Satish Mallya January 20- 22, 2010 1 | 1-7 Manufacturing Basics and Issues: Solid Orals PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21, 2012
Dec 22, 2015
Satish Mallya January 20-22, 20101 |
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, 20102 |
Flow ChartFlow Chart
APIFiller Mixing of
granulation blend
GranulationBinder(s)Preparation of binder solution
Drying
Milling
LOD
Disintegrant
screening
screening Initial Blending
lubricant screening Final Blending
Compression
SolventFilm coating agent Preparation
Film Coating of Tablets
Packaging and Labelling
WeightHardnessFriability
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 20103 |
Manufacturing MethodsManufacturing Methods
WET GRANULATIONDRY GRANULATIONDIRECT COMPRESSION
Milling/ScreeningMilling/ScreeningMilling/Screening
Pre-blendingPre-blendingBlending
Addition of binderSlugging/roller compactionCompression
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
January 18-21, 2012
Satish Mallya January 20-22, 20104 |
What's GoodWhat's Good
WET GRANULATIONDRY GRANULATIONDIRECT COMPRESSION
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
Improved flow by increasing particle size
Improved uniformity of powder density
Improved cohesion during compression
Granulation without addition of liquid
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
January 18-21, 2012
Satish Mallya January 20-22, 20105 |
What's Not So Good What's Not So Good
WET GRANULATIONDRY GRANULATIONDIRECT COMPRESSION
Large number of processing steps
More equipment
Wetting and drying stages are time consuming
Greater possibility of cross contamination
Possible over compaction of slugs/compacts – impact on dissolution
Possible particle segregation
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
January 18-21, 2012
Satish Mallya January 20-22, 20106 |
StepsSteps
Dispensing
Milling/Screening
Blending
Granulation
Drying
Compression
Coating
Packaging
January 18-21, 2012
Satish Mallya January 20-22, 20107 |
DispensingDispensing
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, 20108 |
Raw Material Dispensing Record Raw Material Dispensing Record
RM Code
IngredientQty 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, 2011January 18-21, 2012
Satish Mallya January 20-22, 20109 |
ConsiderationsConsiderations
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)
1AP-1823.5099.40.34 23.28 23.50
2AP-2260.0099.10.50 6.72 6.815
∑E 30.00∑E 30.315
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201010 |
Milling/ScreeningMilling/Screening
Principle: Mixing or blending is more uniform if ingredients are of similar size
Why do itWhat are the equipmentWhat are the problems
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
Fluid energy mill
Comil
Ball mill
Hammer mill
Cutting mill etc.
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
January 18-21, 2012
Satish Mallya January 20-22, 201011 |
Manufacturing Instructionsscreening
Manufacturing Instructionsscreening
StepInstructionsTime start
Time end
Performed by
Verified by
Date
1.1API …… Kg
Exp 1 …… Kg
Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container
√√√√√
1.2Exp 2 …… Kg
Exp 3 …… Kg
Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container
√√√√√
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201012 |
BlendingBlending
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 itWhat are the equipmentWhat are the problems
To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages oftablet manufacturing
Diffusion Mixers (V,double cone, bin,drum blenders)
Convection Mixers (ribbon, planetary blenders)
Pneumatic Mixers
Segregation
Possible over mixing of lubricant
Blend uniformity/ Content uniformity
January 18-21, 2012
Satish Mallya January 20-22, 201013 |
GranulationGranulation
Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates
Why do itWhat are the equipmentWhat are the problems
Provides homogeneity of drug distribution in blend
Improves flow, compressibility and hardness of tablets
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
Loss of material during various stages of processing
Multiple processing steps -validation and control difficult
Incompatibility between formulation components is aggravated
January 18-21, 2012
Satish Mallya January 20-22, 201014 |
Manufacturing Instructions blending & granulation
Manufacturing Instructions blending & granulation
Mixing SOP No.: Granulation SOP No.:
StepInstructionsTime start
Time end
Performed by
Verified by
Date
2.1Load 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
√√√√√
2.2Spray 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
√√√√√
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201015 |
Manufacturing Instructions wet milling
Manufacturing Instructions wet milling
Wet Milling SOP No.:
StepInstructionsTime start
Time end
Performed by
Verified by
Date
3.1Pass wet mass through 1mm screen of Multi Mill
Speed – fast; Knives - forward
collect in FBD
√√√√√
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201016 |
Recent Advances in Granulation TechniquesRecent 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, 201017 |
Recent Advances in Granulation TechniquesRecent 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, 201018 |
DryingDrying
Purpose: To reduce the moisture level of wet granules
Why do itWhat are the equipment
What are the problems
To keep the residual moisture low enough (preferably as a range) to prevent product deterioration
Ensure free flowing properties
Direct Heating Static Solids Bed Dryers
Direct Heating Moving Solids Bed Dryers
Fluid Bed Dryer
Indirect Conduction Dryers
Over drying (bone dry)
Excess fines
Possible fire hazard
January 18-21, 2012
Satish Mallya January 20-22, 201019 |
Manufacturing Instructions drying
Manufacturing Instructions drying
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)
StepInstructionsTime start
Time end
Performed by
Verified by
Date
3.2FBD in let temp 60ºC
Damper 80% open for 15 min
Damper 50% open after 15 minutes ; LOD ……..%
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√
√
√
√
√
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January 18-21, 2012
Satish Mallya January 20-22, 201020 |
Manufacturing Instructions size reduction & blending
Manufacturing Instructions size reduction & blending
Size reduction SOP No.: Blending SOP No.:
StepInstructionsTime start
Time end
Performed by
Verified by
Date
4.1Fit 0. 8 mm screen to Multi Mill and pass material from 3.2
Speed – Medium
Knives - forward
√√√√√
4.2Load dried granules from 4.1 into Conta Blender and blend for 20 mins at 12+1 rpm
√√√√√
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201021 |
Manufacturing Instructions lubrication
Manufacturing Instructions lubrication
Lubrication SOP No.:
StepInstructionsTime start
Time end
Performed by
Verified by
Date
5.1Fit 60 mesh screen to vibratory sifter and pass
Exp 5 ……….Kg
and collect in tared double PE lined container
√√√√√
5.2Add 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
Satish Mallya January 20-22, 201022 |
CompressionCompression
Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing
Why do itWhat are the equipmentWhat 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
January 18-21, 2012
Satish Mallya January 20-22, 201023 |
Manufacturing Instructions compression
Manufacturing Instructions compression
Balance no.: Vernier Caliper no.:
Hardness tester no.: Friability tester no.:
Disintegration tester no.:
ToolingNo. of unitsChecked byVerified 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 shaped1
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201024 |
Manufacturing Instructions compression
Manufacturing Instructions compression
ParameterLimitResults
Machine speed20 rpm (15-25 rpm)
Wt. of 20 tabs12.00g +2 (11.76-12.24g)
Theoretical weight/tab600mg
Hardness25Kg (20-30 Kg)
Thickness (av. of 10 tabs)
4.10mm +0.15mm (3.95 – 4.25mm)
Length10mm + 0.1 mm (9.9 – 10.1 mm)
Width5 mm + 0.1mm (4.9 – 5.1 mm)
Disintegration timeNMT 15 mins
Wt. variation+ 3% of Av. Wt.
Friability (10 tabs)NMT 1.0% w/w
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201025 |
In-process ChecksIn-process Checks
ParameterFrequency
Wt. of 20 tabsEvery hour by production and every two hours by QA
Hardness, thickness, length, widthEvery hour by production, every two hours by QA
Wt. variationEvery half hour by production and every hour by QA
DTEvery half hour by production, every hour by QA
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201026 |
Coating/PolishingCoating/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 itWhat are the equipmentWhat are the problems
Enhance appearance and colour
Mask taste and odour (film/sugar)
Improve patient compliance
Improve stability
Impart enteric, delayed, controlled release properties
Pan (standard/perforated) Coating Machines
Fluidized Bed Coating Machines
Spray Coating Machines
Vacuum, Dip & Electrostatic Coating Machines
Blistering, chipping, cratering, picking, pitting
Color variation
Roughness
January 18-21, 2012
Satish Mallya January 20-22, 201027 |
Manufacturing Instructions coating
Manufacturing Instructions coating
StepInstructionsTime start
Time end
Performed by
Verified by
Date
6.1Introduce 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)
√√√√√
January 19-22, 2011January 18-21, 2012
Satish Mallya January 20-22, 201028 |
Other IssuesOther Issues
Yield:– of lubricated granules– of compressed tablets– of coated tablets
Dedusting
Metal detection
Scale up
Life-cycle management
January 18-21, 2012