Solid Orals - libvolume6.xyzlibvolume6.xyz/medicine/bpharm/semester5/pharmaceutics4/...Solid Orals...

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


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


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


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


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


Steps Steps

� Dispensing

� Milling/Screening

� Blending

� Granulation

� Drying

� Compression

� Coating

� Packaging

January 18-21, 2012


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


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


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


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


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

√

√

√

√

√

January 19-22, 2011 January 18-21, 2012


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


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


Manufacturing Instructions blending & granulation

Manufacturing Instructions blending & granulation

� Mixing SOP No.: Granulation SOP No.:


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

√

√

√

√

√

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

√

√

√

√

√

January 19-22, 2011 January 18-21, 2012


Manufacturing Instructions wet milling

Manufacturing Instructions wet milling

� Wet Milling SOP No.:


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

√

√

√

√

√

January 19-22, 2011 January 18-21, 2012


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


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


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


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

√

√

√

√

√

√

√

√

√

√

FBD in let temp 60ºC

Damper 80% open for 15 min

Damper 50% open after 15 minutes ; LOD ……..%

3.2

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

4.1 Fit 0. 8 mm screen to Multi Mill and pass material from 3.2

Speed – Medium

Knives - forward

√

√

√

√

√

4.2 Load dried granules from 4.1 into Conta Blender and blend for 20 mins at 12+1 rpm

√

√

√

√

√

January 19-22, 2011 January 18-21, 2012


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

√

√

√

√

√

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, 2011 January 18-21, 2012


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


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




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


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


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


Manufacturing Instructions coating

Manufacturing Instructions coating


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)

√

√

√

√

√

January 19-22, 2011 January 18-21, 2012


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

Satish Mallya January 20-22, 2010 29 | ThanksThanksThanksThanks

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