Pilot plant scale up


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Pilot plant scale up

  2. 2. Introduction and definition  Introduction to Pilot Plant  Pilot plant is defined as part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by development of liable and practical procedure for manufacture that effects the orderly transition from laboratory to routine processing in a full scale production facility.  Introduction to Scale Up Plant  The art for designing of prototype using the data obtained from the pilot plant model.  It is a place were the 5 M’s like money, material, man, method and machine are brought together for the manufacturing of the products
  3. 3. + Pilot Scale and Scale-Up R&D Large Scale Production Pilot Scale Scale-Up
  5. 5. + WHY CONDUCT PILOT PLANT STUDIES ?  A pilot plant allows investigation of a product and process on an intermediate scale before large amounts of money are committed to full-scale production  It is usually not possible to predict the effects of a manyfold increase in scale  Reduces the risk associated with the construction of full scale plant. Less capital is required.
  6. 6. + PILOT PLANT CAN BE USED FOR….  Evaluating the results of laboratory studies and making product and process corrections and improvements  Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-live and storage stability studies  Determining possible salable by-products or waste stream requiring treatment before discharge  Providing data that can be used in making a decision on whether or not to proceed to a fullscale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant
  7. 7. + CONSIDERATIONS FOR PILOT PLANT DEVELOPMENT ….  Kind and size – depends on goals; evaluating product and process; producing samples of product for evaluation; market testing or furnishing to potential customers  Location: near R&D facility .At an existing plant Close liaison between R&D and pilot plant staff is essential  Labor requirements and costs: engineering staff, skilled operations and maintenance staff- pilot plant costs may exceed those of usual plant production costs. The pilot plant may be used for training personnel for a full- scale plant
  8. 8. + 8 Why Pilot plant needed…………  Needed to make supplies for  bench studies,  product characterization, purity  animal studies    toxicology pharmacokinetics, ADME efficacy  clinical studies
  9. 9. + 9 Regulations for Scale -Up  Code of Federal Regulations Title 21  Part 210 and 211 - Good Manufacturing Practices for Drugs  Part 600 - 680 Processing of Biological materials  Part 820 - Quality System Regulations for Medical Devices  Subpart C: Design Controls
  10. 10. Why Scale-Up needed…… A well defined process A perfect product in laboratory and pilot plant But May fail in QA Tests Because process are scale dependent Processes behave differently on a small scale and a large scale Scale up is necessary to determine the effect of scale on product quality
  11. 11. OBJECTIVES OF SCALE UP…. To produce physically and chemically stable therapeutic dosage Review of the processing equipment Guidelines for production and process control Evaluation and Validation To identify the critical features of the process To provide master manufacturing forumla
  12. 12. + CLOSE EXAMINATION OF FORMULA TO DETERMINE… Its ability to withstand batch scale Process Modification Compatibility of the equipment with the formulation Cost factor Market requirement Physical space required and the layout related functions
  13. 13. + SCALE UP EFFORTS IN PILOT PLANT…. Production and Process controls are evaluated, validated and finalized Product reprocessing procedures are developed and validated Appropriate records and reports are issued to support cGMP
  15. 15. + Pilot Plant Design…  Formulation and Process Development  Technology evaluation , Scale-Up and Transfer  Clinical Supply Manufacture
  16. 16. Attributes Required.. cGMP Complianc e A flexible highly trained staff Equipment to support multiple dosage form developme nt Equipment at multiple scales based on similarly operating principles to those in production (Intermedi ate sized and Full scale equipment ) Portable equipment Multi purpose rooms Restricted access , regulated personnel flow and material flow Low maintenan ce and operating costs
  18. 18. + Organizational Aspects… Validation QA & QC Training Organizational Aspects Process and Manufacturin g Activities Inventory ,Orders and Labeling Engineerin g Support Maintenance and calibration Material control
  19. 19. Validation…… Design Specifications Installation Qualification Operational Qualification Performance Qualification Compliance with cGMP and FDA Standards
  20. 20. + Training….. Compliance with cGMP Safety and Environmental Responsibilities Compliance with SOP’s Technical Skills and Knowledge
  21. 21. + Engineering Support…. Design, Construction, Co mmissioning and validation of the pilot plant facility Co-ordination ,Scheduling , Direction of ongoing operations
  22. 22. + MAINTENANCE…. To meet cGMP Norms To ensure Data Integrity and Equipment Reliability
  23. 23. + CALIBRATION… Compliance with cGMP Well trained and expert staff Maintaining the integrity of data during development
  24. 24. MATERIAL CONTROL… COMPUTERIZED SYSTEM + Material Control Inventory Orders (FIFO) Labeling (GMPGLP)
  25. 25. + Process And Manufacturing Activities.. Formulation and Process Management Studies Technology Evaluation , Scale-Up and Transfer Clinical Supply Manufacture
  26. 26. + 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
  27. 27. + QUALITY CONTROL….  Release Testing of finished product  Physical, Chemical and Microbiological testing of finished clinical products, components required for clinical supplies  Testing for validation revalidation programs  QC in-process testing during development, Scale-Up and Technology transfer activities and
  28. 28. + REQUIREMENTS
  29. 29. + Requirements for pilot plant and Scale-Up….  Personnel Requirements  Space Requirements  Administration and Information Process  Physical Testing Area  Standard Pilot-plant Equipment Floor Space  Storage Area  Review of Formula  Process Evaluation  Preparation of Master Manufacturing Procedures  Product Stability and Uniformity  GMP Considerations
  30. 30. + GENERAL CONSIDERATIONS REPORTING RESPONSIBILITIES 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
  31. 31. + Personnel Requirement  Scientists with experience in pilot plant operations as well as in actual production area are the most preferable.  As they have to understand the intent of the formulator as well as understand the perspective of the production personnel.  The group should have some personnel with engineering knowledge as well .As scale up also involves engineering principles.
  32. 32. Space Requirement Administration and information processing Physical testing area Storage area Standard equipment floor space
  33. 33. + Administration and information process: Adequate office and desk space should be provided for both scientist and technicians.  The space should be adjacent to the working area. 
  34. 34. + Physical testing area This area should provide permanent bench top space for routinely used physical- testing equipment.
  35. 35. + Standard pilot-plant equipment floor space Discreet pilot plant space, where the equipment needed for manufacturing all types of dosage form is located.   Intermediate – sized and full scale production equipment is essential in evaluating the effects of scaleup of research formulations and processes.  Equipment used should be made portable where ever possible. So that after use it can be stored in the small store room.  Space for cleaning of the equipment should be also provided.
  36. 36. + Storage Area  It should have two areas divided as approved and unapproved area for active ingredient as well as excipient.  Different areas should provided for the storage of the in-process materials, finished bulk products from the pilot-plant & materials from the experimental scale-up batches made in the production.  Storage area for the packing material should also be provided.
  37. 37. + Review of the formula  A thorough review of the each aspect of formulation is important.  The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory equipment should be understood.  Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized.
  38. 38. + Raw materials One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients raw materials. Why? Raw materials used in the small scale production cannot necessarily be the representative for the large scale production
  39. 39. + Equipment  The most economical and the simplest & efficient equipment which are capable of producing product within the proposed specifications are used.  The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches.  If the equipment is too small the process developed will not scale up,  Whereas if equipment is too big then the wastage of the expensive active ingredients.
  40. 40. + Production Rates The immediate as well as the future market trends/requirements are considered while determining the production rates.
  41. 41. + Process Evaluation Drying temp. And drying time Screen size (solids) Order of mixing of components Mixing speed PARAMETERS Mixing time Filters size (liquids) Heating and cooling Rates Rate of addition of granulating agents, solvents, solutions of drug etc.
  42. 42. +  Why  to carry out process evaluation???? The knowledge of the effects of various process parameters as few mentioned above form the basis for process optimization and validation.
  43. 43. + Master manufacturing procedures The three important aspects are Weight sheet Processing directions Manufacturing Procedure
  44. 44. + Master Manufacturing Procedures  The weight sheet should clearly identify the chemicals required in a batch. To prevent confusion the names and identifying no’s for the ingredients should be used on batch records.  The process directions should be precise and explicit.  A manufacturing procedure should be written by the actual operator.  Various specifications like addition rates, mixing time, mixing speed, heating, and cooling rates, temperature, storing of the finished product samples should be mentioned in the batch record directions.
  45. 45. + Product Stability and Uniformity  The primary objective of the pilot plant is the physical as well as chemical stability of the products.  Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability.  Stability studies should be carried out in finished packages as well.
  46. 46. + GMP Considerations…. A checklist of GMP items that should be part of scale-up or new product or processes introduction includes the following:  Equipment qualification  Process validation  Regularly schedule preventative maintenance  Regularly process review & revalidation  Relevant written standard operating procedures  The use of competent technically qualified personnel  Adequate provision for training of personnel  A well-defined technology transfer system  Validated cleaning procedures.  An orderly arrangement of equipment so as to ease material flow & prevent cross- contamination
  47. 47. + Transfer of Analytical Methods  During scale up of new product, the analytic test methods developed in research must be transferred to QA Department.  In early transfer processes, the QA staff should review the processes to make sure that the proper analytic instrumentation is available and personal all trained to perform test.  If requires ASSAY method can be reformatted and re written using technology and procedures consistent with current QA laboratory practice.  To complete transfer, research personal should review the assay procedure and the data obtained during the validation studies, verify the analytical methods have not been altered in a way that might affect the reliability precision or accuracy of the tests.
  48. 48. + Types of organizational structures responsible for pilot operations: A) Research pharmacist responsible for initial scale-up and initial production runs. B) Pharmaceutical pilot plant controlled by Pharmaceutical Research. C) Pharmaceutical pilot plant controlled by production division.
  49. 49. A) Research pharmacist responsible for initial scale-up and initial production runs Department of pharmaceutical research Technical director of production Manager of solid dosage form research Manager of tablet and capsule production Pharmaceutical research staff Section head operators
  50. 50. B) Pilot plant controlled by pharmaceutical research + Technical director of production Director of pharmaceutical research and development Manager of solid dosage form research Pharmaceutical research staff Manager of pilot development Manager of tablet and capsule production Section head in charge of tablet production Pharmacists and engineers Operators
  51. 51. + C) Pharmaceutical pilot plant controlled by production division Director of Pharmaceutical research Technical director of production Manager of solid dosage form research Manager of tablet and capsule production Pharmaceutical Research staff Section head of pilot department operators Section head in charge of tablet production operators
  52. 52. + Educational backgrounds of pilot plant personnel  They should possess the knowledge of physicochemical factors which could adversely affect bioavailability of drug component from the tablet dosage form.  An individual with graduate training in industrial pharmacy is well qualified for such a responsibility.  Industrial pharmacy core curriculum and electives usually include the following courses: Product formulation, mfg. pharmacy, industrial pharmacy, biopharmaceutics, homogene ous system, ph. engineering, evaluation of pharmaceutical dosage form, regulatory aspects, principles of QA.
  53. 53. +  Mechanical and chemical engineers would be advantageous in the selection of new equipment offerings and in the organization of most economical sequences of unit operations.  In addition good communication skills both oral and written are essential, because these individuals must frequently interact with members of the pharmaceutical research and production divisions.  Whatever the technological trend, once the goals are defined, the best combination of trained personnel can be determined for the pilot plant.
  54. 54. + Advantages….. Access to engineering department personnel is provided for equipment installation, maintenance and repair. Supplies of excipients & drugs, cleared by the quality control division, can be drawn from the more spacious areas provided to the production division. Members of the production and quality control divisions can readily observe scale up runs
  55. 55. + Disadvantages….. The frequency of direct interaction of the formulator with the production personnel in the manufacturing area will be reduced. Any problem in manufacturing will be directed towards it’s own pilot-plant personnel's.
  56. 56. + Liquid-Liquid Extraction pilot plant setup
  57. 57. + Pilot plant for medicinal and aromatic plants