Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D By. 08 June 2009SRTM University, NandedDept. of Pharmaceutics2 CONTENTS Introduction Objectives of the Pilot

08 June 2009SRTM University, NandedDept. of Pharmaceutics 1

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

By


CONTENTS Introduction

Objectives of the Pilot Plant

Reasons for pilot plant

Significance of pilot plant

Importance of the Pilot Plant

Pilot plant design for tablets

Pilot plant scale-up techniques for capsules

References


Introduction What is Pilot plant :

“Defined as a part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by the development of liable practical procedure for manufacture.”

R & D Production

Pilot Plant

Scale-up : “The art of designing of prototype using the data

obtained from the pilot plant model.”


Objectives of Pilot Plant“Find mistakes on small scale and make profit on

large scale.”

To produce physically and chemically stable therapeutic dosage forms.

Review of the processing equipment.

Guidelines for productions and process control.

Evaluation and validation.

To identify the critical features of the process.

To provide master manufacturing formula.


REASONS FOR BUILDING A PILOT PLANT

To evaluate on process of large change in scale up operation.

To find and examine all by-products or waste .

To produce a trail lot of quantities of material.

Clinical studies ,analytical development ,process development, stability testing.


SIGNIFICANCE OF PILOT PLANTExamination of formulae.Review of range of relevant processing

equipments.production rate adjustment.Idea about physical space required.Appropriate records and reports to support

GMP.Identification of critical features to maintain

quality.


Importance of Pilot PlantExamination of formulae.

Review of range of relevant processing

equipments.

The specification of the raw materials.

Production rates.

The physical space required.

Appropriate records and reports to support GMP.


Pilot Plant design for TabletsThe primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale.

The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness.

If possible, it should be located on the ground floor to expedite the delivery and shipment of supplies.


Extraneous and microbiological contamination must be guarded against by incorporating the following features in the pilot plant design:

1.Fluorescent lighting fixtures should be the ceiling flush type.

2.The various operating areas should have floor drains to simplify cleaning.

3.The area should be air-conditioned and humidity controlled.

4.High -density concrete floors should be installed.

5.The walls in the processing and packaging areas should be enamel cement finish on concrete.

6.Equipment in the pharmaceutical pilot plant should be similar to that used by production division- manufacture of tablets.




Material handling systemIn the laboratory, materials are simply scooped or poured by hand, but in intermediate- or large-scale operations, handling of this materials often become necessary.

If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination.

Any material handling system must deliver the accurate amount of the ingredient to the destination.

The type of system selected also depends on the characteristics of the materials.More sophisticated methods of handling materials such as vacuum loading systems, metering pumps, screw feed system.


Vacuum loading machine


Dry Blending

Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution.

Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency.

Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates.

For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible.


The equipment used for blending are: V- blenderDouble cone blender Ribbon blenderSlant cone blenderBin blenderOrbiting screw blenders vertical and horizontal high

intensity mixers.

SCALE UP CONSIDERATIONS Time of blending .Blender loading.Size of blender.


V – cone blender Double cone blender


Ribbon blender


GranulationThe most common reasons given to justify granulating are:

1.To impart good flow properties to the material,

2.To increase the apparent density of the powders,

3.To change the particle size distribution,

4.Uniform dispersion of active ingredient.

Traditionally, wet granulation has been carried out using,Sigma blade mixer,Heavy-duty planetary mixer.


Sigma blade mixer Planetary mixer


Wet granulation can also be prepared using tumble blenders equipped with high-speed chopper blades.


More recently, the use of multifunctional “processors” that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment.

Wednesday, April 19, 2023 Dept. of Pharmaceutics 21


Binders:

Used in tablet formulations to make powders more

compressible and to produce tablets that are more resistant

to breakage during handling.

In some instances the binding agent imparts viscosity to

the granulating solution so that transfer of fluid becomes

difficult.

This problem can be overcome by adding some or all

binding agents in the dry powder prior to granulation.


Some granulation, when prepared in production sized equipment, take on a dough-like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.

This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all.


Drying The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity.

The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays.

If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules.

Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load.


Fluidized bed dryers are an attractive alternative to the circulating hot air ovens.

The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity.


Reduction of Particle sizeCompression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity.

First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings.

Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device.


Oscillating type granulator Hammer mill


As part of the scale-up of a milling or sieving operation,

the lubricants and glidants, which in the laboratory are

usually added directly to the final blend, are usually added

to the dried granulation during the sizing operation.

This is done because some of these additives, especially

magnesium stearate, tend to agglomerate when added in

large quantities to the granulation in a blender.


BlendingType of blending equipment often differs from that using in laboratory.

In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action.

Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used.

When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender.


Equipments used for mixing

Sigma blade mixer.

Planetary mixer.

Twin shell blender.

High shear mixer


Slugging (Dry Granulation)A dry powder blend that cannot be directly compressed because of poor flow or compression properties.

This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less.

Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts.

If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation.


Dry CompactionGranulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch.

Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression.

One of the best examples of this process is the densification of aluminum hydroxide.

Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties.




Compression The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press.

During compression, the tablet press performs the following functions:

1.Filling of empty die cavity with granulation.

2.Precompression of granulation (optional).

3.Compression of granules.

4.Ejection of the tablet from the die cavity and take-off of compressed tablet.


When evaluating the compression characteristics of a particular formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be tried.

Only then are potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected.

High-speed tablet compression depends on the ability of the press to interact with granulation.

Following are the parameters to be considered while choosing speed of press.

1.Granulation feed rate.

2.Delivery system should not change the particle size distribution.

3.System should not cause segregation of coarse and fine particles, nor it should induce static charges.


The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame.

The smaller the tablet , the more difficult it is to get a uniform fill a high press speeds.

For high-speed machines, induced die feed systems is necessary.

These are available with a variety of feed paddles and with variable speed capabilities.

So that optimum feed for every granulation can be obtained.


After the die cavities are filled ,the excess is removed by the feed frame to the center of the die table.

Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers.

This cause the punches to the penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between the punches.

The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers.

Larger the compressions roller, the more gradually compression force is applied and released.


Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation.

The final event is ejection of compressed tablets from die cavity.

During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking.

High level of lubricant or over blending can result in a soft tablet, decrease in wettability of the powder and an extension of the dissolution time.

Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the center in order to relieve pressure during ejection.


DIFFERENT PUNCHES &DIES


HIGH SPEED ROTARY MACHINE

MULTI ROTARY MACHINE


DOUBLE ROTARYMACHINE UPPER PUNCH AND

LOWER PUNCH


SINGLE ROTARY MACHINE


Tablet CoatingSugar coating is carried out in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations.

The conventional sugar coating pan has given way to perforated pans or fluidized-bed coating columns.

The development of new polymeric materials has resulted in a change from aqueous sugar coating and more recently, to aqueous film coating.

The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column.


Some tablet core materials are naturally hydrophobic, and in these cases, film coating with an aqueous system may require special formulation of the tablet core and/or the coating solution.

A film coating solution may have been found to work well with a particular tablet in small lab coating pan but may be totally unacceptable on a production scale.

This is because of increased pressure & abrasion to which tablets are subjected when batch size is large & different in temperature and humidity to which tablets are exposed while coating and drying process.



METHODS

DRY BLENDING WET GRANULATION

DRYGRANULATION

WEIGHING SIZING

BLENDINGLUBRICATIONCOMPRESSION

COATING

WEIGHINGSIZING

GRANULATIONDRYING

BLENDINGLUBRICATIONCOMPRESSION

WEIGHINGSIZING

BLENDINGCOMPACTION

MILLINGLUBRICATIONCOMPRESSION


Compression rates of typical production presses


Pilot Plant scale-up techniques for Capsule

Capsules are solid dosage forms in which the drug substance is enclosed in either a hard or soft soluble container or shell of a suitable form of gelatin.

Steps in capsule production

1.Mixing of ingredient

2.Granulation and lubrication

3.Making of capsules

4.Filling of capsules

5.Uniformity testing

6.Packing and labeling


The manufacturing process for capsulated products often same to that tablets.

Both tablets & capsules are produced from ingredients that may be either dry blended or wet granulated to produce a dry powder or granule mix with uniformly dispersed active ingredients.

To produce capsules on high speed equipment ,the powder blend must have the uniform particle size distribution, bulk density & compressibility required to promote good flow properties & result in the formation of compact of the right size and sufficient cohesiveness to be filled in to capsule shells.


Manufacture of Hard Gelatin Capsules

1. Shell composition :

Gelatin : Prepared by the hydrolysis of collagen. Gelatin in its chemical and physical properties, depending

upon the source of the collagen and extraction. There are two basic types of gelatin:

Type – A and Type – B. The two types can be differentiated by their isoelectric

points (7.0 – 9.0 for type A and 4.8 – 5.0 for type B) and by their viscosity and film forming characteristics.


Combination of pork skin and bone gelatin are often used to optimize shell characteristics.

The physicochemical properties of gelatin of most interest to shell manufactures are the bloom strength and viscosity.

Colorants :Various soluble synthetic dyes (“coal tar dyes”) and

insoluble pigments are used.Not only play a role in identifying the product, but also

may play a role in improving patient compliance.

E.g., white, analgesia; lavender, hallucinogenic effects; orange or yellow, stimulants and antidepressants.


Opaquing agents :Titanium dioxide may be included to render the shell

opaque.Opaque capsules may be employed to provide protection

against light or to conceal the contents.

Preservatives :When preservatives are employed, parabens are often

selected.


2) Shell manufacture :


I. Dipping : Pairs of the stainless steel pins are dipped into the dipping

solution to simultaneously form the caps and bodies. The pins are at ambient temperature; whereas the dipping

solution is maintained at a temperature of about 500C in a heated, jacketed dipping pan.

The length of time to cast the film has been reported to be about 12 sec.

II. Rotation : After dipping, pins are elevated and rotated 2-1/2 times

until they are facing upward. This rotation helps to distribute the gelatin over the pins

uniformly and to avoid the formation of a bead at the capsule ends.


III. Drying : The racks of gelatin coated pins then pass into a series

of four drying oven. Drying is mainly done by dehumidification. A temperature elevation of only a less degrees is

permissible to prevent film melting. Under drying will leave the films too sticky for

subsequent operation.

IV. Stripping : A series of bronze jaws strip the cap and body portions

of the capsules from the pins.


V. Trimming : The stripped cap and body portions are delivered to

collects in which they are firmly held. As the collects rotate, knives are brought against the

shells to trim them to the required length.

VI. Joining : The cap and body portions are aligned concentrically in

channels and the two portions are slowly pushed together.


3) Sorting : The moisture content of the capsules as they are from

the machine will be in the range of 15 – 18% w/w. During sorting, the capsules passing on a lighted moving

conveyor are examined visually by inspectors. Defects are generally classified according to their nature

and potential to cause problems in use.

4) Printing : In general, capsules are printed before filling. Generally, printing is done on offset rotary presses

having throughput capabilities as high as three-quarter million capsules per hour.


Size Volume Fill weight(g) at 0.8 g/cm3 powder density

000 1.37 1.096

00 0.95 0.760

0 0.68 0.544

1 0.50 0.400

2 0.37 0.296

3 0.30 0.240

4 0.21 0.168

5 0.15 0.104

5) Sizes and shapes : For human use, empty gelatin capsules are

manufactured in eight sizes, ranging from 000 to 5. Capsule capacities in table:


The largest size normally acceptable to patient is a No: 0.Three larger size are available for veterinary use: 10, 11,

and 12 having capacities of about 30, 15, and 7.5 g, respectively.

The standard shape of capsules is traditional, symmetrical bullet shape.

Some manufactures have employed distinctive shapes.

e.g. Lilly’s pulvule tapers to a bluntly pointed end.

Smith Kline Beacham’s spansule capsules taper at

both the cap and body ends.


6) Sealing : Capsules are sealed and somewhat reshaped in the

Etaseal process. This thermal welding process forms an indented ring

around the waist of the capsule where the cap overlaps the body.

7) Storage : Finished capsules normally contain an equilibrium

moisture content of 13-16%. To maintain a relative humidity of 40-60% when

handling and storing capsules.


Filling of hard gelatin capsules

Equipment used in capsule filling operations involves one often of two types of filling systems.

Zanasi or Martelli encapsulator: Forms slugs in a dosatar which is a hollow tube with a

plunger to eject capsule plug.

Hofliger-Karg machine:Formation of compacts in a die plate using tamping pins

to form a compact.


HOFLIGER KARG AUTOMATICCAPSULE FILLING MACHINE

ZANASI AUTOMATICCAPSULE FILLING MACHINE


In this both system, the scale-up process involve bulk density, powder flow, compressibility, and lubricant distribution.

Overly lubricated granules are responsible for delaying capsule disintegration and dissolution.


OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE

FILLING MACHINE


Manufacture of Soft Gelatin Capsules

I. Composition of the shell: Similar to hard gelatin shells, the basic component of

soft gelatin shell is gelatin; however, the shell has been plasticized.

The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for very hard shell to 1.0-1.8 for very soft shell.

Up to 5% sugar may be included to give a “chewable” quality to the shell.

The residual shell moisture content of finished capsules will be in the range of 6-10%.


II. Formulation : Formulation for soft gelatin capsules involves liquid,

rather than powder technology. Materials are generally formulated to produce the

smallest possible capsule consistent with maximum stability, therapeutic effectiveness and manufacture efficiency.

The liquids are limited to those that do not have an adverse effect on gelatin walls.

The pH of the lipid can be between 2.5 and 7.5. Emulsion can not be filled because water will be

released that will affect the shell.


The types of vehicles used in soft gelatin capsules fall in to two main groups:1. Water immiscible, volatile or more likely more volatile

liquids such as vegetable oils, mineral oils, medium-chain triglycerides and acetylated glycerides.

2. Water miscible, nonvolatile liquids such as low molecular weight PEG have come in to use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs.

All liquids used for filling must flow by gravity at a temperature of 350c or less.

The sealing temperature of gelatin films is 37-400C.


III. Manufacture process :

A. Plate process :

The process involved Placing the upper half of a plasticized gelatin sheet

over a die plate containing numerous die pockets, Application of vacuum to draw the sheet in to the die

pockets, Filling the pockets with liquor or paste, Folding the lower half of gelatin sheet back over the

filled pockets, and Inserting the “ sandwich” under a die press where the

capsules are formed and cut out.


B. Rotary die press: In this process, the die cavities are machined in to the

outer surface of the two rollers. The die pockets on the left hand roller form the left side

of the capsule and the die pockets on the right hand roller form the right side of the capsule.

Two plasticized gelatin ribbons are continuously and simultaneously fed with the liquid or paste fill between the rollers of the rotary die mechanism.

As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules.



C. Accogel process: In general, this is another rotary process involving

A measuring roll, A die roll, and A sealing roll.

As the measuring roll and die rolls rotate, the measured doses are transferred to the gelatin-linked pockets of the die roll.

The continued rotation of the filled die converges with the rotating sealing roll where a second gelatin sheet is applied to form the other half of the capsule.

Pressure developed between the die roll and sealing roll seals and cuts out the capsules.


4. Bubble method: The Globex Mark II capsulator produces truly seamless,

one-piece soft gelatin capsules by a “bubble method”.


A concentric tube dispenser simultaneously discharges the molten gelatin from the outer annulus and the liquid content from the tube.

By means of a pulsating pump mechanism, the liquids are discharged from the concentric tube orifice into a chilled-oil column as droplets that consists of a liquid medicament core within a molten gelatin envelop.

The droplets assume a spherical shape under surface tension forces and the gelatin congeals on cooling.

The finished capsules must be degreased and dried.


IV. Soft/Liquid-filled hard gelatin capsules: Important reason: the standard for liquid filled capsules

was inability to prevent leakage from hard gelatin capsules.

As banding and of self-locking hard gelatin capsules, together with the development of high-resting state viscosity fills, has now made liquid/semisolid-filled hard gelatin capsules.

As with soft gelatin capsules, any materials filled into hard capsules must not dissolve, alter or otherwise adversely affect the integrity of the shell.

Generally, the fill material must be pumpable.


Three formulation strategies based on having a high

resting viscosity after filling have been described.

1. Thixotropic formulations,

2. Thermal-setting formulations,

3. Mixed thermal-Thixotropic systems.

The more lipophilic contents, the slower the release rate.

Thus, by selecting excipients with varying HLB balance,

varying release rate may be achieved.


CAPSULE POLISHING MACHINE

AUTO MATIC CAPSULE

ARRANGEMNT


References 1. The theory and practice of industrial pharmacy. Leon

Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third edition. Varghese publishing house. Page no. 681-703.

2. Pharmaceutical dosage forms: Tablets. Volume 3. second edition. Leon Lachman, Herbert A. Lieberman, Joseph B. Schwartz. Page no. 303-365.

3. Pharmaceutical process scale –up edited by Michael Levin.

4. Modern pharmaceutics. Edited by Gilbert S. Banker & Christopher T. Rhodes. 4th edition.

5. www.google.com

08 June 2009SRTM University, NandedDept. of Pharmaceutics 79Wednesday, April 19, 2023 Dept. of Pharmaceutics 79

E-mail: [email protected]

Cell No: 09742431000

Documents

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D By. 08 June 2009SRTM University, NandedDept. of Pharmaceutics2 CONTENTS Introduction Objectives of the Pilot