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Aspects of Pharmaceutical Pilot Plant is covered...

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PAPER-412

CHAPTER-3,4,5 &6

PILOT PLANT & SCALE UP BY: Sejal Kharadi

PILOT PLANT SCALE UP TECHNQIUES

PRESENTE PRESENTED D BY, SEJAL KH KHARADI, ARADI, ROLL NO . 10, M – PHARM : I .

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L. M. COLLEGE OF PHARMACY.

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CONTENTS: TOPIC

PAGE NO.

INTRODUCTION ON PILOT PLANT AND SCALE UP

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PILOT PLANT DESIGN

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PILOT PLANT OPERATION

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GENERAL CONSIDERATIONS REQUIREMENTS

ABOUT

PILOT

PLANT 112

SCALE UP CONSIDERATIONS FOR SOLID DOSAGE FORM (TABLET)

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SCALE UP FORMS

DOSAGE

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SCALE UP CONSIDERATIONS FOR SEMISOLID DOSAGE FORMS

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CONSIDERATIONS

FOR

LIQUID

SCALE UP CONSIDERATIONS FOR PARENTERAL PRODUCT 119 (SOLUTION) SCALE UP CONSIDERATIONS DERIVED PRODUCTS

FOR

BIOTECHNOLOGY- 120

THEORY OF SIMILARITY

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REFERENCE AND QUSTION BANK

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INTRODUCTION PILOT SCALE : In moving from R & D to production scale , it is essential to have an intermediate batch scale which is known as pilot scale . Pilot scale is defined as manufacturing of drug product by a procedure fully representative of and simulating that used for full manufacturing scale.

Why pilot plant? Main goal is to facilitate 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     

SCALE UP : Scale Up is defined as the process of increasing the batch size . It is also a procedure for applying the same process to different output volumes . But batch size enlargement does not always translate into a size increase of the processing volume . In mixing , first definition fits while in tabletting second definition fits where “Scale Up” simply means enlarging the output by increasing the speed . In other words scale up is used to translate process development to large scale production .

Why scale up? A well defined process may generate a perfect product in both the laboratory and the pilot plant and then fail quality assurance tests in production . This is because processes are scale dependent : they behave differently on a small scale (in laboratories or pilot plants) and on a large scale (in production) . It is because of this reason that scale up is necessary to exactly determine the effect of scale on product quality .

Objective of scale up: 1. Formulation related:- Identification and control of critical components and other Variables. 2. Equipment related:- Identification and control of critical parameters and operating ranges. 3. Production and Process related:- Evaluation, validation, and finalization of Controls. 4. Product related:- Development and validation of reprocessing procedures. 108

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5. Documentation:- Records and reports according to cGMP. Pilot plant studies include the close examination of the formula to determine : Its ability to withstand batch scale . Process modification . Compatibility of the equipment with the formulation . Cost factor . Availability of raw materials meeting the specifications required to produce the product . Market requirement . Physical space required and the layout of the related functions . Thus , during the scale up efforts in the pilot plant : Production and process controls are evaluated , validated and finalized . Product reprocessing procedures are developed and validated . Appropropriate records and reports are issued to support cGMP . In short , all critical features of a process must be identified so that as the process is scaled up , it can be adequately monitored to provide assurance that the process is under control and that the product produced at each level of the scale up maintains the specified attributes originally intended .

PILOT PLANT DESIGN A pilot plant design should support three key strategic objectives : Formulation and process development . Clinical supply manufacture . Technology evaluation , scale up and transfer . Attributes playing a key role in achieving the above objectives are : cGMP Compliance . A flexible highly trained staff . Equipment to support multiple dosage form development . Equipment at multiple scales based on similar operating principles to those in production . The pilot plant design should be according to cGMP norms . The layout should be according to the need for flexibility (portable equipment installed , use of multipurpose rooms) , restricted access , personnel flow and material flow. The facility and equipment should be able to capture critical process information . Intermediate sized and Full scale production equipment should be available in order to evaluate the effects of scale up of research formulations . Adequate space required to carry out each function smoothly (eg., cleaning of pilot plant equipments) . The final design should result in a facility that support the key strategic objectives and should have low maintenance and operating costs . Although the pilot plant design must simulate the manufacturing environment in which the new product will ultimately be produced , there are many differences in operation because of the specific objectives of the two types of facilities i.e. the

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pilot plant facilitates product development activities , whereas the manufacturing plant routinely fabricates products for the market place .

PILOT PLANT OPERATION Operational Aspects of Pilot Plant includes : Validation Training Engineering Support Maintenance Calibration Material Control Inventory Orders Labeling Process and Manufacturing Activities Quality Assurance and Quality Control VALIDATION : A validation master plan should be develop that addresses-The design specifications Installation qualification Operational qualification Performance qualification of all major utility systems , process equipment , and computer control systems . A fully validated pilot plant should ensure compliance with cGMP and should meet current FDA standards . TRAINING : Training in four major area required –Compliance with quality standards such as cGMP Safety and environmental responsibilities Compliance with SOPs Technical skills and knowledge ENGINEERING SUPPORT : It is required for –Design , construction , commissioning and validation of the pilot plant facility Co-ordination , scheduling and direction of ongoing operations MAINTENANCE : It is required to –Meet cGMP norms To ensure data integrity and equipment reliability during the development process. The maintenance program should be documented and written procedures established . 110

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CALIBRATION : Calibration of critical instruments/equipments is required for–Compliance with cGMP Maintaining the integrity of data generated during the development process Calibration should be performed by well trained and expert staff . MATERIAL CONTROL : More flexible and efficient computer based system is required for material control in pilot plant . INVENTORY : Inventory should be maintained in a Computer Based InventoryOrdering-Dispensing System . ORDERS : All orders must be placed through the computer placement of the order , First In First Out (FIFO) criteria is followed .

system . For

LABELING : Labels should comply with GMP-GLP requirements . Computer system must be used for labeling . PROCESS AND MANUFACTURING ACTIVITIES : It includes – Formulation and Process Development Studies Clinical supply manufacture Technology evaluation , scale up and transfer Precise documentation of each trials have to be made . QUALITY ASSURANCE & QUALITY CONTROL : QA Activities –Auditing pilot plant Auditing and approval of component suppliers Reviewing , approving 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 . QC Activities –Release testing of finished products Physical , chemical , and microbiological testing of finished clinical products, components and raw materials Testing for validation and revalidation programs QC in-process testing during development , scale up , and technology transfer activities

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GENERAL CONSIDERATIONS PERSONNEL REQUIREMENTS : Personnel should have –Theoretical knowledge of Pharmaceutics Practical experience in the pharmaceutical industry Ability to communicate Some engineering capability since the scale up of many of the processes involve engineering principles Knowledge of both electronics and computers The number of personnel in pilot plant group depends on the number of products being supported and on the level of support required. SPACE REQUIREMENTS : A pilot plant has the following four types of space requirements –Administration and Information Processing Physical Testing Area Standard Pilot Plant Equipment Floor Space Storage Area Separate provisions for API and excipients further segregated into approved and unapproved areas according to GMP . Storage area for in process materials , finished bulk products , retained samples , experimental production batches , packaging materials (segregated into approved and unapproved areas) . Controlled environment space allocated for storage of stability samples REVIEW OF THE FORMULA : The purpose of each ingredient and its contribution to the final product manufactured should be understood . If there is a need to modify the formulation this should be done as early as possible in Phase III trials to allow times to generate meaningful long-term stability in support of a proposed NDA . RAW MATERIALS : Approval and validation of API and excipient is one of the pilot plot function . This is necessary because materials used during small scale formulation trials may nor be representative of the large volume shipments of materials used in large scale production . Also the quality of materials needs to be verified due to alternate suppliers . RELEVANT PROCESSING EQUIPMENT : Equipment should be selected on the basis of processing characteristics of the product . It should be most economical , simplest and the most efficient . The size should be such that experimental trials can be run that are relevant to the production – sized batches that will eventually be run . Too small ------ Process developed will not scale up Too large ------ Excessive costs will be incurred

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Ease of cleaning should be considered especially if multiple products are manufactured in the equipment . Time required for cleaning between batches should be considered . If time for cleaning is more than that of actual time of manufacturing , this becomes an important consideration . PRODUCTION RATES : It can be determined by the immediate future market requirements. Equipment and the process should be chosen on the basis of production of a batch at a frequency that takes into consideration : 1. Product loss in the equipment during manufacture . 2. The time required to clean the equipment between batches . 3. The number of batches that will need to be tested for release . PROCESS EVALUATION : Following process parameters should be evaluated and optimized –1. 2. 3. 4. 5. 6. 7. 8. 9.

Order of addition of components , including adjustment of their amounts Mixing Speed Mixing Time Rate of addition of granulating agents , solvents , solutions of drugs , slurries etc . Heating and cooling rates Filter sizes (liquids) Screen sizes (solids) Drying Temperatures Drying Time

It is the basis of process validation Documentation of process is to be done . Process is validated only if there are no changes in the formula , quality of the ingredients , or the equipment configuration . Revalidation needs to be done to ensure that changes have not take place . PREPARATION OF MASTER MANUFACTURING PROCEDURES: It includesThe chemical weigh sheet. It should clearly identify the chemicals required in a batch and present the quantities and the order in which they will be used . The sampling directions In-process and finished product specifications Manufacturing directions should be in a language understandable by the operator termed as SOP’s . Batch Record Directions should include specifications for addition rates , mixing times , mixing speeds , heating and cooling rates , temperature . Proper documentation should be carried out. GMP CONSIDERATIONS : GMP items that should be a part of scale up are –-

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1. 2. 3. 4. 5. 6. 7.

Process Validation Regular process review and revalidation Relevant written Standard Operating Procedures Equipment Qualification Regularly scheduled preventive maintenance Validated cleaning procedures An orderly arrangement of equipment so as to ease material flow and prevent cross-contamination 8. A well defined technology transfer system 9. The use of competent , technically qualified personnel 10. Adequate provision for training of personnel

TRANSFER OF ANALYTICAL METHODS TO QUALITY ASSURANCE : Analytical methods developed in research must be transferred department . Transfer process includes –-

to

QA

1. Review the process to make sure that proper analytical instrument is available . 2. Personnel should be trained to perform the test . 3. Reliability of the test should be checked . 4. At last assay procedure should be reviewed before transfer .

SCALE UP CONSIDERATIONS FOR SOLID DOSAGE FORM (TABLET) MATERIAL/POWDER HANDLING : Segregation causes significant deblending of well blended powder leading to poor product uniformity . An ability to control particle segregation during powder handling and transfer is critical to control uniform product . There are two primary concerns with powder handling that cannot be overlooked while scaling processes : achieving reliable flow and maintaining blend uniformity . Segregation can be avoided -1. Modify the powder in a way to reduce its inherent tendency to segregate. a. Change PSD of one or more of the components (If similar PSD then there is lesser tendency to segregate) or b. Change the particle size such that the active segregation mechanism become less dominant or c. Change the cohesiveness of the powder such that the particles in a bed of powder are less likely to move independent of each other ] 2. Modify the equipment to reduce forces that act to segregate the powder . 3. Change the equipment to provide remixing . Handling system -- must deliver the accurate amount of the ingredient, material loss should be less ( It is there , then there must be accountability and compensation ) , there should be no cross contamination ( In case , system is

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used to transfer more than one product equipment must be cleaned by validated cleaning procedures ) . DRY BLENDING : Inadequate dry blending leads to drug content uniformity variation . Points to be taken care of –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 : Parameters to be considered are –The weight of the material and the shear forces generated by the granulating equipment since it affects the granulating time and the amount of granulating fluid required . The use of multifunctional processors . (significant in terms of space and manpower requirements) Viscosity of the granulating solution . Transfer of the fluid may be difficult and a problem may be encountered during the scale up of the process . One way of avoiding this problem is to disperse some or all of the binding agent in the dry powder prior to granulating . Proper ventilation and additional safety precautions must be considered in the selection and design of the equipment and manufacturing area . During the scale up process the quality of the granules may change . A change in granule size distribution , final moisture content , friability , compressibility , and compatibility may strongly influence the properties of the final tablet such as tablet hardness , tablet friability , disintegration time , dissolution rate of the active substance and aging of the tablet . Fluidized Bed Granulations : 1. Process Inlet Air Temperature 2. Atomization Air Pressure 3. Air Volume 4. Liquid Spray Rate 5. Nozzle Position and Number of Spray Heads 6. Product and Exhaust Air Temperature 7. Filter Porosity 8. Cleaning Frequency 9. Bowl Capacity DRYING : Hot Air Oven and Fluidized Bed Dryer are most widely used for drying of granulations . Tray Dryer-- Parameters to be considered for scale up are : 1. Air flow 2. Air temperature 115

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3. Depth of the granulation on the trays 4. Monitoring of the drying process by the use of moisture and temperature probes 5. Drying times at specified temperatures and air flow rates for each product Fluidized Bed Dryer : Parameters to be considered for scale up are : 1. Optimum Load 2. Air Flow Rate 3. Inlet Air Temperature 4. Humidity of the Incoming Air

PARTICLE SIZE REDUCTION : In solid dosage form manufacturing , sizing plays a key role in achieving uniformity . There are two ways in which sizing is performed : Through particle size separation and particle size reduction . A major factor is the feed rate of the material into the equipment (assuming equivalent screen sizes used) . As the feed rate is increased so is residence time with in the chamber of the equipment . This results in a finer distribution . To successfully mimic large scale conditions , overhead feeding equipment can be incorporated into the sizing equipment . BLENDING : In scale up of blending , following parameters should be considered –1. 2. 3. 4. 5.

Blender loads , Blender size , Mixing speeds , Mixing times , Bulk density of the raw material (must be considered in selecting blender and in determining optimum blender load) 6. Characteristics of the material

SPECIALIZED GRANULATION PROCEDURES : Dry Blending and Direct Compression : The following parameters should be adjusted to optimize the process – 1. The order of addition of components to the blender , 2. The blender load , 3. The mixing speed , 4. The mixing time , 5. The use of auxiliary dispersion equipment within the mixer , 6. The mixing action , 7. Compression...