“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 Asangaon
1 DEPT OF PHARMACEUTICS 10/7/2013

CONTENTS
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Definition Significance General Considerations GMP Considerations Product Considerations Advantages Disadvantages References

10/7/2013

DEPT OF PHARMACEUTICS

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DEFINITIONS
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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 10/7/2013

SIGNIFICANCE
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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 10/7/2013

Cont….
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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 dosage DEPT OF PHARMACEUTICS form.

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 DEPT OF PHARMACEUTICS 10/7/2013 .

2. * Engineering principles 10/7/2013 DEPT OF PHARMACEUTICS . * As they have to understand the intent of the formulator as well as understand the perspective of the production personnel. Personnel Requirement:7 * Scientists with experience in pilot plant operations as well as in actual production area are the most preferable.

8 3. Space Requirements:- Administration and information processing Physical testing area Standard equipment floor space Storage area DEPT OF PHARMACEUTICS 10/7/2013 .

a) Administration And Information Process:9    Adequate office and desk space should be provided for both scientist and technicians. 10/7/2013 DEPT OF PHARMACEUTICS . Computers. The space should be adjacent to the working area.

DEPT OF PHARMACEUTICS 10/7/2013 .b) Physical Testing Area:10  This area should provide permanent bench top space for routinely used physical .testing equipment.

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.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. Space for cleaning of the equipment should be also provided. DEPT OF PHARMACEUTICS 10/7/2013 .

Unapproved area for active ingredient as well as excipient. Different areas should provided for the storage of the in-process materials. Storage area for the packaging 10/7/2013 material should also be DEPT OF PHARMACEUTICS   12 .Approved area and 2. finished bulk products from the pilot-plant & materials from the experimental scale-up batches made in the production. 1.d) Storage Area: It should have two areas.

4. it should be done as early as possible in phase III trial . 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. 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 10/7/2013 . If any modification in the formula.

rate of solubility. flow properties.5. etc.    Ingredients may change in particle size. shape or morphology which result in differences in bulk density. DEPT OF PHARMACEUTICS 10/7/2013 Quality of active ingredients needs to be verified . static charges. color. Raw materials used in the small scale production cannot necessarily be the representative for the large scale production. Raw materials :14  One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipient raw materials.

Ease of cleaning Time of cleaning DEPT OF PHARMACEUTICS 10/7/2013 . If too big then the wastage of the expensive active ingredients.6. If too small the process developed will not scale up. Equipment:15       The most economical. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. simplest & efficient equipment which are capable of producing product within the proposed specifications are used.

Non sterile equipments 16     Heating and cooling capability Adequate transfer system (filtration equipment) Made of suitable non reactive sanitary materials Processing tanks. DEPT OF PHARMACEUTICS 10/7/2013 .A. mills. filter housing. are mostly fabricated from stainless still if interaction occurs then use poly poly tetra flouro ethane liners . pipes. kettles.

Suspention 17  For addition & dispersion of suspending agent required vibratinf feed system     Pumps and mills Filling equipment Homogenising equipments Mixing equipment DEPT OF PHARMACEUTICS 10/7/2013 .B.

DEPT OF PHARMACEUTICS 10/7/2013 . Production Rates:18  The immediate as well as the future market trends / requirements are considered while determining the production rates.7.

8. And drying time Order of mixing of components Mixing speed Mixing time Rate of addition of granulating agents. Drying temp. Process Evaluation:…. solvents. Screen size (solids) Filters size (liquids) PARAMETERS Heating and cooling Rates DEPT OF PHARMACEUTICS 10/7/2013 .items that should be examined including 19 the following order of components including adjustments of their amounts……. solutions of drug etc.

The manufacturing process & quality control information should be revived on annual DEPT OF PHARMACEUTICS 10/7/2013 basis.   . 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.

9. Master Manufacturing Procedures:21 The Three important aspects Weight sheet Processing & Sampling directions Manufacturing procedure Finished product spacifacation DEPT OF PHARMACEUTICS 10/7/2013 .

mixing time. To prevent confusion the names and identifying numbers for the ingredients should be used on batch records. A manufacturing procedure should be written by the actual operator.Cont…. storing of the finished product samples DEPT OF PHARMACEUTICS 10/7/2013 should be mentioned in the batch record directions. and cooling rates. heating. . Various specifications like addition rates. mixing speed. temperature. 22     The weight sheet should clearly identify the chemicals required in a batch. The process directions should be precise and explicit.

 DEPT OF PHARMACEUTICS 10/7/2013 . Early in the transfer process.23 Transfer of Analytical Method to 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. 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.

Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability. DEPT OF PHARMACEUTICS 10/7/2013   . Product Stability And Uniformity:24  The primary objective of the pilot plant is the physical as well as chemical stability of the products.10. Stability studies should be carried out in finished packages as well.

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 10/7/2013 DEPT OF PHARMACEUTICS 25 .

DEPT OF repair PHARMACEUTICS 10/7/2013  . Access to engineering department personnel is provided for equipment installation.ADVANTAGES 26  Members of the production and quality control divisions can readily observe scale up runs. cleared by the quality control division. maintenance and . can be drawn from the more spacious areas provided to the production division.  Supplies of excipient & drugs.

DISADVANTAGES 27  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 10/7/2013 .

28 DEPT OF PHARMACEUTICS 10/7/2013 .

DEPT OF PHARMACEUTICS 10/7/2013 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.

especially when the tablet or capsule is small & the drug concentration is relatively low. Inadequate blending could result in drug content uniformity variation. Dry Blending Powders should be used for encapsulation or to be granulated prior to tabletting must be well blend to ensure good drug distribution. 30 DEPT OF PHARMACEUTICS 10/7/2013 . otherwise it could cause flow problems. Ingredients should be lumps free.2.

when the drug is dissolved in granulating solution and added during the granulating process.3.  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. Granulations  Reasons :* To improve the flow properties. 10/7/2013 DEPT OF PHARMACEUTICS 31 . * To change the particle size distribution so that the binding properties on compaction can be improved. * To increase the apparent density of the powder.

 Wet granulation has been carried out by using. dry blending. drying.Sigma Blades . 32 DEPT OF PHARMACEUTICS 10/7/2013 .  Effect of Binding Agent. sizing & lubricating. . wet granulation.Heavy-duty planetary mixture -Tumble Blenders -High Speed Chopper Blades used in mixing of light powders.  Multifunctional Processors.Cont….

DEPT OF PHARMACEUTICS 10/7/2013 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.

content uniformity.5. compressibility. tablet hardness.  Equipments :* oscillating granulator a mechanical sieving device * a hammer mill * screening device  If too large particle size :* weight variation * mottling 10/7/2013 DEPT OF PHARMACEUTICS 34 .  Compression factors that may affected by the particle size distribution are flow ability. uniformity of tablet weight. tablet color uniformity. Reduction In Particle Size  Particle size to particle size distribution is important to the compression characteristics of a granulation.

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 blend 35 DEPT OF PHARMACEUTICS 10/7/2013 .

shape. Low dose active ingredients – directly compressed.6. In any blending operation segregation and mixing occurs simultaneously. both processes are a function a particle size. mixing speeds. mixing timing are properly established. hardness. Blending Consequent attention should be paid to scale up of the right design is used and blender loads. Equipments :* Planetory type mixer * Twin shell mixture * Cone type 36 DEPT OF PHARMACEUTICS 10/7/2013 . density and dynamics of the mixing action.

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 mixing 37 DEPT OF PHARMACEUTICS 10/7/2013 .

 Instruments :* Tablet press – which operates at pressure of 15 tons. which operates at pressure of 4 tons or less. 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. 38 DEPT OF PHARMACEUTICS 10/7/2013 . compared with a normal tablet press.7.

 Steps involved during compression. Compression  The ultimate test of the tablet formulation and granulation can be compressed on a high-speed tablet press. * 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.8. 39 DEPT OF PHARMACEUTICS 10/7/2013 .

40 DEPT OF PHARMACEUTICS 10/7/2013 . bonds within the compressible materials must be formed.  During compression.Cont…. * sticking to punch surface * tablet hardness * capping * weight variation  Granules must be delivered at adequate rate.  Then detect the problems such as. the granules are compacted. and in order for a tablet to form.

drying air flow rate. solution application rate.  Operation conditions to be established for pan or column operation are optimum tablet load. temperature. Film coating  Tablet must be sufficiently hard to withstand the the tumbling to which they are subjected while coating.TABLET COATING  Equipments :* conventional coating pan * perforated pans of fluidized-bed coating column  Types :1. operating tablet. Sugar coating 2. DEPT OF PHARMACEUTICS 10/7/2013 41 . bed temperature.

* uniform particle size distribution * bulk density * formation of compact of the right size and of sufficient cohesiveness to be filled into capsule shells.CAPSULES  To produce capsules on high-speed equipment. Hoflinger – Karg – Tamping pins  Weight variation problem can be encountered with these two methods.  Overly lubricated granules – delaying disintegration. Zanasi or Mertalli – Dosator(hollow tube) 2. the powder blend must have.  Equipments :1. 42 DEPT OF PHARMACEUTICS 10/7/2013 .

Cont….  At low humidity – capsule brittle increased static charge interfere with the encapsulation operation. 43 DEPT OF PHARMACEUTICS 10/7/2013 .  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.

 All the equipments must be made up of suitable nonreactive material and be designed and constructed to facilitate easy cleaning. kettles. mills. are most frequently fabricated from stainless steel 44 DEPT OF PHARMACEUTICS 10/7/2013 . filter houses etc.LIQUID ORALS  Simple solutions are the straight forward to scale up but they require tanks of adequate size and suitable mixing capability. pipes.  Most equipment has heating or cooling capabilities to effect rapid disollution of components of the system.  Liquid pharmaceutical processing tank.

 Two types of steel – 1.  Although they are highly inert materials. 316  Stainless steel is most non reactive.  Interaction with metallic surfaces can be minimized by use of glass or Teflon coating. however it does react with some acidic pharmaceutical liquids. they have the disadvantages of cracking.Cont…. 308 2. breaking and flaking with resultant product contamination. 45 DEPT OF PHARMACEUTICS 10/7/2013 . this problem can be minimized by PASSIVATION.

PARENTERALS DEPT OF PHARMACEUTICS 46 10/7/2013 .

 The vessels can be equiped with external jackets for heating and/or cooling and various types of agitators. transfer and related equipments.Cont…. depending upon the mixing requirements of the individual formulation.  The majority of the equipments are composed of 300 series austenitic stainless steel.  Equipments :* tankage * piping * ancillary equipment for liquid mixing * filteration. 47 DEPT OF PHARMACEUTICS 10/7/2013 . with glass lined vessels employed for preparation of formulations sensitive to iron and other metal ions.

 Active ingredients must be uniformly dispersed throughout the batch. which may affect physical or chemical stability of the product.SUSPENSIONS  Suspensions require more attention during scale up than simple solutions because of additional processing needs.  Mixing at too high speed can result in entrapment of air. 10/7/2013 DEPT OF PHARMACEUTICS 48 .  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.

having 100 microns are used.  Screens of 150 mesh. 49 DEPT OF PHARMACEUTICS 10/7/2013 .  Transfer and filling of finished suspension should be carefully monitored.VACUUM UNIT VERSATOR  Filteration – remove unwanted particles.  Active ingredients – particle size 10 – 25 microns.  It should be constantly mixed during transfer to maintain uniform distribution of the active ingredients.

 Equipments :* mixing equipment * homogenizing equipment * screens * pumps * filling equipment  High shear mixers may lead to air entrapment.EMULSIONS  Manufacturing of liquid emulsion products entails specialized procedures as result scale up into production equipment involves extensive process development and validation. this problem can be avoid by carrying out operation under controlled vacuum. 10/7/2013 DEPT OF PHARMACEUTICS 50 .

 Equipments :* blenders * mixers * pressure filling equipments 51 DEPT OF PHARMACEUTICS 10/7/2013 .SEMI SOLID PRODUCTS  The main difference of semi solid formulation with comparison to suspensions.  Viscosity renders certain aspects of the scale-up of semi solid products more critical. liquids and emulsions is their higher viscosity.

DEPT OF PHARMACEUTICS 10/7/2013 .SUPPOSITORIES  The manufacturing of suppositories on a laboratory scale usually involves. of moulds & large size Pan for melting of drug & base. * 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 52  More no.

high specialized technology or specialized equipments.CONTRACT MANUFACTURE  On occasional. 53 DEPT OF PHARMACEUTICS 10/7/2013 .  The reasons for considering contract manufacture include the needs for additional manufacturing capacity. contract manufacturer. scale-up or manufacture of a product may need to be done at an outside.

VII. (Nov ‘11) 10/7/2013 DEPT OF PHARMACEUTICS 54 . What do you mean by pilot plant scale up and give examples ? (May ‘06) What is the significance of pilot plant scale up with routine production procedure ? (May ‘07) Explain the procedure for pilot plant scale up for liquid orals. (Sep ‘07 & Apr ‘08) Pilot plant scale up for tablets. (Oct ‘09) Write in detail pilot plant scale up concepts & techniques for parenterals. IV. III. (May ‘09) Pilot plant scale up for liquid dosage forms. V. II. (May ‘11) Explain the concepts of pilot plant scale up for tablets. VI.IMPORTANT QUESTIONS I.

Kenig.REFERENCE 55 1. published by Varghese Publishing house. www. 3rd edition. Lieberman. Herbert A.in DEPT OF PHARMACEUTICS 10/7/2013 . 2.co. The theory & practice of industrial pharmacy by Leon Lachman. Joseph L.google.

56 DEPT OF PHARMACEUTICS 10/7/2013 .

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