1-7 Manufacturing Basics and Issues:

Solid Orals

PQP Assessment Training

January 18-21, 2012

Satish Mallya

1| Satish Mallya January

January20-22,
18-21,2010
2012
 Flow Chart
API
Filler Mixing of
screening
granulation blend

Preparation of Granulation
Binder(s) binder solution

Drying LOD

Milling

Disintegrant screening Initial Blending

lubricant screening Final Blending

Weight
Compression Hardness
Friability

Film Coating of Tablets

Solvent
Preparation Packaging
Film coating agent
and Labelling

2| Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 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

3| Satish Mallya January

January20-22,
18-21,2010
2012
 What's Good
WET GRANULATION DRY GRANULATION DIRECT COMPRESSION

Improved flow by increasing Improved flow by increasing Fewer processing steps

particle size and sphericity particle size blending and compression -
reduced processing time
Uniform distribution of API, Improved uniformity of
colour etc. improved content powder density Processing without moisture
uniformity and heat fewer stability
Improved cohesion during problems
Good for bulky powders, less compression
dust and environmental Rapid and most direct method
contamination Granulation without addition of tablet compression
of liquid
Lower compression pressure, Changes in dissolution less
less wear and tear on tooling likely on ageing since there are
less formulation variables

4| Satish Mallya January

January20-22,
18-21,2010
2012
 What's Not So Good
WET GRANULATION DRY GRANULATION DIRECT COMPRESSION

Large number of processing Possible over compaction Possibility of lot to lot variations due
steps of slugs/compacts to differences in psd, flowability and
impact on dissolution moisture of excipients
More equipment
Possible particle Higher risk of content uniformity
Wetting and drying stages segregation failure in low dose products
are time consuming (geometric granulation indicated)
Greater possibility of cross Lack of moisture can create static
contamination charges that can result in un-
blending

Differences in particle size/density

between API and excipient can result
in un-blending in hopper

5| Satish Mallya January

January20-22,
18-21,2010
2012
 Steps

Dispensing
Milling/Screening
Blending
Granulation
Drying
Compression
Coating
Packaging

6| Satish Mallya January

January20-22,
18-21,2010
2012
 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

7| Satish Mallya January

January20-22,
18-21,2010
2012
 Raw Material Dispensing Record

RM Ingredient Qty AR Gross Tare Net Wt. Weighed Checked Date

Code Kg No Wt. Wt. by by
API

Exp 1

Exp 2

Exp 3

Exp 4

Exp 5

8| Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 Considerations

Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg

Sr. AR No. Total available Actual Water Equivalent Equivalent

No quantity (as is basis) Assay content quantity on quantity on
. (Kg) (%) 100% assay as is basis
(% w/w) and nil water
(A) (B) basis (Kg) (Kg)
(C)
(D) (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

9| Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 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 - Fluid energy mill Possible change in

may enhance rate of polymorphic form
dissolution Comil
An increase in surface
Improved content uniformity Ball mill area may promote the
due to increased number of adsorption of air - may
particles per unit weight Hammer mill inhibit wetting of the drug
Cutting mill etc. could be the limiting factor
Enhanced flow properties of in dissolution rate
raw materials

Uniformly sized wet granules

promotes uniform drying

10 | Satish Mallya January

January20-22,
18-21,2010
2012
 Manufacturing Instructions
screening
Step Instructions Time Time Performed Verified Date
start end by by
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

11 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
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

Why do it What are the equipment What are the problems

To achieve optimum mixing Diffusion Mixers (V,double Segregation

of different ingredients in cone, bin,drum blenders)
powder/granules at pre Possible over mixing of
granulation and/or post Convection Mixers (ribbon, lubricant
granulation stages of planetary blenders)
tablet manufacturing Blend uniformity/ Content
Pneumatic Mixers uniformity

12 | Satish Mallya January

January20-22,
18-21,2010
2012
 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 Dry Granulator (roller Loss of material during

drug distribution in blend compactor, tabletting various stages of
machine) processing
Improves flow,
compressibility and Wet High-Shear Granulator Multiple processing steps -
hardness of tablets (horizontal, vertical) validation and control
difficult
Wet Low-Shear Granulator
(planetary, kneading, screw) Incompatibility between
formulation components is
Fluid Bed Granulator, Spray aggravated
Dry Granulator, RMG

13 | Satish Mallya January

January20-22,
18-21,2010
2012
 Manufacturing Instructions
blending & granulation
Mixing SOP No.: Granulation SOP No.:

Step Instructions Time Time Performed Verified Date

start end by by
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

14 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 Manufacturing Instructions
wet milling
Wet Milling SOP No.:

Step Instructions Time Time Performed Verified Date

start end by by
3.1 Pass wet mass through 1mm
screen of Multi Mill

Speed fast; Knives - forward

collect in FBD

15 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
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

16 | Satish Mallya January

January20-22,
18-21,2010
2012
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 | Satish Mallya January

January20-22,
18-21,2010
2012
 Drying
Purpose: To reduce the moisture level of wet granules

Why do it What are the equipment What are the problems

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

Ensure free flowing Fluid Bed Dryer

properties
Indirect Conduction
Dryers

18 | Satish Mallya January

January20-22,
18-21,2010
2012
 Manufacturing Instructions
drying
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105C)

Step Instructions Time Time Performed Verified Date

start end by by

3.2 FBD in let temp 60C

Damper 80% open for

15 min

Damper 50% open

after 15 minutes ; LOD
..%

19 | Satish Mallya January

January20-22,
18-21,2010
2012
 Manufacturing Instructions
size reduction & blending
Size reduction SOP No.: Blending SOP No.:
Step Instructions Time Time Performed Verified Date
start end by by

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

20 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 Manufacturing Instructions
lubrication
Lubrication SOP No.:

Step Instructions Time Time Perform Verifie Date

start end ed by d by

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

21 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
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 Multiple Stations (Rotary) Poor flow in hopper

tablets and High Speed Tablet
Presses Inadequate lubrication

Capping, chipping, cracking,

lamination, sticking, picking,
binding, mottling

Double compression

22 | Satish Mallya January

January20-22,
18-21,2010
2012
 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 55

shaped concave embossed.

Lower punch: mm x mm oval 55

shaped concave embossed.

Dies: mm x .mm oval shaped 1

23 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 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 4.10mm +0.15mm (3.95 4.25mm)
tabs)
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

24 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 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 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
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 Pan (standard/perforated) Blistering, chipping,

colour Coating Machines cratering, picking, pitting

Mask taste and odour Fluidized Bed Coating Color variation

(film/sugar) Machines
Roughness
Improve patient compliance Spray Coating Machines

Improve stability Vacuum, Dip & Electrostatic

Coating Machines
Impart enteric, delayed,
controlled release properties

26 | Satish Mallya January

January20-22,
18-21,2010
2012
 Manufacturing Instructions
coating
Step Instructions Time Time Performed Verified Date
start end by by

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)

27 | Satish Mallya January

January20-22,
January 18-21,2010
19-22, 2012
2011
 Other Issues

Yield:
of lubricated granules
of compressed tablets
of coated tablets

Dedusting

Metal detection

Scale up

Life-cycle management

28 | Satish Mallya January

January20-22,
18-21,2010
2012
29 | Satish Mallya January 20-22, 2010 Thanks