Satish Mallya

January 20-22, 2010

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1-7 Manufacturing Basics and Issues:
Solid Orals




PQP Assessment Training
January 18-21, 2012
Satish Mallya
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Flow Chart
API
Filler

Mixing of
granulation blend
Granulation
Binder(s)
Preparation of
binder solution
Drying
Milling
LOD
Disintegrant
screening
screening
Initial Blending
lubricant screening
Final Blending
Compression
Solvent
Film coating agent
Preparation
Film Coating of Tablets
Packaging
and Labelling
Weight
Hardness
Friability
January 19-22, 2011
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Methods
DIRECT COMPRESSION

DRY GRANULATION WET GRANULATION
Milling/Screening Milling/Screening Milling/Screening
Blending Pre-blending Pre-blending
Compression Slugging/roller compaction Addition of binder
Dry screening Screening of wet mass
Blending of lubricant Drying of the wet granules
Compression Screening of dry granules
Blending of lubricant (and
disintegrant)
Compression
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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What's Good
DIRECT COMPRESSION DRY GRANULATION

WET GRANULATION

Fewer processing steps
blending and compression -
reduced processing time
Processing without moisture
and heat fewer stability
problems
Rapid and most direct method
of tablet compression
Changes in dissolution less
likely on ageing since there are
less formulation variables
Improved flow by increasing
particle size
Improved uniformity of
powder density
Improved cohesion during
compression
Granulation without addition
of liquid

Improved flow by increasing
particle size and sphericity
Uniform distribution of API,
colour etc. improved content
uniformity
Good for bulky powders, less
dust and environmental
contamination
Lower compression pressure,
less wear and tear on tooling
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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What's Not So Good
DIRECT COMPRESSION DRY GRANULATION

WET GRANULATION
Possibility of lot to lot variations due
to differences in psd, flowability and
moisture of excipients
Higher risk of content uniformity
failure in low dose products
(geometric granulation indicated)
Lack of moisture can create static
charges that can result in un-
blending
Differences in particle size/density
between API and excipient can result
in un-blending in hopper
Possible over compaction
of slugs/compacts
impact on dissolution
Possible particle
segregation

Large number of processing
steps
More equipment
Wetting and drying stages
are time consuming
Greater possibility of cross
contamination
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Steps

Dispensing
Milling/Screening
Blending
Granulation
Drying
Compression
Coating
Packaging
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Dispensing
One of the most critical steps in pharmaceutical manufacturing
manual weighing on a weight scale with material lifting assistance like
vacuum transfer and bag lifters
automated weighing

Issues:
dust control (laminar air flow booths, glove boxes)
weighing accuracy
multiple lots of active ingredient with different assays, moisture and residual
solvent content
cross contamination
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Raw Material Dispensing Record
RM
Code
Ingredient Qty
Kg
AR
No
Gross
Wt.
Tare
Wt.
Net Wt. Weighed
by
Checked
by
Date
API
Exp 1
Exp 2
Exp 3
Exp 4
Exp 5
January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Sr.
No
.
AR No. Total available
quantity (as is basis)
(Kg)
(A)
Actual
Assay
(%)
(B)
Water
content
(% w/w)
(C)
Equivalent
quantity on
100% assay
and nil water
basis (Kg)
(D)
Equivalent
quantity on
as is basis
(Kg)
(E)
1 AP-18 23.50 99.4 0.34 23.28 23.50
2 AP-22 60.00 99.1 0.50 6.72 6.815
E 30.00 E 30.315
January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Milling/Screening
Principle: Mixing or blending is more uniform if ingredients are of similar size
What are the problems What are the equipment Why do it

Possible change in
polymorphic form
An increase in surface
area may promote the
adsorption of air - may
inhibit wetting of the drug
could be the limiting factor
in dissolution rate
Fluid energy mill
Comil
Ball mill
Hammer mill
Cutting mill etc.

Increased surface area -
may enhance rate of
dissolution
Improved content uniformity
due to increased number of
particles per unit weight
Enhanced flow properties of
raw materials
Uniformly sized wet granules
promotes uniform drying
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
screening
Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
1.1 API Kg
Exp 1 Kg
Pass through # 40 screen of
Vibratory sifter and collect
material in tared double PE
lined container








1.2 Exp 2 Kg
Exp 3 Kg
Pass through # 20 screen of
Vibratory sifter and collect
material in tared double PE
lined container










January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Blending
Blending is the most difficult operation in the manufacturing process since perfect
homogeneity is practically impossible due to differences in size, shape and density
of particles

What are the problems What are the equipment

Why do it

Segregation
Possible over mixing of
lubricant
Blend uniformity/ Content
uniformity
Diffusion Mixers (V,double
cone, bin,drum blenders)
Convection Mixers (ribbon,
planetary blenders)
Pneumatic Mixers
To achieve optimum mixing
of different ingredients in
powder/granules at pre
granulation and/or post
granulation stages of
tablet manufacturing
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Granulation

Principle: A size enlargement process that converts small particles into physically stronger
& larger agglomerates
What are the problems What are the equipment Why do it

Loss of material during
various stages of
processing
Multiple processing steps -
validation and control
difficult
Incompatibility between
formulation components is
aggravated
Dry Granulator (roller
compactor, tabletting
machine)
Wet High-Shear Granulator
(horizontal, vertical)
Wet Low-Shear Granulator
(planetary, kneading, screw)
Fluid Bed Granulator, Spray
Dry Granulator, RMG
Provides homogeneity of
drug distribution in blend
Improves flow,
compressibility and
hardness of tablets
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
blending & granulation
Mixing SOP No.: Granulation SOP No.:


Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
2.1
Load material from 1.1 & 1.2 in RMG
Exp 4 .Kg
and mix for 5 minutes with following
settings: Impeller speed-fast; Chopper
speed-fast













2.2
Spray purified water into contents of RMG
Impeller speed fast; Chopper speed -
fast
Peristaltic pump atomization press: 0.5-
2.5 b Spray until all purified water is
sprayed Ammeter reading 18-22 amps


















January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
wet milling
Wet Milling SOP No.:

Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
3.1 Pass wet mass through 1mm
screen of Multi Mill
Speed fast; Knives - forward
collect in FBD













January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Recent Advances in Granulation Techniques
Steam Granulation: Modification of wet granulation; steam is used
as a binder instead of water; granules are more spherical and
exhibit higher rate of dissolution
Melt Granulation / Thermoplastic Granulation: Granulation is
achieved by the addition of meltable binder i.e. binder is in solid
state at room temperature but melts in the temperature range of 50
80C [e.g. PEG (water soluble), stearic acid, cetyl or stearyl
alcohol (water insoluble)] - drying phase unnecessary since dried
granules are obtained by cooling them to room temperature
Moisture Activated Dry Granulation (MADG): Involves
distribution of moisture to induce agglomeration drying time is
reduced
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Recent Advances in Granulation Techniques
Moist Granulation Technique (MGT): A small amount of
granulating fluid is added to activate dry binder and to facilitate
agglomeration. Then a moisture absorbing material like
Microcrystalline Cellulose (MCC) is added to absorb any excess
moisture making drying step unnecessary. Mainly employed for
controlled release formulations
Thermal Adhesion Granulation Process (TAGP): Granules are
prepared by moisturizing excipient mixtures with very little solvent
in a closed system (tumble mixing) with low heating mainly
employed for preparing direct compression formulations
Foam Granulation: Binders are added as aqueous foam
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Drying
Purpose: To reduce the moisture level of wet granules
What are the problems What are the equipment

Why do it

Over drying (bone dry)
Excess fines
Possible fire hazard
Direct Heating Static
Solids Bed Dryers
Direct Heating Moving
Solids Bed Dryers
Fluid Bed Dryer
Indirect Conduction
Dryers
To keep the residual
moisture low enough
(preferably as a range) to
prevent product
deterioration
Ensure free flowing
properties

January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
drying
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105C)

Date

Verified
by

Performed
by
Time
end
Time
start

Instructions

Step


















FBD in let temp 60C
Damper 80% open for
15 min
Damper 50% open
after 15 minutes ; LOD
..%

3.2
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
size reduction & blending
Size reduction SOP No.: Blending SOP No.:

Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
4.1 Fit 0. 8 mm screen to Multi
Mill and pass material from
3.2
Speed Medium
Knives - forward


















4.2 Load dried granules from
4.1 into Conta Blender and
blend for 20 mins at 12+1
rpm














January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
lubrication
Lubrication SOP No.:


Step Instructions Time
start
Time
end
Perform
ed by
Verifie
d by
Date
5.1 Fit 60 mesh screen to vibratory
sifter and pass
Exp 5 .Kg
and collect in tared double PE
lined container


















5.2 Add contents from 5.1 to 4.2 and
blend for 3 mins and collect in
tared double PE lined container














January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Compression
Principle: Powder/granules are pressed inside a die and compressed by two
punches into required size, shape and embossing

What are the problems

What are the equipment

Why do it

Poor flow in hopper
Inadequate lubrication
Capping, chipping, cracking,
lamination, sticking, picking,
binding, mottling
Double compression
Multiple Stations (Rotary)
and High Speed Tablet
Presses

To compress powder into
tablets
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
compression
Balance no.: Vernier Caliper no.:
Hardness tester no.: Friability tester no.:
Disintegration tester no.:

Tooling No. of units Checked by Verified by
Upper punch: mm x mm oval
shaped concave embossed.
55
Lower punch: mm x mm oval
shaped concave embossed.
55
Dies: mm x .mm oval shaped 1
January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
compression


Parameter Limit Results
Machine speed 20 rpm (15-25 rpm)
Wt. of 20 tabs 12.00g +2 (11.76-12.24g)
Theoretical weight/tab 600mg
Hardness 25Kg (20-30 Kg)
Thickness (av. of 10
tabs)
4.10mm +0.15mm (3.95 4.25mm)
Length 10mm + 0.1 mm (9.9 10.1 mm)
Width 5 mm + 0.1mm (4.9 5.1 mm)
Disintegration time NMT 15 mins
Wt. variation + 3% of Av. Wt.
Friability (10 tabs) NMT 1.0% w/w
January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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In-process Checks
Parameter Frequency
Wt. of 20 tabs Every hour by production and every two
hours by QA
Hardness, thickness, length, width Every hour by production, every two hours
by QA
Wt. variation Every half hour by production and every
hour by QA
DT Every half hour by production, every hour by
QA
January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Coating/Polishing
Principle: Application of coating solution to a moving bed of tablets with concurrent
use of heated air to facilitate evaporation of solvent

What are the problems

What are the equipment

Why do it

Blistering, chipping,
cratering, picking, pitting
Color variation
Roughness
Pan (standard/perforated)
Coating Machines
Fluidized Bed Coating
Machines
Spray Coating Machines
Vacuum, Dip & Electrostatic
Coating Machines

Enhance appearance and
colour
Mask taste and odour
(film/sugar)
Improve patient compliance
Improve stability
Impart enteric, delayed,
controlled release properties
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Manufacturing Instructions
coating
Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
6.1 Introduce compressed tablets
into Auto Coater and spray
coating solution
Inlet air temp .C (30-60C)
Pan speed..rpm (2-8 rpm)
Solution rate ..ml/min (20-60
ml/min)
Distance of gun from tablet
bedcm (20-40cm)




























January 19-22, 2011 January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Other Issues
Yield:
of lubricated granules
of compressed tablets
of coated tablets
Dedusting
Metal detection
Scale up
Life-cycle management
January 18-21, 2012
Satish Mallya
January 20-22, 2010

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Thanks