PILOT PLANT SCALE UP FOR

TABLETS

BY:-Robin Gulati

Introduction

Objectives of the Pilot Plant

Significance of pilot plant

Pilot plant design for tablets

◦ Typical unit operations

Contents:

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.”

Introduction

R & D

Pilot Plant

Produ-ction

Art of designing of prototype using the data obtained from the pilot plant model.

Scale up

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.

Objectives of Pilot Plant

Examination of formulae.

Review of range of relevant processing equipment.

Production rate adjustment.

Idea about physical space required.

Appropriate records and reports to support GMP.

Identification of critical features to maintain quality.

Significance of Pilot Plant

Each stage considered carefully from experimental lab batch size to intermediate and large scale production.

Same process, same equipment but different performance when amount of material increased significantly.

May involve a major process change that utilizes techniques and equipment that were either unavailable or unsuitable on a lab scale.

Pilot Plant Design for Tablets

Material handling Dry blending Granulation Drying Reduction of particle size Blending

◦ Dry blending ◦ Direct compression◦ Slugging (Dry granulation)

Typical Unit Operations

Granulation handling and feed system Compression Tablet coating

In lab: materials scooped, dumped or poured by hand.

May work well for small or intermediate scale productions.

Large scale productions: mechanical means necessary.

Simple means: post hoist devices, devices for lifting, and tilting drums.

Sophisticated: vacuum loading systems, screw feed systems and meter pumping systems.

Material Handling

Type of system selected depends on the characteristics of the material, e.g., density.

Material handling system should cause no/minimum loss of material.

Lengthy transfer more material loss. If one system being used for more than one

material cross contamination should be avoided.

Accomplished by using validated cleaning procedures.

Vacuum Loading Machine

Powders granulated prior to tabletting well blended to ensure proper mixing.

Inadequate blending drug content uniformity variation (more when drug conc/n is low) high or low potency.

Large batch blended in batches ensuring no lump and agglomerate formations.

Dry Blending

Problems of improper blending:-◦ Flow problem through the equipment ◦ Non-reproducible compression◦ No content uniformity.

Screening and/or milling of the ingredients prior to blending done to make the process more reliable and reproducible.

Equipment used for blending are: ◦ V- blender◦ Double cone blender ◦ Ribbon blender◦ Slant cone blender◦ Bin blender◦ Orbiting 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

The most common reasons given to justify granulating are:

a) To impart good flow properties to the material,b) To increase the apparent density of the powders,c) To change the particle size distribution,d) Uniform dispersion of active ingredient.

Traditionally, wet granulation has been carried out using:

◦ Sigma blade mixer◦ Heavy-duty planetary mixer (100-200kgs)

Granulation

Sigma Blade Mixer

Planetary Mixer

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

These greatly affect the granulating time as well as the granulating fluid relative to that used in experimental laboratories trials.

High shear mixers often more effective in densifying light powders, but require large amount of energy and have limited load size.

Now-a-days equipment involving continuous process are in use.

Advantages:-◦ Less space and manpower.◦ Less handling of materials since they are closed

systems.◦ Reduce danger of personnel exposure to potent

materials.◦ Prevent from potentially hazardous substances.

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 (when

dissolved in granulating solution) as a result

transfer of fluid becomes difficult.

◦ This problem can be overcome by adding some or

all binding agents in the dry powder prior to

granulation.

Gelatin Acacia Tragacanth Methylcellulose Ethylcellulose Hydroxypropyl cellulose Polyvinylpyrolidone

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.

The most common conventional method circulating hot air oven, which is heated by either steam or electricity.

Scale-up considerations for an oven drying operation are:◦ airflow◦ air temperature, and ◦ the depth of the granulation on the trays.

Drying

Too deep or too dense bed makes the drying process 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.

Compression factors

Flowability

Compressibility

Uniformity of tablet weight

Content uniformity

Tablet hardness

Tablet color uniformity

Reduction of Particle Size

Problems due to improper particle size:

◦ Too large particle size- insufficient filling of the die cavity- weight variation

◦ For colored granulation- coarser the granulation- mottling

◦ Too many fines- flowability problems- wt variation

◦ Capping (also occurs if speed of the press in increased).

Eq

uip

men

ts

Oscillating granulator (for not too hard

oversized granulation)

Hammer mill

Mechanical sieving device

Screening device

Control factors

Speed of the mill

Type of equipmen

t

Rate of material

feed

Oscillating type granulator Hammer mill

Use of lubricants & glidants:

◦ In lab: added to the final blend

◦ Scale up: added to the dry granulation during size reduction

◦ This is done because additives like magnesium stearate, agglomerate when added in large quantities to the granulation in a blender.

◦ Over mixing or under mixing should be avoided.

Blending

Control

factors

Design

Blender loads

Mixing speed

Mixing time

Mixing

Segregation

Particle size

ShapeHardne

ss Density Dynami

cs of the

mixing action

Characteristics of the material:

◦ Fragile particles or agglomerates: more readily abbraided more fines improper mixing flow problems, fill problems, content uniformity problems.

◦ Particle abbraision is more when high-shear mixing with spiral screws or blades are used.

◦ Tumble blenders: for prolonged mixing

◦ Bulk density of raw materials considered in selection of the blender and determining optimum blender load.

◦ Excessive granulation: poor content uniformity, poor lubrication & improper color dispersion.

“Direct Compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients.

No pretreatment of the powder blend by wet or dry granulation procedure is required.

Direct compression is one of the most advanced technologies to prepare tablets.

Requires only blending and compression of excipients. Economical process. Suitable for heat and moisture sensitive API. Not suitable for very low and very high dose drugs.

Dry Blending and Direct Compression

Manufacturing steps for direct compression

Stepwise process for direct compression

Control factors:Particle characteristics (mixing & segregation): size, size distribution, shape, static charge

Blender load

Optimum mixing speed

Blending time

Optimizing the process and validation of its performance

Order of addition of components to the blender Mixing speed: can be varied with the original

direction as necessary. Mixing time: excessive mixing may fracture the

fragile excipients and ruin their compressibility. Use of auxiliary dispersion material within the

mixer (chopper blade in a twin shell mixer):◦ Increase efficiency◦ Reduce agglomerates

Aspects for optimization:

Mixing action: ◦ Determined by the mechanics of the mixer.◦ Changed by converting from one blender to the

other or by modifying the blender through addition of baffles or plates, which would alter the mixing characteristics.

Blender load: affects efficiency◦ Overload: reduced free flow of granules and

reduced efficiency◦ Localized concentration: content uniformity◦ Small load: sliding and rolling of powders in the

blender, no proper mixing & increased time for mixing.

1. Simple2. Requires least complicated equipment3. Requires minimum amount of handling and

operator time4. Modification in the process is easy5. Free flowing granules can be obtained without the

granulating solution.6. Saves time and energy necessary to volatilize the

solvent used in conventional granulation powders

Merits:

7. Suitable for thermolabile and moisture sensitive API’s

8. Chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer.

9. Particle size uniformity

Excipient Related1. Problems in the uniform distribution of low dose drugs.2. High dose drugs having high bulk volume, poor

compressibility and poor flowability are not suitable for direct compression. For example, Aluminium Hydroxide, Magnesium Hydroxide

3. Direct compression diluents and binders must possess both good compressibility and good flowability.

4. Many active ingredients are not compressible either in crystalline or amorphous forms.

5. May lead to unblending because of difference in particle size or density of drug and excipients. Similarly the lack of moisture may give rise to static charges, which may lead to unblending.

6. Non-uniform distribution of colour, especially in tablets of deep colours.

Demerits:

Process Related

i) Capping, lamination, splitting, or layering of tablets related to air entrapment during direct compression. When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet.

ii) In some cases require greater sophistication in blending and compression equipment.

iii) Expensive equipment

For dry powder blend that cannot be directly compressed because of poor flow or compression properties.

Done on a tablet press designed for slugging. Pressure of 15 tons; normal: 4 tons or less Speed is slow since poorly flowable powders require

more time to be compressed. Diameter of slugs:

◦ 1 inch for more easily slugged material◦ ¾ inch for materials difficult to compress

Slugging (Dry Granulation)

Schematic of slugging operation (lab)

Vertical screw

Pressure applied Pre-break

Granulator

Finished product

Screener

Recycle

Lower hopper

Original powder feed

Recycle system

Feed & recycle

Screen

Compaction rolls

Horizontal feed screw

Upper feed hopper

Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. E.g.- densification of aluminium hydroxide

Additional handling can affect content uniformity of the drug and the particle size distribution.

Segregation due to static charges may lead to flow problems through tablet press hoppers and feed frames.

This affects tablet weight, thickness and hardness. Finally poor content uniformity.

More sophisticated equipment cleaning problem. Equipment to be engineered for efficient and total

cleaning. Well written, documented and validated cleaning

procedures are essential for such systems.

Granulation handling & Feed Systems

Functions of a tablet press: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.

Potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected.

Compression

Control factors while selecting the speed of the 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 at high press speeds.

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

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.

Single Rotary Press

Double Rotary Press

Different types of punches

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 found to work well with a particular tablet in small lab coating pan may be totally unacceptable on a production scale.

Tablet Coating

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.

Coating machine

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