Pilot plant Scale Up Techniques: General considerations

General Considerations of Pilot Plant Scale up for Various Dosage forms

1. PILOT PLANT SCALE UP TECHNIQUES:
GENERAL CONSIDERATION
Dr.Mahesh Kumar Kataria
Professor and Head, Department of Pharmaceutics,
Seth G. L. Bihani S. D. College of Technical
Education, Sri Ganganagar
Email: [email protected]
Dr. Mahesh Kumar Kataria 1

2. GENERAL CONSIDERATIONS OR REQUIREMENTS
DURING PILOT SCALE UP
To have an intermediate batch scale representing procedures
used for commercial manufacturing, generally the following
should be considered.
Dr. Mahesh Kumar Kataria 2

3. 1.Reporting responsibilities
•Adequate records & reporting arrangement.
•Pilot plant functions can be part of the R&D groups with
separate staffing.
•The formulator who developed the product can take it into
the production and continuously provide support even after
the transition into production.
•Separate pilot plant and technical service group.
•Good relationship & effective communication between the
pilot plant group and the other groups like R &D, processing,
packaging, engineering, QA/ QC and marketing.
Dr. Mahesh Kumar Kataria 3

4. 2. Personnel Requirement
SIGNIFICANCE OFPERSONNEL
•Scientistsexperienceinpilotplant,actualproduction,R&D,
formulationandQC.
•Knowledgeaboutphysical&chemicalpropertiesofmaterial
anditsstabilityinvariousdosageformareimportant.
Scientistshouldhave;
•Goodtheoreticalknowledgeaboutformulations&practical
experienceinpharm.industry.
•Capableofunderstandingobjectivesofformulatorand
productionpersonnel.
•Engineeringknowledgeaswellasscaleup.
•Appropriatequalificationaccordingtotheresponsibility.
•Abilitytocommunicatewell,developandmaintaingood
relationshipwithotherpersonnelinvolvedinscaleup.
Dr. Mahesh Kumar Kataria 4

5. 3. Space Requirements
SIGNIFICANCE OFSPACEREQUIREMENTS
Thespacerequirementsofapilotplantareoffourtypes:
a.Administrativeandinformationprocessing
•Adequateoffice&deskspaceforboththescientistsand
technicianstofacilitateproperdocumentationoftheir
activitiesandobservationswithadequatecomputers.
•Spaceadjacenttotheactualworkingareawithsufficient
isolationtoavoidanyhindrancesinthesmoothfunctioning.
b.PhysicalTestingArea
•Adequateworkingareaforanalysisandphysicaltesting.
•Inprocessqualitycontrol(IPQC)helpsinearly
identificationofproductionandothertypeoferrors.
•Areashouldprovidepermanentbenchtopspacefor
routinelyusedphysicaltestingequipmentlikebalances,pH
meters,viscometers,disintegrationapparatus,IRmoisture
balanceetc.
Dr. Mahesh Kumar Kataria 5

6. ….cont…
c. Standard pilot plant equipment floor space
•Specific floor space for different equipments required.
•Should be as per production line of different dosage forms
•Should also be utilized in an effective way.
•Equipment used should be preferably portable.
•Space for cleaning of the equipment.
d. Storage Area
•As per GMP two separate storage areas-
Approved (for API) and Unapproved area (Excipients)
•Different storage area for in-process materials, finished bulk
products from pilot plant, packaging materials & materials
from experimental scale-up batches made in production.
•Controlled environment space for storage of stability samples.
•Storage area for packaging materials.
Dr. Mahesh Kumar Kataria 6

7. 4. Review of the formula:
•Closeexaminationofformulatodetermineitsabilityto
withstandbatch-scaleandprocessmodifications.
•Eachaspectrequirethoroughreviewabouttheroleofeach
ingredientanditscontributiontofinalproduct
manufacturedonthesmall-scalelaboratory.
•Importanttounderstandtheeffectofscale-upprocess
usingdifferentsizeofequipmentthatmaysubjectthe
producttodifferenttypesanddegreesofstresseswhich
affectthepredeterminedquality&specificationsoffinal
product.
•Byreviewingtheformula,itcanbemorereadilypredicted
orrecognizedallthecharacteristicsrelatedtofinal
formulation.
Dr. Mahesh Kumar Kataria 7

8. 5. Raw Materials
SIGNIFICANE OFRAWMATERIALS
•Material(API,excipientsetc.)forprocessinginpilotplantmay
notbeapprovedandvalidated.
•Materialsshouldmeetupwithrisingneedsoftheproduct.
•Asthebatchsizeincreasesthevariationsinmicrometrics
propertiesofpowderingredientslikeparticlesize,shape,or
morphologymayresultingindifferencesindensity,static
charges,rateofsolubility,flowpropertiesanddifferent
handlingpropertiesofactive/inertingredients.
•Approval&validationistheresponsibilityofpilot-plant.
•Singlesuppliermaycreateproblemwithrespecttoprice&
qualityofmaterialsomusthavealternativesuppliers.
Dr. Mahesh Kumar Kataria 8

9. 6. Relevant Processing Equipment
•Economical, simplest & efficient equipment capable
of producing product within the proposed specifications are
considered for scale up process.
•Size of euipmentsoptimum-Too small euipments, the process
developed will not scale up, whereas if too big then the
wastage of active ingredients.
•The ease of cleaning should be considered.
7. Production Rates
All parameters should be considered during scale up to decide
production rate. The production rate depends upon;
•Type of process and equipment
•The immediate and future demand of product.
•Product loss in equipment
•Time required to clean-up equipment between batches
•Numbers of batches.
Dr. Mahesh Kumar Kataria 9

10. 8. Process Evaluation
•Theknowledgeoftheeffectsofvariousprocessparameters
requiredforoptimizationandvalidationofprocess.
•Optimizationperformedbymonitoringwithinbatch
variationofmeasurableparameterslikecontentuniformity,
moisturecontent,weightvariationandcompressibility.
Dr. Mahesh Kumar Kataria 10

11. 9. Preparation of Master Manufacturing Procedure
Manufacturing procedures should be presented for easy
compliance & understanding for the technicians.
The process directions should be;
•Specific & unambiguous in form of SOPs.
•The weight sheet should clearly identify the chemicals, their
quantities and order in which use.
•Provide sampling plan and procedure viz. time of sampling,
method of sampling and storage of samples.
•In-process specifications like addition rates, mixing time,
mixing speed, heating and cooling rates, drying temp. etc.
and finished product specifications.
Proper documentation should be carried out during process.
Dr. Mahesh Kumar Kataria 11

12. 10.Productstabilityanduniformity
•Eachpilotbatchshouldbestudiedforstabilityanduniformityof
contentaspertheprimaryobjectiveofthepilotplant.
11.GoodManufacturingPractice(GMP)Considerations
•ComplianceofcGMPguidelinesisenforcedbytheFDAduringnew
productorprocessdevelopment.
Guidelinesprovideguidanceformanufacturing,testingandQA;
•Toensurethesafetyandconsistentqualityoffinishedproduct.
•Clean&hygienicarea,controlledenvironmentalconditionsto
preventcrosscontamination,validationofcriticalprocess,
controlled&clearlydefinedmanufacturingprocess,qualification&
trainingofpersonnel,documentedproceduresintheformof
SOPs,MFR,batchprocessingrecords(BPR),sitemasterfile(SMF)
•Emphasizeonequipmentqualification,regularprocessreviewand
revalidation,awell-definedtechnologytransfersystem,validated
cleaningprocedures andregularlyscheduledpreventive
maintenanceoffacilities.
Dr. Mahesh Kumar Kataria 12

13. 12.TransferofAnalyticalMethodstoQualityAssurance
•Analyticaltestmethodsdevelopedatlaboratoryscalemust
betransferredtotheQAdepartment.
•TheQApersonnelresponsibleforreviewtheprocessto
makesurethatproperanalyticalinstrumentisavailable,
trainedpersonalperformthetest,reliabilityofthetestand
reviewofassayprocedurebeforetransfer.
•QAwillultimatelyberesponsibleforthereleaseofthe
productforeitherclinicalstudiesorcommercialization.
•QAmustbeaccountedfordesignofthefacilityliketesting
areas,properproductcontainmentareas(quarantine),
work-in-process(WIP)areasaswellasreleasedmaterial
areas. Dr. Mahesh Kumar Kataria 13