1-7 Manufacturing Basics and Issues:

Solid Orals

PQP Assessment Training

January 18-21, 2012
Satish Mallya

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Flow Chart
API
Filler

screening

Mixing of
granulation blend

Binder(s)

Preparation of
binder solution

Granulation
Drying

LOD

Milling

Disintegrant

screening

Initial Blending

lubricant

screening

Final Blending

Compression

Film Coating of Tablets

Solvent
Film coating agent

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Preparation

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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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What's Good
WET GRANULATION

DRY GRANULATION

DIRECT COMPRESSION

Improved flow by increasing

particle size and sphericity

Improved flow by increasing

particle size

Uniform distribution of API,

colour etc. improved content
uniformity

Improved uniformity of
powder density

Fewer processing steps

blending and compression
-reduced processing time

Good for bulky powders, less

dust and environmental
contamination
Lower compression pressure,
less wear and tear on tooling

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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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Steps
Dispensing
Milling/Screening
Blending
Granulation
Drying
Compression
Coating
Packaging

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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

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Raw Material Dispensing Record

RM
Code

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Ingredient

Qty
Kg

AR
No

API

Exp 1

Net Wt.

Weighed
by

Checked
by

Date

Exp 2

Exp 3

Exp 4

Exp 5

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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
(%)

(A)

(B)

Water
content
(% w/w)
(C)

Equivalent
quantity on
100% assay
and nil water
basis (Kg)

Equivalent
quantity on
as is basis

(D)

(E)

(Kg)

AP-18

23.50

99.4

0.34

23.28

AP-22

60.00

99.1

0.50

6.72

6.815

E 30.00

E 30.315

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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

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

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Comil

Hammer mill

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

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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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

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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)

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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)
Fluid Bed Granulator, Spray
Dry Granulator, RMG

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Incompatibility between
formulation components is
aggravated

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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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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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
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

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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

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Drying
Purpose: To reduce the moisture level of wet granules

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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

Over drying (bone dry)

Ensure free flowing

properties

Fluid Bed Dryer

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Direct Heating Moving

Solids Bed Dryers

Indirect Conduction
Dryers

Excess fines
Possible fire hazard

Manufacturing Instructions
drying
Drying SOP No.:

LOD: 1.0-2.5% (moisture balance at 105C)

Step

Instructions

Time
start

Time
end

Performed
by

Verified
by

Date

3.2

FBD in let temp 60C

Damper 80% open for

15 min

Damper 50% open

after 15 minutes ; LOD
..%

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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

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Load dried granules from

4.1 into Conta Blender and
blend for 20 mins at 12+1
rpm

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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

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Add contents from 5.1 to 4.2 and

blend for 3 mins and collect in
tared double PE lined container

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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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Manufacturing Instructions
compression
Balance no.:

Vernier Caliper no.:

Hardness tester no.:

Friability tester no.:

Disintegration tester no.:

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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

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Checked by

Verified by

Manufacturing Instructions
compression

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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

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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

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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

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

Improve patient compliance

Spray Coating Machines

Improve stability

Vacuum, Dip & Electrostatic

Coating Machines

Impart enteric, delayed,

controlled release properties

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Roughness

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 .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)

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Other Issues
Yield:
of lubricated granules
of compressed tablets
of coated tablets
Dedusting
Metal detection
Scale up
Life-cycle management

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29 |

Satish Mallya January 20-22, 2010

Thanks