pilot plant scale up for tablets
TRANSCRIPT
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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