1. DEPT OF PHARMACEUTICS16/13/2016

2. 2 CONTENTS  Definition  Significance  General Considerations  GMP Considerations  Product Considerations  Advantages  Disadvantages  References 6/13/2016DEPT OF PHARMACEUTICS

3. 3  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. DEFINITIONS 6/13/2016DEPT OF PHARMACEUTICS

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. 6/13/2016DEPT OF PHARMACEUTICS

5. 5  Appropriate records and reports are issued to support good manufacturing practices.  Procedure can be developed and validated. Cont…. 6/13/2016DEPT OF PHARMACEUTICS

6. 6 GENERAL CONSIDERATIONS 1. Reporting Responsibility:- 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 6/13/2016DEPT OF PHARMACEUTICS

7. 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 * Knowledge of computers & electronics 2. Personnel Requirement:- 6/13/2016DEPT OF PHARMACEUTICS

8. 8 3. Space Requirements:- Administration and information processing Physical testing area Standard equipment floor space Storage area 6/13/2016DEPT OF PHARMACEUTICS

9. 9  Adequate office and desk space should be provided for both scientist and technicians.  The space should be adjacent to the working area.  Computers. a) Administration And Information Process:- 6/13/2016DEPT OF PHARMACEUTICS

10. 10 b) Physical Testing Area:-  This area should provide permanent bench top space for routinely used physical - testing equipment. 6/13/2016DEPT OF PHARMACEUTICS

11. 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. c) Standard Pilot-plant Equipment Floor Space :- 6/13/2016DEPT OF PHARMACEUTICS

12. 12  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. d) Storage Area:- 6/13/2016DEPT OF PHARMACEUTICS

13. 13  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. 4. Review of the formula:- 6/13/2016DEPT OF PHARMACEUTICS

14. 14  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. 5. Raw materials :- 6/13/2016DEPT OF PHARMACEUTICS

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 cleaning 6/13/2016DEPT OF PHARMACEUTICS

16. 16  The immediate as well as the future market trends / requirements are considered while determining the production rates. 7. Production Rates:- 6/13/2016DEPT OF PHARMACEUTICS

17. 17 PARAMETERS Order of mixing of components Mixing speed Mixing time Rate of addition of granulating agents, solvents, solutions of drug etc. Heating and cooling Rates Filters size (liquids) Screen size (solids) Drying temp. And drying time 8. Process Evaluation:- 6/13/2016DEPT OF PHARMACEUTICS

18. 18 The three important aspects Weight sheet Processing & Sampling directions Manufacturing procedure 9. Master Manufacturing Procedures:- 6/13/2016DEPT OF PHARMACEUTICS

19. 19  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. Cont…. 6/13/2016DEPT OF PHARMACEUTICS

20. 20  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. Transfer of Analytical Method to Quality Assurance 6/13/2016DEPT OF PHARMACEUTICS

21. 21  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. 10. Product Stability And Uniformity:- 6/13/2016DEPT OF PHARMACEUTICS

22. 22 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 6/13/2016DEPT OF PHARMACEUTICS

23. 23 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. 6/13/2016DEPT OF PHARMACEUTICS

24. 24 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. 6/13/2016DEPT OF PHARMACEUTICS

25. 256/13/2016

26. DEPT OF PHARMACEUTICS26  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. 6/13/2016

27. DEPT OF PHARMACEUTICS27 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. 6/13/2016

28. DEPT OF PHARMACEUTICS 28 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. 6/13/2016

29. DEPT OF PHARMACEUTICS29  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. Cont…. 6/13/2016

30. DEPT OF PHARMACEUTICS30 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. 6/13/2016

31. DEPT OF PHARMACEUTICS31 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 * mottling 6/13/2016

32. DEPT OF PHARMACEUTICS32  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 blend Cont…. 6/13/2016

33. DEPT OF PHARMACEUTICS33 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 type 6/13/2016

34. DEPT OF PHARMACEUTICS34  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 mixing Cont…. 6/13/2016

35. DEPT OF PHARMACEUTICS35 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. 6/13/2016

36. DEPT OF PHARMACEUTICS36 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. 6/13/2016

37. DEPT OF PHARMACEUTICS37  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. Cont…. 6/13/2016

38. DEPT OF PHARMACEUTICS38 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. 6/13/2016

39. DEPT OF PHARMACEUTICS39 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. 6/13/2016

40. DEPT OF PHARMACEUTICS40  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. Cont…. 6/13/2016

41. DEPT OF PHARMACEUTICS41 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 steel 6/13/2016

42. DEPT OF PHARMACEUTICS42  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. Cont…. 6/13/2016

43. PARENTERALS 436/13/2016DEPT OF PHARMACEUTICS

44. 44  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. Cont…. 6/13/2016

45. DEPT OF PHARMACEUTICS45 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. 6/13/2016

46. DEPT OF PHARMACEUTICS46 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. 6/13/2016

47. DEPT OF PHARMACEUTICS47 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. 6/13/2016

48. DEPT OF PHARMACEUTICS48 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 equipments 6/13/2016

49. DEPT OF PHARMACEUTICS49 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 drug & base. 6/13/2016

50. DEPT OF PHARMACEUTICS50 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. 6/13/2016

51. 516/13/2016DEPT OF PHARMACEUTICS