1-7 manufacturing basics.ppt
TRANSCRIPT
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Satish Mallya January 20-22, 20101|
1-7 Manufacturing Basics and Issues:Solid Orals
PQP Assessment Training
January 18-21, 2012
Satish Mallya
January 18-21, 2012
http://www.google.ca/imgres?imgurl=http://www.victorie-inc.us/images/incense/VictorieInc.MortarPestle.jpg&imgrefurl=http://www.victorie-inc.us/biblical_incense_ingredients_A-F.html&usg=__B13kezOfjEwoV9mNqlZi7BFpL64=&h=480&w=448&sz=46&hl=en&start=9&zoom=1&tbnid=zwv0rbnPFIGX6M:&tbnh=129&tbnw=120&ei=Wfj4TvKdJqHw0gHimcSNAg&prev=/images%3Fq%3Dimage%2Bof%2Bmortar%2Band%2Bpestle%26hl%3Den%26sa%3DX%26gbv%3D2%26tbm%3Disch&itbs=1 -
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Flow Chart
API
Filler Mixing of
granulation blend
GranulationBinder(s)Preparation of
binder solution
Drying
Milling
LOD
Disintegrant
screening
screening Initial Blending
lubricant screeningFinal 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
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Manufacturing Methods
DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION
Milling/ScreeningMilling/ScreeningMilling/Screening
BlendingPre-blendingPre-blending
CompressionSlugging/roller compactionAddition of binder
Dry screeningScreening of wet mass
Blendingof lubricantDrying of the wet granules
CompressionScreening of dry granules
Blendingof lubricant (anddisintegrant)
Compression
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What's Good
DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION
Fewer processing stepsblending and compression -
reduced processing time
Processing without moistureand heatfewer stabilityproblems
Rapid and most direct method
of tablet compression
Changes in dissolution less
likely on ageing since there areless 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 contentuniformity
Good for bulky powders, less
dust and environmental
contamination
Lower compression pressure,
less wear and tear on tooling
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What's Not So Good
DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION
Possibility of lot to lot variations due
to differences in psd, flowability and
moisture of excipients
Higher risk of content uniformityfailure in low dose products
(geometric granulation indicated)
Lack of moisture can create static
charges that can result in un-
blending
Differences in particle size/densitybetween API and excipient can result
in un-blending in hopper
Possible over compaction
of slugs/compactsimpact on dissolution
Possible particlesegregation
Large number of processing
steps
More equipment
Wetting and drying stages
are time consuming
Greater possibility of cross
contamination
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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
January 18-21, 2012
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Raw Material Dispensing Record
RMCode
Ingredient QtyKg
ARNo
GrossWt.
TareWt.
Net Wt. Weighedby
Checkedby
Date
API
Exp 1
Exp 2
Exp 3
Exp 4
Exp 5
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Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30Kg
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, 2011January 18-21, 2012
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Milling/Screening
Principle: Mixing or blending is more uniform if ingredients are of similar size
What are the problemsWhat are the equipmentWhy 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
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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 collectmaterial in tared double PE
lined container
1.2 Exp 2 Kg
Exp 3 Kg
Pass through # 20 screen ofVibratory sifter and collect
material in tared double PE
lined container
January 19-22, 2011January 18-21, 2012
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Blending
Blending is the most difficult operation in the manufacturing process since perfecthomogeneity is practically impossible due to differences in size, shape and density
of particles
What are the problemsWhat are the equipmentWhy 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
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Granulation
Principle:A size enlargement process that converts small particles into physically stronger& larger agglomerates
What are the problemsWhat are the equipmentWhy do it
Loss of material during
various stages ofprocessing
Multiple processing steps -
validation and control
difficult
Incompatibility betweenformulation components is
aggravated
Dry Granulator (roller
compactor, tablettingmachine)
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
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Manufacturing Instructions
blend ing & granulat ion
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 followingsettings: Impeller speed-fast; Chopper
speed-fast
2.2 Spray purified water into contents of RMG
Impeller speedfast; Chopper speed -fast
Peristaltic pump atomization press: 0.5-
2.5 b Spray until all purified water is
sprayed Ammeter reading18-22 amps
January 19-22, 2011January 18-21, 2012
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Manufacturing Instructions
wet mi l l ing
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
Speedfast; Knives - forward
collect in FBD
January 19-22, 2011January 18-21, 2012
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Recent Advances in Granulation Techniques
Steam Granulation: Modification of wet granulation; steam is usedas a binder instead of water; granules are more spherical andexhibit higher rate of dissolution
Melt Granulation / Thermoplastic Granulation: Granulation isachieved by the addition of meltable binder i.e. binder is in solid
state at room temperature but melts in the temperature range of 5080C [e.g. PEG (water soluble), stearic acid, cetyl or stearylalcohol (water insoluble)] - drying phase unnecessary since driedgranules are obtained by cooling them to room temperature
Moisture Activated Dry Granulation (MADG): Involves
distribution of moisture to induce agglomerationdrying time isreduced
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Recent Advances in Granulation Techniques
Moist Granulation Technique (MGT): A small amount ofgranulating 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 heatingmainly
employed for preparing direct compression formulations
Foam Granulation: Binders are added as aqueous foam
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Drying
Purpose: To reduce the mo isture level of w et granules
What are the problemsWhat are the equipmentWhy 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
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Manufacturing Instructions
dry ing
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105C)
DateVerified
by
Performed
by
Time
end
Time
start
InstructionsStep
FBD in let temp 60C
Damper 80% open for
15 min
Damper 50% open
after 15 minutes ; LOD
..%
3.2
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Manufacturing Instructionssize reduct ion & blend ing
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
SpeedMedium
Knives - forward
4.2 Load dried granules from
4.1 into Conta Blender and
blend for 20 mins at 12+1rpm
January 19-22, 2011January 18-21, 2012
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ManufacturingInstructionslubr icat ion
Lubrication SOP No.:
Step Instructions Time
start
Time
end
Perform
ed by
Verifie
d by
Date
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
January 19-22, 2011January 18-21, 2012
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Compression
Principle:Powder/granules are pressed inside a die and c ompressed by tw o
pun ches into required size, shape and embos sing
What are the problemsWhat are the equipmentWhy 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
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ManufacturingInstructionscompress ion
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 ovalshaped concave embossed.
55
Lower punch: mm x mm ovalshaped concave embossed.
55
Dies: mm x .mm oval shaped 1
January 19-22, 2011January 18-21, 2012
http://www.google.ca/imgres?imgurl=http://www.rotarytabletpress.com/images/rotarytablet_press_%2520machine1.jpg&imgrefurl=http://www.rotarytabletpress.com/Products.htm&usg=__8QMh2eRwo-kDdkHx_ZPioWABGJs=&h=206&w=165&sz=23&hl=en&start=10&zoom=1&tbnid=L1t6pTfXZ3oEUM:&tbnh=105&tbnw=84&prev=/images%3Fq%3Dtabletting%2Bmachine%26hl%3Den%26sa%3DX%26tbs%3Disch:1&itbs=1http://www.google.ca/imgres?imgurl=http://www.indusealing.com/pics/prod5.gif&imgrefurl=http://www.indusealing.com/tabletting_machine.htm&h=232&w=289&sz=19&tbnid=hiC9oQ8HE_ImdM:&tbnh=92&tbnw=115&prev=/images%3Fq%3Dtabletting%2Bmachine&zoom=1&q=tabletting+machine&hl=en&usg=__y3Rz6sGNhdt0Ghaf76IpJZVvxTU=&sa=X&ei=2iwiTZfwDtOcnweLw7TEDg&ved=0CBQQ9QEwAg -
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ManufacturingInstructionscompress ion
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 10tabs)
4.10mm +0.15mm (3.954.25mm)
Length 10mm + 0.1 mm (9.910.1 mm)
Width 5 mm + 0.1mm (4.95.1 mm)
Disintegration time NMT 15 mins
Wt. variation + 3% of Av. Wt.
Friability (10 tabs) NMT 1.0% w/w
January 19-22, 2011January 18-21, 2012
http://www.google.ca/imgres?imgurl=http://www.indusealing.com/pics/prod5.gif&imgrefurl=http://www.indusealing.com/tabletting_machine.htm&h=232&w=289&sz=19&tbnid=hiC9oQ8HE_ImdM:&tbnh=92&tbnw=115&prev=/images%3Fq%3Dtabletting%2Bmachine&zoom=1&q=tabletting+machine&hl=en&usg=__y3Rz6sGNhdt0Ghaf76IpJZVvxTU=&sa=X&ei=2iwiTZfwDtOcnweLw7TEDg&ved=0CBQQ9QEwAghttp://www.google.ca/imgres?imgurl=http://www.rotarytabletpress.com/images/rotarytablet_press_%2520machine1.jpg&imgrefurl=http://www.rotarytabletpress.com/Products.htm&usg=__8QMh2eRwo-kDdkHx_ZPioWABGJs=&h=206&w=165&sz=23&hl=en&start=10&zoom=1&tbnid=L1t6pTfXZ3oEUM:&tbnh=105&tbnw=84&prev=/images%3Fq%3Dtabletting%2Bmachine%26hl%3Den%26sa%3DX%26tbs%3Disch:1&itbs=1 -
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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: App l icat ion of coat ing solut ion to a movin g bed of tablets with concu rrent
us e of heated air to faci l i tate evaporat ion o f solv ent
What are the problemsWhat are the equipmentWhy do it
Blistering, chipping,
cratering, picking, pitting
Color variation
Roughness
Pan (standard/perforated)
Coating Machines
Fluidized Bed Coating
Machines
Spray Coating Machines
Vacuum, Dip & ElectrostaticCoating 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
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ManufacturingInstructionscoat ing
Step Instructions Timestart Timeend Performedby Verifiedby Date
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)
January 19-22, 2011January 18-21, 2012
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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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