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Solid Orals
Satish Mallya
1| January
Satish Mallya January 18-21,
20-22, 20102012
Flow Chart
API
Filler screening Mixing of
granulation blend
Preparation of Granulation
Binder(s) binder solution
Drying LOD
Milling
Weight
Compression Hardness
Friability
Solvent
Preparation Packaging
Film coating agent
and Labelling
2| January
January
Satish Mallya January 19-22,
20102011
18-21,
20-22, 2012
Manufacturing Methods
WET GRANULATION DRY GRANULATION DIRECT COMPRESSION
3| January
Satish Mallya January 18-21,
20-22, 20102012
What's Good
WET GRANULATION DRY GRANULATION DIRECT COMPRESSION
4| January
Satish Mallya January 18-21,
20-22, 20102012
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)
5| January
Satish Mallya January 18-21,
20-22, 20102012
Steps
Dispensing
Milling/Screening
Blending
Granulation
Drying
Compression
Coating
Packaging
6| January
Satish Mallya January 18-21,
20-22, 20102012
Dispensing
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| January
Satish Mallya January 18-21,
20-22, 20102012
Raw Material Dispensing Record
Exp 1
Exp 2
Exp 3
Exp 4
Exp 5
8| January
Satish Mallya January
January 18-21,
20-22, 2010
19-22, 2012
2011
Considerations
E 30.00 E 30.315
9| January
Satish Mallya January
January 18-21,
20-22, 2010
19-22, 2012
2011
Milling/Screening
Principle: Mixing or blending is more uniform if ingredients are of similar size
10 | January
Satish Mallya January 18-21,
20-22, 20102012
Manufacturing Instructions
screening
Step Instructions Time Time Performed Verified Date
start end by by
1.1 API Kg
Exp 1 Kg
1.2 Exp 2 Kg
Exp 3 Kg
11 | January
Satish Mallya January
January 18-21,
20-22, 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
12 | January
Satish Mallya January 18-21,
20-22, 20102012
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
13 | January
Satish Mallya January 18-21,
20-22, 20102012
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
14 | January
Satish Mallya January
January 18-21,
20-22, 2010
19-22, 2012
2011
Manufacturing Instructions
wet milling
Wet Milling SOP No.:
collect in FBD
15 | January
Satish Mallya January
January 18-21,
20-22, 2010
19-22, 2012
2011
Recent Advances in Granulation Techniques
16 | January
Satish Mallya January 18-21,
20-22, 20102012
Recent Advances in Granulation Techniques
17 | January
Satish Mallya January 18-21,
20-22, 20102012
Drying
Purpose: To reduce the moisture level of wet granules
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
18 | January
Satish Mallya January 18-21,
20-22, 20102012
Manufacturing Instructions
drying
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105C)
19 | January
Satish Mallya January 18-21,
20-22, 20102012
Manufacturing Instructions
size reduction & blending
Size reduction SOP No.: Blending SOP No.:
Step Instructions Time Time Performed Verified Date
start end by by
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 | January
Satish Mallya January
January 18-21,
20-22, 2010
19-22, 2012
2011
Manufacturing Instructions
lubrication
Lubrication SOP No.:
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 | January
Satish Mallya January
January 18-21,
20-22, 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
Double compression
22 | January
Satish Mallya January 18-21,
20-22, 20102012
Manufacturing Instructions
compression
Balance no.: Vernier Caliper no.:
23 | January
Satish Mallya January
January 18-21,
20-22, 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 | January
Satish Mallya January
January 18-21,
20-22, 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 | January
Satish Mallya January
January 18-21,
20-22, 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
26 | January
Satish Mallya January 18-21,
20-22, 20102012
Manufacturing Instructions
coating
Step Instructions Time Time Performed Verified Date
start end by by
27 | January
Satish Mallya January
January 18-21,
20-22, 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 | January
Satish Mallya January 18-21,
20-22, 20102012
29 | Satish Mallya January 20-22, 2010 Thanks