Slide 1: Pilot Plant Scale Up Techniques By, Mr. Nitin M. Kadam M.Pharm [Pharmaceutics] R&D (Formulation- Technology Transfer) Ipca Laboratories ltd. Content: Content Introduction Pilot plant design Pilot plant operation Requirements Scale up consideration Principles of similarity Development milestones Slide 3: INTRODUCTION Pilot Scale and Scale-Up : Pilot Scale and Scale-Up Pilot Scale Scale-Up R & D Large Scale Production Pilot Scale and Scale-Up Means ? : 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 ) Slide 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 ? Slide 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 Slide 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 Objectives of the Scale-Up Slide 9: Examination of the Formula to determine ..... 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 Slide 10: Scale-Up ..... Should Adequately monitor the process To provide the assurance that the process is under control The product produced maintains the specified attributes originally intended Slide 11: Pilot Plant Design Slide 12: Pilot Plant Design Formulation and Process Development Technology evaluation, Scale-Up and Transfer Clinical supply manufacture Attributes required …..: 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 Slide 14: Pilot Plant Operation Slide 15: Operational Aspects Validation Training Engineering support Maintenance and Calibration Inventory, Orders, Labeling Material control Process & Manufacturing Activities QA & QC Slide 16: V A L I D A T I O N Design specifications Installation Qualification Operational Qualification Performance Qualification Compliance with cGMP and FDA standards Slide 17: Compliance with GMP Safety and environmental responsibilities Compliance with SOPs Technical skills and knowledge Training Slide 18: Engineering Support Design of facility Construction of facility Co-ordination, scheduling, direction of ongoing operations Validation of facility Slide 19: To ensure data integrity and equipment reliability To meet cGMP norms Maintenance & Calibration Slide 20: Computerized System Material control Inventory Orders (FIFO) Labeling (GMP-GLP) Slide 21: Process And Manufacturing Activities Formulation & Process Development studies Technology evaluation, Scale Up, & Transfer Clinical supply manufacture Slide 22: Quality 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 Slide 23: QUALITY 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 Slide 24: REQUIREMENTS Slide 25: Requirements for Pilot scale and Scale-Up Personnel Requirements Equipment Requirements Space Requirements Process Evaluation Preparation of Master Manufacturing Procedures 6. GMP Considerations Slide 26: PERSONNEL REQUIREMENTS Theoretical Knowledge of Pharmaceutics Ability to communicate Practical experience in pharmaceutical industry Engineering Capability Knowledge of electronics and computers Slide 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 Slide 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 Slide 29: Process parameters should be evaluated and optimized. For example : Mixing Order of addition Mixing speed Mixing time Rate of addition etc., PROCESS EVALUATION Slide 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 MASTER MANUFACTURING PROCEDURE Slide 31: Process Validation Regular process review and revalidation Relevant written Standard Operating Procedures Equipment Qualification Regularly scheduled preventive maintenance contd….. GMP CONSIDERATIONS Slide 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 Slide 33: Scale-up Considerations For Tablets Material/Powder Handling: 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 …..: 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 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: 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: 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: DRYING HOT AIR OVEN FLUIDIZED BED DRYER Hot Air Oven: 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: Fluidized Bed Dryer Optimum Load Air Flow Rate Inlet Air Temperature Humidity of the Incoming Air PARTICLE SIZE REDUCTION: 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. BLENDING: 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 SPECIALISED GRANULATION PROCEDURES: SPECIALISED GRANULATION PROCEDURES Dry Blending and Direct Compression Slugging (Dry Granulation) Dry Blending and Direct Compression: 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): Slugging (Dry Granulation) Forces used for slugging operation The diameter of the punches Subsequent sizing and screening operations GRANULATION HANDLING AND FEED SYSTEM: 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: 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): TABLET COATING (FILM COATING) Pan Coating Fluidized Bed Coating Pan and Fluidized Coating: 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) Pan Coating: 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 Fluidized Bed Coating: Fluidized Bed Coating Batch size Drying/fluidizing air volumes Spray nozzle dynamics Spray evaporation rate Slide 53: Liquid Dosage Forms SOLUTION: 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 ….. Slide 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) SUSPENSION: 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: EMULSION Temperature Mixing Equipment Homogenizing Equipment In process or final product filters Screens, pumps and filling equipment Phase volumes Phase viscosities Phase densities Slide 58: Semisolid Products Slide 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) Slide 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 Slide 61: Parenteral Products PARENTERAL SOLUTION: 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 Slide 63: Sterilization equipment Filtration equipment Pumps Packaging equipment also have to be scaled up. Slide 64: Biotechnology Derived Products Slide 65: The design and Scale-up of biological processes is very challenging. Parameters to be considered for scale-up of biotechnology products are : Bioreactor Operation Filtration Operation Centrifugation Chromatography Viral Clearance BIOREACTOR OPERATION (STIRRED TANK): BIOREACTOR OPERATION (STIRRED TANK) Impeller rate Aeration rate Hydrostatic pressure Agitation rate Mixing time FILTERATION OPERATION: FILTERATION OPERATION Transmembrane pressure Volume Operating time Temperature Flux rate Protein concentration Solution viscosity Retentate flow rate Permeate flux Slide 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. CHROMATOGRAPHY: 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: VIRAL CLEARANCE It is very important part of the process design for biotechnology product. It is also to be scaled up. Slide 71: Principles Of Similarity Slide 72: PRINCIPLES OF SIMILARITY GEOMETRIC SIMILARITY MECHANICAL SIMILARITY THERMAL SIMILARITY CHEMICAL SIMILARITY STATIC SIMILARITY KINEMATIC SIMILARITY DYNAMIC SIMILARITY GEOMETRIC 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: 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. Systems exhibit mechanical similarity only if they are geometrically similar.: NOTE Systems exhibit mechanical similarity only if they are geometrically similar. THERMAL SIMILARITY: 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: 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. Slide 78: Development Milestones Slide 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 Slide 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 Slide 81: 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.: 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 Slide 83: What is the difference between Pilot Scale and Scale-Up? Outline the Pilot Plant Operation and give brief note on each . Enumerate the parameters that should be considered during the scale up of Tablet Coating ? Give a brief note on Scale-Up of Biotechnology-Derived Products and Parenteral Solutions . What are the steps involved in transfer of a formulation right from F&D to Production Facility ? FAQs Slide 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 Slide 85: Believe In ‘Application Of Knowledge’ Rather Than The ‘Knowledge’ It Self. - Mr. Nitin Kadam Thank You.