Pilot Scale and Scale-UpPilot ScaleScale-UpR & DLarge ScaleProduction
Pilot Scale and Scale-Up Means ?IntermediateBatch scaleManufactures DrugProduct By A ProcedureFully Represrntative Of AndSimulatory To That OfManufacturing ScalePILOT SCALE SCALE-UPNext toPilot scaleProcess Of IncreasingThe Batch Size (Mixing) /Procedure For ApplyingThe Same Process ToDifferent Output Volumes(Tabletting)
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 andevaluation Increasing knowledge about the product Increasing knowledge about the possible problems, snags, pitfalls with manufacturing,processing, packing, storing (and installing) the productNeed of PilotScale ?
Need of Scale-Up ? A well definedprocessA perfect productin laboratory andpilot plantBut may fail inQA testsBecauseprocesses arescale dependentProcessesbehavedifferently on asmall scale andon a large scaleScale-Up is necessary todetermine the effect of scaleon product quality
Formulation relatedIndentification andcontrol of criticalcomponents and othervariablesEquipment relatedIdentification andcontrol of criticalparameters and operatingrangesProduction andProcess relatedEvaluation, validation,and finalization ofcontrolsProduct relatedDevelopment andvalidation ofreprocessingproceduresDocumentationRecords and reports according to cGMP
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
Should Adequately monitor the process To provide the assurance that the process is under control The product produced maintains the specified attributesoriginally intended
Pilot Plant DesignFormulation andProcess DevelopmentTechnology evaluation,Scale-Up andTransferClinical supplymanufacture
Attributes required ….. cGMP Compliance A flexible highly trained staff Equipment to support multiple dosage form development Equipment at multiple scales based on similarly operatingprinciples to those in production (Intermediate sized and Fullscale equipment) Portable equipment Multipurpose rooms Restricted access , regulated personnel flow and material flow Low maintenance and operating costs
VALIDATIONVALIDATIONDesignspecificationsDesignspecificationsInstallationQualificationInstallationQualificationOperationalQualificationOperationalQualificationPerformanceQualificationPerformanceQualificationCompliance with cGMP and FDA standardsCompliance with cGMP and FDA standards
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 forclinical 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 finishedclinical products, components required for clinical supplies Testing for validation and revalidation programs QC in-process testing during development, Scale-Up and Technology transfer activities
1. Personnel Requirements2. Equipment Requirements3. Space Requirements4. Process Evaluation5. Preparation of Master ManufacturingProcedures6. GMP Considerations
Equipment selected based on processing characteristicsof productMost economical, simplest and efficientThe size should be relevant to production sized batchesEase of cleaningTime of cleaningEQUIPEMENT REQUIREMENT
Administration and Information ProcessingPhysical Testing AreaStandard Pilot Plant Equipment Floor SpaceStorage AreaSeparate for API and Excipients and further segregated into area forapproved and unapproved materialsIn process materials, finished bulk products, retained samples, experimentalproduction batches, packaging materialsControlled environment space for Stability SamplesSPACE REQUIREMENTS
Process parameters should be evaluated and optimized.For example : MixingOrder of additionMixing speedMixing timeRate of addition etc.,PROCESS EVALUATION
Chemical weigh sheetIdentify the chemicalsIts quantityThe order of usingThe sampling directionsProcess specificationsShould be in understandable languageIn process and finished product specificationsProper documentation required
Process ValidationRegular process review and revalidationRelevant written Standard Operating ProceduresEquipment QualificationRegularly scheduled preventive maintenancecontd…..GMP CONSIDERATIONS
Validated cleaning proceduresAn orderly arrangement of equipment so as to easematerial flow and prevent cross-contaminationA well defined technology transfer systemThe use of competent, technically qualified personnelAdequate provision for training of personnel
Material/Powder HandlingTwo primary concerns : Achieving reliable flow andmaintaining blend uniformity.Segregation leads to poor product uniformity.Handling system :- Must deliver the accurate amount of theingredient- Material loss should be less- There should be no cross contamination
Avoiding segregation …..Modify the powder in a way to reduce its inherent tendencyto segregateChange the particle size such that the active segregationmechanism becomes less dominantChange the cohesiveness of the powder such that the particlesin a bed of powder are less likely to move independent ofeach otherModify the equipment to reduce forces that act to segregatethe powderChange the equipment to provide remixing
Dry BlendingDry blend should take place in granulation vesselLarger batch may be dry blended and then subdividedinto multiple sections for granulation.All ingredients should be free of lumps otherwise itcauses flow problems.Screening and/or milling of the ingredients prior toblending usually makes the process more reliableand reproducible.
GRANULATIONThe weight of the material and the shear forcesgenerated by granulation equipment.The use of multifunctional processors (significant interms of space and manpower requirements).Viscosity of the granulating solution.
FLUIDISED BED GRANULATIONSProcess inlet air temperatureAtomization Air PressureAir VolumeLiquid Spray RateNozzle Position and Number of Spray HeadsProduct and Exhaust Air TemperatureFilter PorosityCleaning FrequencyBowl Capacity
Hot Air OvenAir flowAir TemperatureDepth of the granulation on the traysMonitoring of the drying process by the use of moisture andtemperature probesDrying times at specified temperatures and air flowrates for each product
Fluidized Bed DryerOptimum LoadAir Flow RateInlet Air TemperatureHumidity of the Incoming Air
PARTICLE SIZE REDUCTIONSizing plays a key role in achieving uniformity.There are two ways of sizing : Particle size separationand Particle size reduction.Major Factor – Feed rate of the material.During scale up, overhead feeding equipment isincorporated to mimic large scale production.
BLENDINGBlender loadsBlender sizeMixing speedMixing timeBulk density of the raw material (considered in selectingblender and in determining optimum load)Characteristics of the material
SPECIALISED GRANULATIONPROCEDURESDry Blending and Direct CompressionSlugging (Dry Granulation)
Dry Blending and Direct CompressionThe order of addition of components to the blenderThe blender loadThe mixing speedThe mixing timeThe use of auxiliary dispersion equipment within themixerThe mixing actionCompression force
Slugging (Dry Granulation)Forces used for slugging operationThe diameter of the punchesSubsequent sizing and screening operations
GRANULATION HANDLING ANDFEED SYSTEMEvaluation of vacuum automated handling systems andmechanical systemsSegregation : Due to static charges built up due tovacuum can alter material flow propertyThe effect of above system on the content uniformityof the drug and on the particle size
COMPRESSIONPress speedHandling and compression characteristics (in theselection of a tablet press)Die filling rateFlow rate of granulesInduced die feed systems (for high speed machines) –speed of feed paddlesThe clearance between the scraper blade and the dietableDesign and condition of the punches
TABLET COATING (FILM COATING)Pan CoatingFluidized Bed Coating
Pan and Fluidized CoatingOptimum tablet loadOperating tablet bed temperatureDrying airflow rate and temperatureThe solution application rateThe size and shape of the nozzle aperture (for airless sprayer)The atomizing air pressure and the liquid flow rate (for airatomized sprayers)
Pan CoatingFixed OperatingParametersVariable OperatingParametersOther ParametersPan Loading (kg)Solid content of coatingsuspension (%w/w)Spray gun dynamicsDrying Air (cfm)Inlet air temperature( ْC )Gun to tablet beddistanceCoating System Spray rate (g min-1)Quantity of coatingapplied (%w/w)Atomizing air pressure (psi,bar)Air Pressure (psi, bar)Pan speedNumber of spray guns
Fluidized Bed CoatingBatch sizeDrying/fluidizing air volumesSpray nozzle dynamicsSpray evaporation rate
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 tankFiltration equipment (should not remove active oradjuvant ingredients)Transfer systemPassivation of stainless steel (pre reacting the SS withacetic acid or nitric acid solution to remove the surfacealkalinity of the SS)
SUSPENSION Addition and dispersion of suspending agents (Vibrating feedsystem at production scale) Hydration/Wetting of suspending agent Time and temperature required for hydration of suspendingagent 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)
EMULSIONTemperatureMixing EquipmentHomogenizing EquipmentIn process or final product filtersScreens, pumps and filling equipmentPhase volumesPhase viscositiesPhase densities
Mixing equipment Motors (used to drive mixing system and must be sized to handle the productat 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 toholding tank to filling linesTransfer pumpsWhile choosing size and type of pump :Product viscosityPumping rateProduct compatibility with the pump surfacePumping pressure required should be considered
PARENTERAL SOLUTIONIt is liquid scale up task.Mixing is one of the important process to be scaled up.Large scale mixing -- FlowSmall scale mixing -- ShearGeometric factors :--- Diameter of the impeller (D)-- Diameter of the tank (T)-- Height of the liquid in the vessel (Z)-- Impeller speed
Sterilization equipment Filtration equipment Pumps Packaging equipmentalso have to be scaled up.
The design and Scale-up of biological processes is verychallenging. Parameters to be considered for scale-up of biotechnologyproducts are :1. Bioreactor Operation2. Filtration Operation3. Centrifugation4. Chromatography5. Viral Clearance
BIOREACTOR OPERATION(STIRRED TANK)Impeller rateAeration rateHydrostatic pressureAgitation rateMixing time
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 rateand 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 CLEARANCEIt is very important part of the process design forbiotechnology product.It is also to be scaled up.
PRINCIPLES OF SIMILARITYGEOMETRICSIMILARITYMECHANICALSIMILARITYTHERMALSIMILARITYCHEMICALSIMILARITYSTATICSIMILARITYKINEMATICSIMILARITYDYNAMICSIMILARITY
Similarity with respect to geometrical factorsi.e. shape, height, thickness, breadth, etc., Small scale and large scale equipments must bein scale ratio of 1:2, 1:5, 1:20 etc.,
MECHANICAL SIMILARITYConcerned with application of force to a stationary or movingsystem.Static similarity – It is the deformation of one body orstructure to that of an other under constant stress.Kinematic similarity – Corresponding moving particles takesimilar path in the corresponding time interval.Dynamic similarity – Forces which accelerate or retard themotion of materials.Moving systems are dynamically similar when the ratio ofall forces is equal.It is useful in the prediction of pressure drops, powerconsumption.
THERMAL SIMILARITYIt is concerned with flow of heat (by radiation,conduction, convection, or the bulk transfer ofmaterial).Geometrically similar systems are thermally similarwhen temperature difference bears constant ratio andin moving systems it must have Kinematic similarity.
CHEMICAL SIMILARITYIt is concerned with the variation in chemicalcomposition from point to point as a function oftime.It is related to existence of comparable concentrationgradients.It is dependent upon both thermal and Kinematicsimilarity.
Scale-Up ReportNDA SubmissionManufacture ValidationBatchesLarge scale process qualificationstudiesProduct transfer document issuedProduct acceptance by manufacturingValidation protocol writtenPre approval inspection by FDAManufacturing site preparationValidation Report
1. What is the difference between Pilot Scale and Scale-Up?2. Outline the Pilot Plant Operation and give brief note oneach .3. Enumerate the parameters that should be consideredduring the scale up of Tablet Coating ?4. Give a brief note on Scale-Up of Biotechnology-DerivedProducts and Parenteral Solutions .5. What are the steps involved in transfer of a formulationright from F&D to Production Facility ?
The Theory and Practice of Industrial Pharmacy : Leon Lachman,Herbert A Lieberman , Joseph L Kanig : Section IV : Chapter 23 : PilotPlant Scale-Up Techniques : Page No . 681 – 710 .Encyclopedia of Pharmaceutical Technology : James Swarbrick , JamesC Boylan : Volume 12 : Pilot Plant Design : Page No . 171 – 186 .Pilot Plant Operation : Page No . 187 – 208 .Drugs and The Pharmaceutical Sciences : Pharmaceutical ProcessScale-Up : Marcel Dekker series : Michael Levin : Volume 118Parenteral Drug Scale-Up : Page No. 43 – 56 .Scale-Up Considerations for Biotechnology-Derived Products :Page No. 95 – 114Powder Handling : Page No. 133 – 150 .Scale-Up of Film Coating : Page No. 259 – 310 .REFERENCES
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