablet press, which operates at
pressure of 4 tons or less.
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8. Compression
The ultimate test of the tablet formulation and
granulation can be compressed on a high-speed tablet
press.
Steps involved during compression,
* Filling empty die cavity with granulation
* Pre compression of granules
* Compression of granules
* Ejection of tablet from the die cavity
Compression characteristics can be evaluated by press
speed equal to normal production speed.
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Then detect the problems such as,
* sticking to punch surface
* tablet hardness
* capping
* weight variation
Granules must be delivered at adequate rate.
During compression, the granules are compacted, and in
order for a tablet to form, bonds within the compressible
materials must be formed.
Cont….
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TABLET COATING
Equipments :-
* conventional coating pan
* perforated pans of fluidized-bed coating column
Types :-
1. Sugar coating
2. Film coating
Tablet must be sufficiently hard to withstand the the
tumbling to which they are subjected while coating.
Operation conditions to be established for pan or column
operation are optimum tablet load, operating tablet, bed
temperature, drying air flow rate, temperature, solution
application rate.
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CAPSULES
To produce capsules on high-speed equipment, the
powder blend must have,
* uniform particle size distribution
* bulk density
* formation of compact of the right size and of sufficient
cohesiveness to be filled into capsule shells.
Equipments :-
1. Zanasi or Mertalli –Dosator(hollow tube)
2. Hoflinger –Karg –Tamping pins
Weight variation problem can be encountered with these
two methods.
Overly lubricated granules –delaying disintegration.
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Humidity affect moisture content of –
* granulation
* on the empty gelatin capsules
Empty gelatin capsules have a recommended storage
condition of 15-25 ºC temperature & humidity 35-65 %
RH.
At high humidity –capsule swells make separation of the
capsule parts difficult to interfere with the transport of the
capsule through the process.
At low humidity –capsule brittle increased static charge
interfere with the encapsulation operation.
Cont….
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LIQUID ORALS
Simple solutions are the straight forward to scale up but
they require tanks of adequate size and suitable mixing
capability.
Most equipment has heating or cooling capabilities to
effect rapid disollution of components of the system.
All the equipments must be made up of suitable non-
reactive material and be designed and constructed to
facilitate easy cleaning.
Liquid pharmaceutical processing tank, kettles, pipes,
mills, filter houses etc. are most frequently fabricated
from stainless steel
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Twotypesofsteel–
1.308
2.316
Stainlesssteelismostnonreactive,howeveritdoesreact
withsomeacidicpharmaceuticalliquids,thisproblemcan
beminimizedbyPASSIVATION.
Interactionwithmetallicsurfacescanbeminimizedby
useofglassorTefloncoating.
Althoughtheyarehighlyinertmaterials,theyhavethe
disadvantagesofcracking,breakingandflakingwith
resultantproductcontamination.
Cont….
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43. PARENTERALS
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Equipments:-
*tankage
*piping
*ancillaryequipmentforliquidmixing
*filteration,transferandrelatedequipments.
Themajorityoftheequipmentsarecomposedof300
seriesausteniticstainlesssteel,withglasslined
vesselsemployedforpreparationofformulations
sensitivetoironandothermetalions.
Thevesselscanbeequipedwithexternaljacketsfor
heatingand/orcoolingandvarioustypesofagitators,
dependinguponthemixingrequirementsofthe
individualformulation.
Cont….
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SUSPENSIONS
Suspensions require more attention during scale up than
simple solutions because of additional processing needs.
Equipments :-
* vibrating feed system and power for production scale.
* high shear mixing equipment
Slurries facilitate rapid and complete hydration of
suspending agent when added to large portion of the
vehicle.
Active ingredients must be uniformly dispersed
throughout the batch.
Mixing at too high speed can result in entrapment of air,
which may affect physical or chemical stability of the
product.
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VACUUM UNIT VERSATOR
Filteration –remove unwanted particles.
Screens of 150 mesh, having 100 microns are used.
Active ingredients –particle size 10 –25 microns.
Transfer and filling of finished suspension should be
carefully monitored.
It should be constantly mixed during transfer to maintain
uniform distribution of the active ingredients.
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EMULSIONS
Manufacturing of liquid emulsion products entails
specialized procedures as result scale up into production
equipment involves extensive process development and
validation.
Equipments :-
* mixing equipment
* homogenizing equipment
* screens
* pumps
* filling equipment
High shear mixers may lead to air entrapment, this
problem can be avoid by carrying out operation under
controlled vacuum.
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SEMI SOLID PRODUCTS
The main difference of semi solid formulation with
comparison to suspensions, liquids and emulsions is their
higher viscosity.
Viscosity renders certain aspects of the scale-up of semi
solid products more critical.
Equipments :-
* blenders
* mixers
* pressure filling equipments
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SUPPOSITORIES
The manufacturing of suppositories on a laboratory scale
usually involves,
* the preparation of a molten mass
* the dispersion of drug in the molten base
* casting of suppositories in a suitable mold
* cooling of the mold
* opened & remove the suppositories
More no. of moulds & large size Pan for melting of drug
& base.
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CONTRACT MANUFACTURE
On occasional, scale-up or manufacture of a product
may need to be done at an outside, contract
manufacturer.
The reasons for considering contract manufacture
include the needs for additional manufacturing
capacity, high specialized technology or specialized
equipments.
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