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01/25/13   DEPT OF PHARMACEUTICS   1
CONTENTS Definition Significance General Considerations GMP Considerations Product Considerations Advantages Disadv...
DEFINITIONS Plant:- It is a place where the 3 M’s that are Man,    Material and Money are brought together for the    man...
SIGNIFICANCE Permits close examination of formulae to determine its  ability to withstand batch scale and process  modifi...
Cont…. Appropriate records and reports are issued to support  good manufacturing practices. Procedure can be developed a...
GENERAL CONSIDERATIONS           1. Reporting Responsibility:- R & D group           The formulator who developed the with...
2. Personnel Requirement:-* Scientists with experience inpilot plant operations as wellas in actual production areaare the...
3.        Space Requirements:-Administration     Physical          Standard      Storageand information    testing area   ...
a) Administration And Information Process:-  Adequate office and desk space should be provided for   both scientist and t...
b) Physical Testing Area:- This area should provide permanent bench top space for routinely   used physical - testing equ...
c) Standard Pilot-plant Equipment Floor       Space :- Discreet pilot plant space, where the equipment needed  for manufa...
d) Storage Area:- It should have two areas,    1.Approved area and    2.Unapproved area for active      ingredient as wel...
4. Review of the formula:- A thorough review of the each aspect of formulation is    important. The purpose of each ingr...
5. Raw materials :- One purpose/responsibility of the pilot-plant is the  approval & validation of the active ingredient ...
6. Equipment:- The most economical, simplest & efficient equipment    which are capable of producing product within the  ...
7. Production Rates:- The immediate as well as the future market trends /   requirements are considered while determining...
8. Process Evaluation:-                     Order of mixing ofDrying temp.         components            MixingAnd drying ...
 Why to carry out process evaluation???? The knowledge of the effects of various process   parameters on in-process and ...
9. Master Manufacturing Procedures:-           The three important aspects Weight sheet      Processing &            Manuf...
Cont…. The weight sheet should clearly identify the chemicals  required in a batch. To prevent confusion the names and  i...
Transfer of Analytical Methodto Quality Assurance During the scale-up of a new product, the analytic test   methods devel...
10. Product Stability And Uniformity:- The primary objective of the pilot plant is the physical as   well as chemical sta...
GMP CONSIDERATION Equipment qualification Process validation Regularly process review & revalidation Relevant written ...
ADVANTAGES Members of the production and quality control divisions    can readily observe scale up runs. Supplies of exc...
DISADVANTAGES The frequency of direct interaction of the formulator    with the production personnel in the manufacturing...
01/25/13   DEPT OF PHARMACEUTICS   26
         SOLID DOSAGE FORM           1. Material Handling Laboratory Scale Deliver accurate amount to the destination ...
2. Dry BlendingPowders should be used for encapsulation or to be granulated prior to tabletting must be well blend to ens...
3. Granulations Reasons :-     * To improve the flow properties.     * To increase the apparent density of the powder.   ...
Cont….  Wet granulation has been carried out by using,   - Sigma Blades   - Heavy-duty planetary mixture   -Tumble Blende...
4. Drying  Hot Air Oven   * air temperature   * rate of air flow   * depth of granulation on the trays  Fluidized Bed Dr...
5. Reduction In Particle Size Particle size to particle size distribution is important to  the compression characteristic...
Cont….  If too fines particle size,   * weight variation   * capping  Both oversized and undersized granulation can adve...
6. Blending Consequent attention should be paid to scale up of the   right design is used and blender loads, mixing speed...
Cont…. Over loading in blender –  * retards the free flow of granules  * reduce the efficiency  * cause content un-unifor...
7. Slugging A dry powder blend that can not be directly compressed  because of poor flow properties may in some instances...
8. Compression  The ultimate test of the tablet formulation and   granulation can be compressed on a high-speed tablet   ...
Cont…. Then detect the problems such as,  * sticking to punch surface  * tablet hardness  * capping  * weight variation ...
TABLET COATING Equipments :-  * conventional coating pan  * perforated pans of fluidized-bed coating column Types :-   1...
CAPSULES To produce capsules on high-speed equipment, the  powder blend must have,  * uniform particle size distribution ...
Cont…. Humidity affect moisture content of –  * granulation  * on the empty gelatin capsules Empty gelatin capsules have...
LIQUID ORALS Simple solutions are the straight forward to scale up but  they require tanks of adequate size and suitable ...
Cont…. Two types of steel –  1. 308  2. 316 Stainless steel is most non reactive, however it does react  with some acidi...
PARENTERALS01/25/13   DEPT OF PHARMACEUTICS                     44
Cont…. Equipments :- * tankage * piping * ancillary equipment for liquid mixing * filteration, transfer and related equip...
SUSPENSIONS Suspensions require more attention during scale up than  simple solutions because of additional processing ne...
VACUUM UNIT VERSATOR Filteration – remove unwanted particles. Screens of 150 mesh, having 100 microns are used. Active ...
EMULSIONS Manufacturing of liquid emulsion products entails  specialized procedures as result scale up into production  e...
SEMI SOLID PRODUCTS The main difference of semi solid formulation with  comparison to suspensions, liquids and emulsions ...
SUPPOSITORIES The manufacturing of suppositories on a laboratory scaleusually involves,   * the preparation of a molten m...
CONTRACT MANUFACTURE On occasional, scale-up or manufacture of a product  may need to be done at an outside, contract  ma...
IMPORTANT QUESTIONSI.   What do you mean by pilot plant scale up and give     examples ? (May ‘06)II. What is the signific...
REFERENCE1. The theory & practice of industrial pharmacy         by Leon Lachman, Herbert A. Lieberman,      Joseph L. Ken...
01/25/13   DEPT OF PHARMACEUTICS   54
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Pilot plant scale up techniques

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  1. 1. 01/25/13 DEPT OF PHARMACEUTICS 1
  2. 2. CONTENTS Definition Significance General Considerations GMP Considerations Product Considerations Advantages Disadvantages References01/25/13 DEPT OF PHARMACEUTICS 2
  3. 3. DEFINITIONS 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.01/25/13 DEPT OF PHARMACEUTICS 3
  4. 4. SIGNIFICANCE 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.01/25/13 DEPT OF PHARMACEUTICS 4
  5. 5. Cont…. Appropriate records and reports are issued to support good manufacturing practices. Procedure can be developed and validated.01/25/13 DEPT OF PHARMACEUTICS 5
  6. 6. GENERAL 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 completed01/25/13 DEPT OF PHARMACEUTICS 6
  7. 7. 2. Personnel Requirement:-* Scientists with experience inpilot plant operations as wellas in actual production areaare the most preferable. * As they have to understandthe intent of the formulator aswell as understand theperspective of the productionpersonnel.* Engineering principles * Knowledge of computers &electronics 01/25/13 DEPT OF PHARMACEUTICS 7
  8. 8. 3. Space Requirements:-Administration Physical Standard Storageand information testing area equipment areaprocessing floor space01/25/13 DEPT OF PHARMACEUTICS 8
  9. 9. a) 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.  Computers. 9 01/25/13 DEPT OF PHARMACEUTICS
  10. 10. b) Physical Testing Area:- This area should provide permanent bench top space for routinely used physical - testing equipment. 01/25/13 DEPT OF PHARMACEUTICS 10
  11. 11. c) 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 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.01/25/13 DEPT OF PHARMACEUTICS 11
  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 provided. PHARMACEUTICS 01/25/13 DEPT OF 12
  13. 13. 4. Review of the formula:- A thorough review of the each aspect of formulation is important. The purpose of each ingredient and it’s 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.01/25/13 DEPT OF PHARMACEUTICS 13
  14. 14. 5. Raw materials :- One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients 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.01/25/13 DEPT OF PHARMACEUTICS 14
  15. 15. 6. Equipment:- 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 cleaning01/25/13 DEPT OF PHARMACEUTICS 15
  16. 16. 7. Production Rates:- The immediate as well as the future market trends / requirements are considered while determining the production rates.01/25/13 DEPT OF PHARMACEUTICS 16
  17. 17. 8. Process Evaluation:- Order of mixing ofDrying temp. components MixingAnd 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 Rates01/25/13 DEPT OF PHARMACEUTICS 17
  18. 18.  Why to carry out process evaluation???? 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.01/25/13 DEPT OF PHARMACEUTICS 18
  19. 19. 9. Master Manufacturing Procedures:- The three important aspects Weight sheet Processing & Manufacturing Sampling procedure directions01/25/13 DEPT OF PHARMACEUTICS 19
  20. 20. Cont…. 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 mentioned in the batch record directions.01/25/13 DEPT OF PHARMACEUTICS 20
  21. 21. Transfer of Analytical Methodto 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.01/25/13 DEPT OF PHARMACEUTICS 21
  22. 22. 10. 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.01/25/13 DEPT OF PHARMACEUTICS 22
  23. 23. 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-contamination01/25/13 DEPT OF PHARMACEUTICS 23
  24. 24. ADVANTAGES Members of the production and quality control divisions can readily observe scale up runs. Supplies of excipients & 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 repair.01/25/13 DEPT OF PHARMACEUTICS 24
  25. 25. 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.01/25/13 DEPT OF PHARMACEUTICS 25
  26. 26. 01/25/13 DEPT OF PHARMACEUTICS 26
  27. 27.  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.01/25/13 DEPT OF PHARMACEUTICS 27
  28. 28. 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.01/25/13 DEPT OF PHARMACEUTICS 28
  29. 29. 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 the granulating process.01/25/13 29 DEPT OF PHARMACEUTICS
  30. 30. 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.01/25/13 DEPT OF PHARMACEUTICS 30
  31. 31. 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.01/25/13 DEPT OF PHARMACEUTICS 31
  32. 32. 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 * mottling01/25/13 DEPT OF PHARMACEUTICS 32
  33. 33. 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 blend01/25/13 DEPT OF PHARMACEUTICS 33
  34. 34. 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 type01/25/13 DEPT OF PHARMACEUTICS 34
  35. 35. 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 mixing01/25/13 DEPT OF PHARMACEUTICS 35
  36. 36. 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.01/25/13 DEPT OF PHARMACEUTICS 36
  37. 37. 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.01/25/13 DEPT OF PHARMACEUTICS 37
  38. 38. 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.01/25/13 DEPT OF PHARMACEUTICS 38
  39. 39. 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.01/25/13 DEPT OF PHARMACEUTICS 39
  40. 40. 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.01/25/13 DEPT OF PHARMACEUTICS 40
  41. 41. 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.01/25/13 DEPT OF PHARMACEUTICS 41
  42. 42. 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 steel01/25/13 DEPT OF PHARMACEUTICS 42
  43. 43. 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.01/25/13 DEPT OF PHARMACEUTICS 43
  44. 44. PARENTERALS01/25/13 DEPT OF PHARMACEUTICS 44
  45. 45. 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.01/25/13 DEPT OF PHARMACEUTICS 45
  46. 46. 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.01/25/13 DEPT OF PHARMACEUTICS 46
  47. 47. 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.01/25/13 DEPT OF PHARMACEUTICS 47
  48. 48. 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.01/25/13 DEPT OF PHARMACEUTICS 48
  49. 49. 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 equipments01/25/13 DEPT OF PHARMACEUTICS 49
  50. 50. SUPPOSITORIES The manufacturing of suppositories on a laboratory scaleusually 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 drug & base.01/25/13 DEPT OF PHARMACEUTICS 50
  51. 51. 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.01/25/13 DEPT OF PHARMACEUTICS 51
  52. 52. 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)01/25/13 DEPT OF PHARMACEUTICS 52
  53. 53. REFERENCE1. 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.in01/25/13 DEPT OF PHARMACEUTICS 53
  54. 54. 01/25/13 DEPT OF PHARMACEUTICS 54
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