pilot plant scale up techniques

DEPT OF PHARMACEUTICS 104/12/23

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CONTENTS

Definition SignificanceGeneral ConsiderationsGMP ConsiderationsProduct ConsiderationsAdvantages DisadvantagesReferences

04/12/23 DEPT OF PHARMACEUTICS

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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.

DEFINITIONS


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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.


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Appropriate records and reports are issued to support good manufacturing practices.

Procedure can be developed and validated.

Cont….


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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


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* 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:-


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3. Space Requirements:-

Administration and information processing

Physical testing area

Standard equipment floor space

Storage area


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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:-


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b) Physical Testing Area:-

This area should provide permanent bench top space for routinely used physical - testing equipment.


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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 :-


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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:-


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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:-


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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 :-


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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


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The immediate as well as the future market trends / requirements are considered while determining the production rates.

7. Production Rates:-


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PARAMETERS

Order of mixing of components Mixing

speed

Mixing time

Rate of addition ofgranulating agents, solvents,solutions of drug etc.

Heating and coolingRates

Filters size (liquids)

Screen size(solids)

Drying temp.And drying time

8. Process Evaluation:-


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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.

Why to carry out process evaluation????


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The three important aspects

Weight sheet Processing & Sampling directions

Manufacturing procedure

9. Master Manufacturing Procedures:-


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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….


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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


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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:-


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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-contamination04/12/23 DEPT OF PHARMACEUTICS

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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.


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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.


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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.

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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.

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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. 04/12/23


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….

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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 * humidityData used for small scale batches(1-5 kg) cannot be extrapolate processing conditions for intermediated scale (100 kg) or large batches.

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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 04/12/23


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….

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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

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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….

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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. 04/12/23


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.

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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….

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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. 04/12/23


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. 04/12/23


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….

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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 04/12/23


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….

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PARENTERALS



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….

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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.

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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.

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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. 04/12/23


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

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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.04/12/23


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.

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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)


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REFERENCE

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


pilot plant scale up techniques

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