Satish Mallya January 20-22, 2010 1 |1 | 1-7 Manufacturing Basics and Issues: Solid Orals PQP...

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


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


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


What's GoodWhat's Good


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


What's Not So Good What's Not So Good


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


StepsSteps

Dispensing

Milling/Screening

Blending

Granulation

Drying

Compression

Coating

Packaging

January 18-21, 2012


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


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


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


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


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


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


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


GranulationGranulation

Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates


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


Manufacturing Instructions blending & granulation

Manufacturing Instructions blending & granulation

Mixing SOP No.: Granulation SOP No.:


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


Manufacturing Instructions wet milling

Manufacturing Instructions wet milling

Wet Milling SOP No.:


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


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


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


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


Manufacturing Instructions drying

Manufacturing Instructions drying

Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)


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 ……..%

√

√

√

√

√

√

√

√

√

√

January 18-21, 2012


Manufacturing Instructions size reduction & blending

Manufacturing Instructions size reduction & blending

Size reduction SOP No.: Blending SOP No.:


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


Manufacturing Instructions lubrication

Manufacturing Instructions lubrication

Lubrication SOP No.:


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


CompressionCompression

Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing


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


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




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


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


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


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


Manufacturing Instructions coating

Manufacturing Instructions coating


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


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

Satish Mallya January 20-22, 201029 | Thanks

Satish Mallya January 20-22, 2010 1 |1 | 1-7 Manufacturing Basics and Issues: Solid Orals PQP...

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Transcript of Satish Mallya January 20-22, 2010 1 |1 | 1-7 Manufacturing Basics and Issues: Solid Orals PQP...