Satish Mallya January 20-22, 2010 1 |
1-7 Manufacturing Basics and Issues: Solid Orals
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 2 |
Flow Chart 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 3 |
Manufacturing Methods 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 4 |
What's Good 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 5 |
What's Not So Good 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 6 |
Steps Steps
� Dispensing
� Milling/Screening
� Blending
� Granulation
� Drying
� Compression
� Coating
� Packaging
January 18-21, 2012
Satish Mallya January 20-22, 2010 7 |
Dispensing 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 8 |
Raw Material Dispensing Record 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 9 |
Considerations 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 10 |
Milling/Screening 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 11 |
Manufacturing Instructions screening
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
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√
January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 12 |
Blending 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 13 |
Granulation
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 14 |
Manufacturing Instructions blending & granulation
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
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√
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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
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January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 15 |
Manufacturing Instructions wet milling
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
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January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 16 |
Recent Advances in Granulation Techniques 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
January 18-21, 2012
Satish Mallya January 20-22, 2010 17 |
Recent Advances in Granulation Techniques 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 18 |
Drying 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 19 |
Manufacturing Instructions drying
Manufacturing Instructions drying
� Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)
Date
Verified by
Performed by
Time end
Time start
Instructions
Step
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FBD in let temp 60ºC
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 20 |
Manufacturing Instructions size reduction & blending
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
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4.2 Load dried granules from 4.1 into Conta Blender and blend for 20 mins at 12+1 rpm
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January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 21 |
Manufacturing Instructions lubrication
Manufacturing Instructions lubrication
� Lubrication SOP No.:
Step Instructions Time
start Time end
Performed by
Verified by
Date
5.1 Fit 60 mesh screen to vibratory sifter and pass
Exp 5 ……….Kg
and collect in tared double PE lined container
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5.2 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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January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 22 |
Compression 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 23 |
Manufacturing Instructions compression
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 24 |
Manufacturing Instructions compression
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 25 |
In-process Checks 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 26 |
Coating/Polishing 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 27 |
Manufacturing Instructions coating
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 …….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)
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January 19-22, 2011 January 18-21, 2012
Satish Mallya January 20-22, 2010 28 |
Other Issues Other Issues
� Yield:
– of lubricated granules
– of compressed tablets
– of coated tablets
� Dedusting
� Metal detection
� Scale up
� Life-cycle management
January 18-21, 2012