Tablet Manufacturing Basics.ppt

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Satish Mallya January 20-22, 2010 1 |

Manufacturing Basics and Issues

Solid Orals

Manufacturing Basics and Issues

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Satish Mallya January 20-22, 2010 2 |

Flow Chart

API

Filler Mixing of granulation blend

Granulation Binder(s) _{binder solution}Preparation of

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

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Satish Mallya January 20-22, 2010 3 |

Manufacturing Methods

WET GRANULATION DRY GRANULATION

DIRECT COMPRESSION

Milling/Screening Milling/Screening

Milling/Screening

Pre-blending Pre-blending

Blending

Addition of binder Slugging/roller compaction

Compression

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

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What'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

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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

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Steps



Dispensing



Milling/Screening



Blending



Granulation



Drying



Compression



Coating



Packaging

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Satish Mallya January 20-22, 2010 7 |

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

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Satish Mallya January 20-22, 2010 8 |

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 √ √ √ √ √ √

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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

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Satish Mallya January 20-22, 2010 10 |

Milling/Screening



Principle:

Mixing or blending is more uniform if ingredients are of similar size

Why do it

What are the equipment

What 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

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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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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

Why do it

To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages of tablet 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

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Satish Mallya January 20-22, 2010 13 |

Granulation

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

Why do it

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

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Satish Mallya January 20-22, 2010 14 |

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

√ √

√

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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Manufacturing Instructions

wet milling

 Wet Milling SOP No.:

Step Instructions

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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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

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Satish Mallya January 20-22, 2010 17 |

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

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Satish Mallya January 20-22, 2010 18 |

Drying

 Purpose: To reduce the moisture level of wet granules

Why do it

What are the

equipment

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

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Satish Mallya January 20-22, 2010 19 |

Manufacturing Instructions

drying

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

Step Instructions

by Verified

by Date

3.2 FBD in let temp 60ºC

Damper 80% open for 15 min

Damper 50% open

after 15 minutes ; LOD ……..%

√

√ √

√

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Manufacturing Instructions

size reduction & blending



Size reduction SOP No.: Blending SOP No.:

Step Instructions

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

√ √

√

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Manufacturing

Instructions

lubrication

Manufacturing

Instructions

lubrication



Lubrication SOP No.

:

Step Instructions

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 √

√ √

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Satish Mallya January 20-22, 2010 22 |

Compression

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

Why do it

What 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

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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

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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

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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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Satish Mallya January 20-22, 2010 26 |

Coating/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 it

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

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Satish Mallya January 20-22, 2010 27 |

Manufacturing

Instructions

coating

Manufacturing

Instructions

coating

Step Instructions

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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Other Issues



Yield:

–

of lubricated granules

–

of compressed tablets

–

of coated tablets



Dedusting



Metal detection



Scale up



Life-cycle management

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