Pilotplantscale uptechniques by kailash vilegave


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General Considerations
GMP Considerations
Product Considerations

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Pilotplantscale uptechniques by kailash vilegave

  1. 1. “Make your mistakes on a small scale and our profits on a large one”. Mr. Kailash Vilegave M Pharma Lecturer, Dept of Pharmaceutics Shivajirao S. Jondhle College of Pharmacy Asangaon1 DEPT OF PHARMACEUTICS 3/15/2013
  2. 2. CONTENTS  Definition  Significance  General Considerations  GMP Considerations  Product Considerations  Advantages  Disadvantages  References 3/15/2013 DEPT OF PHARMACEUTICS 2
  3. 3. DEFINITIONS3  Plant:- It is a place where the 3 M’s that are Man, Material and Money are brought together for the manufacturing of products.  Pilot Plant:- It is the part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by development of liable practical procedure of manufacturing.  Scale-up:- The art for designing of prototype using the data obtained from the pilot plant model. DEPT OF PHARMACEUTICS 3/15/2013
  4. 4. SIGNIFICANCE4  Permits close examination of formulae to determine its ability to withstand batch scale and process modification.  Review of Equipment - most compatible with the formulation & most economical, simple and reliable in producing product.  Raw materials - consistently meet the specifications required to produce the product can be determined.  Production rate adjustment after considering marketing requirements.  Give rough idea about physical space required and of related functions. DEPT OF PHARMACEUTICS 3/15/2013
  5. 5. 5 Cont….  Appropriate records and reports are issued to support good manufacturing practices.  Procedure can be developed and validated.  To evaluate the effect on the process of a large change in the scale of operation and to gather other data so that a good design of a larger unit may be made with a high probability of commercial success.  To produce trial lot quantities of the material in question so that its properties may be critically examined.  To find and examine all by – products or waste. These may not be seen in laboratory scale. By the use of pilot plant, it is possible to minimize the waste, hence better yield of prescribed dosage3/15/2013 form. DEPT OF PHARMACEUTICS
  6. 6. GENERAL6 CONSIDERATIONS 1. Reporting Responsibility:- R & D group The formulator who developed the with separate product can take into the production staffing and can provide support even after transition into production has been completed DEPT OF PHARMACEUTICS 3/15/2013
  7. 7. 2. Personnel Requirement:-7 * 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. * Engineering principles 3/15/2013 DEPT OF PHARMACEUTICS
  8. 8. 8 3. Space Requirements:- Administration Physical Standard Storage and information testing area equipment area processing floor space DEPT OF PHARMACEUTICS 3/15/2013
  9. 9. a) Administration And Information Process:-9  Adequate office and desk space should be provided for both scientist and technicians.  The space should be adjacent to the working area.  Computers. 3/15/2013 DEPT OF PHARMACEUTICS
  10. 10. b) Physical Testing Area:-10  This area should provide permanent bench top space for routinely used physical - testing equipment. DEPT OF PHARMACEUTICS 3/15/2013
  11. 11. c) Standard Pilot-plant Equipment Floor Space :-11  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 scale-up of research formulations and processes.  Equipments 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. DEPT OF PHARMACEUTICS 3/15/2013
  12. 12. d) Storage Area:- It should have two areas, 1.Approved area and 2.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 packaging material should also be DEPT OF PHARMACEUTICS 3/15/2013 12
  13. 13. 4. Review of the formula:-13  A thorough review of the each aspect of formulation is important and carried out early in the scale up process.  The purpose of each ingredient and it’s contribution to the final product manufactured on the small-scale laboratory equipment should be understood.  If any modification in the formula, it should be done as early as possible in phase III trial .  To allow time to generate meaningful long term stability in support of a proposed new drug application (NDA)  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. DEPT OF PHARMACEUTICS 3/15/2013
  14. 14. 5. Raw materials :-14  One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipient raw materials.  Raw materials used in the small scale production cannot necessarily be the representative for the large scale production.  Ingredients may change in particle size, shape or morphology which result in differences in bulk density, static charges, rate of solubility, flow properties, color, etc. DEPT OF PHARMACEUTICS 3/15/2013  Quality of active ingredients needs to be verified
  15. 15. 6. Equipment:-15  The most economical, 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 too small the process developed will not scale up.  If too big then the wastage of the expensive active ingredients.  Ease of cleaning  Time of cleaning DEPT OF PHARMACEUTICS 3/15/2013
  16. 16. A. Non sterile equipments16  Heating and cooling capability  Adequate transfer system (filtration equipment)  Made of suitable non reactive sanitary materials  Processing tanks, kettles, pipes, mills, filter housing, are mostly fabricated from stainless still if interaction occurs then use poly poly tetra flouro ethane liners . DEPT OF PHARMACEUTICS 3/15/2013
  17. 17. B. Suspention17  For addition & dispersion of suspending agent required vibratinf feed system  Pumps and mills  Filling equipment  Homogenising equipments  Mixing equipment DEPT OF PHARMACEUTICS 3/15/2013
  18. 18. 7. Production Rates:-18  The immediate as well as the future market trends / requirements are considered while determining the production rates. DEPT OF PHARMACEUTICS 3/15/2013
  19. 19. 8. Process Evaluation:- ….items that should be examined including19 the following order of components including adjustments of their amounts……. Order of mixing of Drying temp. components Mixing And drying time speed Mixing Screen size PARAMETERS time (solids) Rate of addition of granulating agents, Filters size solvents, (liquids) solutions of drug etc. Heating and cooling Rates DEPT OF PHARMACEUTICS 3/15/2013
  20. 20.  Why to carry out process evaluation????20  The knowledge of the effects of various process parameters on in-process and finished product quality is the basis for process optimization and validation.  The purpose of process validation is to confirm that the selected manufacturing procedure assure the quality of the product at various critical stages in the process and in finished form.  The manufacturing process & quality control information should be revived on annual basis. DEPT OF PHARMACEUTICS 3/15/2013
  21. 21. 9. Master Manufacturing Procedures:-21 The Three important aspects Weight sheet Processing & Manufacturing Sampling procedure directions Finished product spacifacation DEPT OF PHARMACEUTICS 3/15/2013
  22. 22. Cont….22  The weight sheet should clearly identify the chemicals required in a batch. To prevent confusion the names and identifying numbers 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 PHARMACEUTICS in3/15/2013 DEPT OF mentioned the batch record
  23. 23. Transfer of Analytical Method to23 Quality Assurance  During the scale-up of a new product, the analytic test methods developed in research must be transferred to the quality assurance department.  Early in the transfer process, the quality assurance staff should review the process to make sure that the proper analytic instrumentation is available and that personnel are trained to perform the tests. DEPT OF PHARMACEUTICS 3/15/2013
  24. 24. 10. Product Stability And Uniformity:-24  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. OF PHARMACEUTICS 3/15/2013 DEPT
  25. 25. GMP CONSIDERATION Equipment qualification Process validation 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 3/15/2013 DEPT OF PHARMACEUTICS 25
  26. 26. ADVANTAGES26  Members of the production and quality control divisions can readily observe scale up runs.  Supplies of excipient & drugs, cleared by the quality control division, can be drawn from the more spacious areas provided to the production division.  Access to engineering department personnel is provided for equipment installation, maintenance and 3/15/2013 DEPT OF PHARMACEUTICS repair.
  27. 27. DISADVANTAGES27  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. DEPT OF PHARMACEUTICS 3/15/2013
  28. 28. 28 DEPT OF PHARMACEUTICS 3/15/2013
  29. 29.  SOLID DOSAGE FORM 1. Material Handling Laboratory Scale Deliver accurate amount to the destination Large Scale * Lifting drums * More Sophisticated Methods -Vacuum Loading System -Metering Pumps Prevent Cross Contamination by Validation Cleaning Procedures.29 DEPT OF PHARMACEUTICS 3/15/2013
  30. 30. 2. Dry Blending Powders should be used for encapsulation or to be granulated prior to tabletting must be well blend to ensure good drug distribution. Inadequate blending could result in drug content uniformity variation, especially when the tablet or capsule is small & the drug concentration is relatively low. Ingredients should be lumps free, otherwise it could cause flow problems.30 DEPT OF PHARMACEUTICS 3/15/2013
  31. 31. 3. Granulations  Reasons :- * To improve the flow properties. * To increase the apparent density of the powder. * To change the particle size distribution so that the binding properties on compaction can be improved.  Types :- a) Wet Granulation b) Dry Granulation c) Direct Compression Method  A small amount potent active ingredient can be dispersed most effectively in a carrier granulation, when the drug is dissolved in granulating solution and added during the31 granulating process. 3/15/2013 DEPT OF PHARMACEUTICS
  32. 32. Cont….  Wet granulation has been carried out by using, - Sigma Blades - Heavy-duty planetary mixture -Tumble Blenders -High Speed Chopper Blades used in mixing of light powders.  Multifunctional Processors, dry blending, wet granulation, drying, sizing & lubricating.  Effect of Binding Agent.32 DEPT OF PHARMACEUTICS 3/15/2013
  33. 33. 4. Drying  Hot Air Oven * air temperature * rate of air flow * depth of granulation on the trays  Fluidized Bed Dryer * optimum loads * rate of airflow * inlet air temperature * humidity Data used for small scale batches(1-5 kg) cannot be extrapolate processing conditions for intermediated scale (100 kg) or large batches. DEPT OF PHARMACEUTICS 3/15/201333
  34. 34. 5. Reduction In Particle Size Particle size to particle size distribution is important to the compression characteristics of a granulation. Compression factors that may affected by the particle size distribution are flow ability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, tablet color uniformity. Equipments :- * oscillating granulator a mechanical sieving device * a hammer mill * screening device If too large particle size :- * weight variation * mottling3/15/2013 DEPT OF PHARMACEUTICS 34
  35. 35. Cont….  If too fines particle size, * weight variation * capping  Both oversized and undersized granulation can adversely affect tablet content uniformity.  Lubricants & Gildants are added at final blend35 DEPT OF PHARMACEUTICS 3/15/2013
  36. 36. 6. Blending Consequent attention should be paid to scale up of the right design is used and blender loads, mixing speeds, mixing timing are properly established. In any blending operation segregation and mixing occurs simultaneously, both processes are a function a particle size, shape, hardness, density and dynamics of the mixing action. Low dose active ingredients – directly compressed. Equipments :- * Planetory type mixer * Twin shell mixture * Cone type36 DEPT OF PHARMACEUTICS 3/15/2013
  37. 37. Cont….  Over loading in blender – * retards the free flow of granules * reduce the efficiency * cause content un-uniformity  If the load is to small – * powder blend slides rather than roll in blender * improper mixing37 DEPT OF PHARMACEUTICS 3/15/2013
  38. 38. 7. Slugging  A dry powder blend that can not be directly compressed because of poor flow properties may in some instances be processed using a slugging operation.  Instruments :- * Tablet press – which operates at pressure of 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less.38 DEPT OF PHARMACEUTICS 3/15/2013
  39. 39. 8. Compression  The ultimate test of the tablet formulation and granulation can be compressed on a high-speed tablet press.  Steps involved during compression, * Filling empty die cavity with granulation * Pre compression of granules * Compression of granules * Ejection of tablet from the die cavity  Compression characteristics can be evaluated by press speed equal to normal production speed.39 DEPT OF PHARMACEUTICS 3/15/2013
  40. 40. Cont….  Then detect the problems such as, * sticking to punch surface * tablet hardness * capping * weight variation  Granules must be delivered at adequate rate.  During compression, the granules are compacted, and in order for a tablet to form, bonds within the compressible materials must be formed.40 DEPT OF PHARMACEUTICS 3/15/2013
  41. 41. TABLET COATING  Equipments :- * conventional coating pan * perforated pans of fluidized-bed coating column  Types :- 1. Sugar coating 2. Film coating  Tablet must be sufficiently hard to withstand the the tumbling to which they are subjected while coating.  Operation conditions to be established for pan or column operation are optimum tablet load, operating tablet, bed temperature, drying air flow rate, temperature, solution application rate.41 DEPT OF PHARMACEUTICS 3/15/2013
  42. 42. CAPSULES  To produce capsules on high-speed equipment, the powder blend must have, * uniform particle size distribution * bulk density * formation of compact of the right size and of sufficient cohesiveness to be filled into capsule shells.  Equipments :- 1. Zanasi or Mertalli – Dosator(hollow tube) 2. Hoflinger – Karg – Tamping pins  Weight variation problem can be encountered with these two methods.  Overly lubricated granules – delaying disintegration.42 DEPT OF PHARMACEUTICS 3/15/2013
  43. 43. Cont….  Humidity affect moisture content of – * granulation * on the empty gelatin capsules  Empty gelatin capsules have a recommended storage condition of 15-25 ºC temperature & humidity 35-65 % RH.  At high humidity – capsule swells make separation of the capsule parts difficult to interfere with the transport of the capsule through the process.  At low humidity – capsule brittle increased static charge interfere with the encapsulation operation.43 DEPT OF PHARMACEUTICS 3/15/2013
  44. 44. LIQUID ORALS  Simple solutions are the straight forward to scale up but they require tanks of adequate size and suitable mixing capability.  Most equipment has heating or cooling capabilities to effect rapid disollution of components of the system.  All the equipments must be made up of suitable non- reactive material and be designed and constructed to facilitate easy cleaning.  Liquid pharmaceutical processing tank, kettles, pipes, mills, filter houses etc. are most frequently fabricated from stainless steel44 DEPT OF PHARMACEUTICS 3/15/2013
  45. 45. Cont….  Two types of steel – 1. 308 2. 316  Stainless steel is most non reactive, however it does react with some acidic pharmaceutical liquids, this problem can be minimized by PASSIVATION.  Interaction with metallic surfaces can be minimized by use of glass or Teflon coating.  Although they are highly inert materials, they have the disadvantages of cracking, breaking and flaking with resultant product contamination.45 DEPT OF PHARMACEUTICS 3/15/2013
  47. 47. Cont….  Equipments :- * tankage * piping * ancillary equipment for liquid mixing * filteration, transfer and related equipments.  The majority of the equipments are composed of 300 series austenitic stainless steel, with glass lined vessels employed for preparation of formulations sensitive to iron and other metal ions.  The vessels can be equiped with external jackets for heating and/or cooling and various types of agitators, depending upon the mixing requirements of the individual formulation.47 DEPT OF PHARMACEUTICS 3/15/2013
  48. 48. SUSPENSIONS Suspensions require more attention during scale up than simple solutions because of additional processing needs. Equipments :- * vibrating feed system and power for production scale. * high shear mixing equipment Slurries facilitate rapid and complete hydration of suspending agent when added to large portion of the vehicle. Active ingredients must be uniformly dispersed throughout the batch. Mixing at too high speed can result in entrapment of air, which may affect physical or chemical stability of the product.3/15/2013 DEPT OF PHARMACEUTICS 48
  49. 49. VACUUM UNIT VERSATOR  Filteration – remove unwanted particles.  Screens of 150 mesh, having 100 microns are used.  Active ingredients – particle size 10 – 25 microns.  Transfer and filling of finished suspension should be carefully monitored.  It should be constantly mixed during transfer to maintain uniform distribution of the active ingredients.49 DEPT OF PHARMACEUTICS 3/15/2013
  50. 50. EMULSIONS Manufacturing of liquid emulsion products entails specialized procedures as result scale up into production equipment involves extensive process development and validation. Equipments :- * mixing equipment * homogenizing equipment * screens * pumps * filling equipment High shear mixers may lead to air entrapment, this problem can be avoid by carrying out operation under controlled vacuum.3/15/2013 DEPT OF PHARMACEUTICS 50
  51. 51. SEMI SOLID PRODUCTS  The main difference of semi solid formulation with comparison to suspensions, liquids and emulsions is their higher viscosity.  Viscosity renders certain aspects of the scale-up of semi solid products more critical.  Equipments :- * blenders * mixers * pressure filling equipments51 DEPT OF PHARMACEUTICS 3/15/2013
  52. 52. SUPPOSITORIES  The manufacturing of suppositories on a laboratory scale usually involves, * the preparation of a molten mass * the dispersion of drug in the molten base * casting of suppositories in a suitable mold * cooling of the mold * opened & remove the suppositories  More no. of moulds & large size Pan for melting of drug52 & base. DEPT OF PHARMACEUTICS 3/15/2013
  53. 53. CONTRACT MANUFACTURE  On occasional, scale-up or manufacture of a product may need to be done at an outside, contract manufacturer.  The reasons for considering contract manufacture include the needs for additional manufacturing capacity, high specialized technology or specialized equipments.53 DEPT OF PHARMACEUTICS 3/15/2013
  54. 54. IMPORTANT QUESTIONSI. What do you mean by pilot plant scale up and give examples ? (May ‘06)II. What is the significance of pilot plant scale up with routine production procedure ? (May ‘07)III. Explain the procedure for pilot plant scale up for liquid orals. (Sep ‘07 & Apr ‘08)IV. Pilot plant scale up for tablets. (May ‘09)V. Pilot plant scale up for liquid dosage forms. (Oct ‘09)VI. Write in detail pilot plant scale up concepts & techniques for parenterals. (May ‘11)VII. Explain the concepts of pilot plant scale up for tablets. (Nov ‘11) 3/15/2013 DEPT OF PHARMACEUTICS 54
  55. 55. REFERENCE55 1. The theory & practice of industrial pharmacy by Leon Lachman, Herbert A. Lieberman, Joseph L. Kenig, 3rd edition, published by Varghese Publishing house. 2. www.google.co.in DEPT OF PHARMACEUTICS 3/15/2013
  56. 56. 56 DEPT OF PHARMACEUTICS 3/15/2013