1-7 Manufacturing Basics and Issues:
Solid Orals
PQP Assessment Training
January 18-21, 2012
Satish Mallya
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January20-22,
18-21,2010
2012
Satish Mallya January
Flow Chart
API
Filler
Binder(s)
screening
Mixing of
granulation blend
Preparation of
binder solution
Granulation
Drying
LOD
Milling
Disintegrant
screening
lubricant
screening
Initial Blending
Final Blending
Compression
Film Coating of Tablets
Solvent
Film coating agent
2|
Preparation
January20-22,
19-22,
2011
January
18-21,2010
2012
Satish Mallya January
Packaging
and Labelling
Weight
Hardness
Friability
Manufacturing Methods
WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Milling/Screening
Milling/Screening
Milling/Screening
Pre-blending
Pre-blending
Blending
Addition of binder
Slugging/roller compaction
Compression
Screening of wet mass
Dry screening
Drying of the wet granules
Blending of lubricant
Screening of dry granules
Compression
Blending of lubricant (and
disintegrant)
Compression
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January20-22,
18-21,2010
2012
Satish Mallya January
What's Good
WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Improved flow by increasing
particle size and sphericity
Improved flow by increasing
particle size
Fewer processing steps –
blending and compression reduced processing time
Uniform distribution of API,
colour etc. – improved content
uniformity
Improved uniformity of
powder density
Good for bulky powders, less
dust and environmental
contamination
Lower compression pressure,
less wear and tear on tooling
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January20-22,
18-21,2010
2012
Satish Mallya January
Improved cohesion during
compression
Granulation without addition
of liquid
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
What's Not So Good
WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Large number of processing
steps
Possible over compaction
of slugs/compacts –
impact on dissolution
Possibility of lot to lot variations due
to differences in psd, flowability and
moisture of excipients
Possible particle
segregation
Higher risk of content uniformity
failure in low dose products
(geometric granulation indicated)
More equipment
Wetting and drying stages
are time consuming
Greater possibility of cross
contamination
Lack of moisture can create static
charges that can result in unblending
Differences in particle size/density
between API and excipient can result
in un-blending in hopper
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January20-22,
18-21,2010
2012
Satish Mallya January
Steps
 Dispensing
 Milling/Screening
 Blending
 Granulation
 Drying
 Compression
 Coating
 Packaging
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January20-22,
18-21,2010
2012
Satish Mallya January
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
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January20-22,
18-21,2010
2012
Satish Mallya January
Raw Material Dispensing Record
RM
Code
8|
Ingredient
Qty
Kg
AR
No
API
√
Exp 1
Net Wt.
Weighed
by
Checked
by
Date
√
√
√
√
√
√
√
√
√
√
√
Exp 2
√
√
√
√
√
√
Exp 3
√
√
√
√
√
√
Exp 4
√
√
√
√
√
√
Exp 5
√
√
√
√
√
√
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Gross
Wt.
Tare
Wt.
Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Sr.
No
.
AR No.
Total available
quantity (as is basis)
(Kg)
Actual
Assay
(%)
Water
content
(% w/w)
(A)
(B)
(C)
Equivalent
quantity on
100% assay
and nil water
basis (Kg)
Equivalent
quantity on
as is basis
(D)
(E)
(Kg)
1
AP-18
23.50
99.4
0.34
23.28
2
AP-22
60.00
99.1
0.50
6.72
6.815
∑E 30.00
∑E 30.315
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January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
23.50
Milling/Screening
 Principle: Mixing or blending is more uniform if ingredients are of similar size
Why do it
What are the equipment What are the problems
Increased surface area may enhance rate of
dissolution
Fluid energy mill
10 |
Comil
Improved content uniformity
due to increased number of
particles per unit weight
Ball mill
Enhanced flow properties of
raw materials
Cutting mill etc.
Uniformly sized wet granules
promotes uniform drying
January20-22,
18-21,2010
2012
Satish Mallya January
Possible change in
polymorphic form
Hammer mill
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
Manufacturing Instructions
screening
Step
Instructions
1.1
API
…… Kg
Exp 1
…… Kg
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
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
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January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
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
12 |
Why do it
What are the equipment What are the problems
To achieve optimum mixing
of different ingredients in
powder/granules at pre
granulation and/or post
granulation stages of
tablet manufacturing
Diffusion Mixers (V,double
cone, bin,drum blenders)
January20-22,
18-21,2010
2012
Satish Mallya January
Convection Mixers (ribbon,
planetary blenders)
Pneumatic Mixers
Segregation
Possible over mixing of
lubricant
Blend uniformity/ Content
uniformity
Granulation
 Principle: A size enlargement process that converts small particles into physically stronger
& larger agglomerates
Why do it
What are the equipment What are the problems
Provides homogeneity of
drug distribution in blend
Dry Granulator (roller
compactor, tabletting
machine)
Loss of material during
various stages of
processing
Wet High-Shear Granulator
(horizontal, vertical)
Multiple processing steps validation and control
difficult
Improves flow,
compressibility and
hardness of tablets
Wet Low-Shear Granulator
(planetary, kneading, screw) Incompatibility between
formulation components is
Fluid Bed Granulator, Spray aggravated
Dry Granulator, RMG
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January20-22,
18-21,2010
2012
Satish Mallya January
Manufacturing Instructions
blending & granulation
 Mixing SOP No.:
Granulation SOP No.:
Step
Instructions
2.1
Load material from 1.1 & 1.2 in RMG
Exp 4
……….Kg
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
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: 0.52.5 b Spray until all purified water is
sprayed Ammeter reading 18-22 amps
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January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Manufacturing Instructions
wet milling
 Wet Milling SOP No.:
Step
Instructions
3.1
Pass wet mass through 1mm
screen of Multi Mill
Speed – fast; Knives - forward
collect in FBD
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January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
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
– 80˚C [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
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January20-22,
18-21,2010
2012
Satish Mallya January
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
17 |
January20-22,
18-21,2010
2012
Satish Mallya January
Drying
 Purpose: To reduce the moisture level of wet granules
18 |
Why do it
What are the equipment What are the problems
To keep the residual
moisture low enough
(preferably as a range) to
prevent product
deterioration
Direct Heating Static
Solids Bed Dryers
Ensure free flowing
properties
Fluid Bed Dryer
January20-22,
18-21,2010
2012
Satish Mallya January
Over drying (bone dry)
Excess fines
Direct Heating Moving
Solids Bed Dryers
Indirect Conduction
Dryers
Possible fire hazard
Manufacturing Instructions
drying
 Drying SOP No.:
LOD: 1.0-2.5% (moisture balance at 105ºC)
Step
Instructions
Time
start
Time
end
Performed
by
Verified
by
Date
3.2
FBD in let temp 60ºC
√
√
√
√
√
Damper 80% open for
15 min
√
√
√
√
√
Damper 50% open
after 15 minutes ; LOD
……..%
19 |
January20-22,
18-21,2010
2012
Satish Mallya January
Manufacturing Instructions
size reduction & blending
 Size reduction SOP No.:
Step
Instructions
4.1
Fit 0. 8 mm screen to Multi
Mill and pass material from
3.2
Speed – Medium
Blending SOP No.:
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
Knives - forward
4.2
20 |
Load dried granules from
4.1 into Conta Blender and
blend for 20 mins at 12+1
rpm
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Manufacturing Instructions
lubrication
 Lubrication SOP No.:
Step
Instructions
5.1
Fit 60 mesh screen to vibratory
sifter and pass
Exp 5
……….Kg
Time
start
Time
end
Perform
ed by
Verifie
d by
Date
√
√
√
√
√
√
√
√
√
√
and collect in tared double PE
lined container
5.2
21 |
Add contents from 5.1 to 4.2 and
blend for 3 mins and collect in
tared double PE lined container
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Compression
 Principle: Powder/granules are pressed inside a die and compressed by two
punches into required size, shape and embossing
Why do it
What are the equipment What are the problems
To compress powder into
tablets
Multiple Stations (Rotary)
and High Speed Tablet
Presses
Poor flow in hopper
Inadequate lubrication
Capping, chipping, cracking,
lamination, sticking, picking,
binding, mottling
Double compression
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January20-22,
18-21,2010
2012
Satish Mallya January
Manufacturing Instructions
compression
 Balance no.:
Vernier Caliper no.:
 Hardness tester no.:
Friability tester no.:
 Disintegration tester no.:
23 |
Tooling
No. of units
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
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Checked by
Verified by
Manufacturing Instructions
compression
24 |
Parameter
Limit
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
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Results
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
25 |
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Coating/Polishing
 Principle: Application of coating solution to a moving bed of tablets with concurrent
use of heated air to facilitate evaporation of solvent
Why do it
What are the equipment What are the problems
Enhance appearance and
colour
Pan (standard/perforated)
Coating Machines
Blistering, chipping,
cratering, picking, pitting
Mask taste and odour
(film/sugar)
Fluidized Bed Coating
Machines
Color variation
Roughness
Improve patient compliance
Spray Coating Machines
Improve stability
Vacuum, Dip & Electrostatic
Coating Machines
Impart enteric, delayed,
controlled release properties
26 |
January20-22,
18-21,2010
2012
Satish Mallya January
Manufacturing Instructions
coating
Step
Instructions
6.1
Introduce compressed tablets
into Auto Coater and spray
coating solution
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
Inlet air temp …….ºC (30-60ºC)
Pan speed……..rpm (2-8 rpm)
Solution rate …..ml/min (20-60
ml/min)
Distance of gun from tablet
bed……cm (20-40cm)
27 |
January20-22,
18-21,2010
2012
Satish Mallya January
January
19-22,
2011
Other Issues
 Yield:
– of lubricated granules
– of compressed tablets
– of coated tablets
 Dedusting
 Metal detection
 Scale up
 Life-cycle management
28 |
January20-22,
18-21,2010
2012
Satish Mallya January
29 |
Satish Mallya January 20-22, 2010
Thanks