1-7 Manufacturing Basics.ppt

8/11/2019 1-7 Manufacturing Basics.ppt

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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

January 18-21, 2012


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What's Good


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

January 18-21, 2012


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What's Not So Good


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

January 18-21, 2012


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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


8/29Satish Mallya January 20-22, 20108|

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

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


9/29Satish Mallya January 20-22, 20109|

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
http://www.ecvv.com/product/989333.html


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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


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


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Granulation

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


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

January 18-21, 2012


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blend ing & granulat ion

Mixing SOP No.: Granulation SOP No.:


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
http://www.google.ca/imgres?imgurl=http://www.sunnyengineers.com/products/fluid_bed_dryer.jpg&imgrefurl=http://www.sunnyengineers.com/products.htm&usg=__muUfmdcholYRqXj0XNFHxKS8tto=&h=221&w=180&sz=10&hl=en&start=78&zoom=1&tbnid=TO_r_QjkvaoTXM:&tbnh=107&tbnw=87&prev=/images%3Fq%3Drapid%2Bmixer%2Bgranulator%26start%3D60%26hl%3Den%26sa%3DN%26tbs%3Disch:1&itbs=1


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wet mi l l ing

Wet Milling SOP No.:


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
http://product-image.tradeindia.com/00161388/b/0/Fluid-Bed-Dryer.jpghttp://product-image.tradeindia.com/00161388/b/0/Fluid-Bed-Dryer.jpghttp://www.google.ca/imgres?imgurl=http://pharmac.in/images/img_multi_mill.jpg&imgrefurl=http://pharmac.in/pharma_machines/tablet_machinery/multi_mill.htm&h=303&w=226&sz=11&tbnid=cioUoK4wCYTAPM:&tbnh=116&tbnw=87&prev=/images%3Fq%3Dmulti%2Bmill&zoom=1&q=multi+mill&hl=en&usg=__8H91wP5SEJFVuGsVyJ1PIYQoFg8=&sa=X&ei=w5MgTezTA8r8nAfKnMDbDQ&ved=0CBkQ9QEwAw


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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

January 18-21, 2012


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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

January 18-21, 2012


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Drying

Purpose: To reduce the mo isture level of w et granules


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


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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

January 18-21, 2012


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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
http://www.google.ca/imgres?imgurl=http://pharmac.in/images/img_multi_mill.jpg&imgrefurl=http://pharmac.in/pharma_machines/tablet_machinery/multi_mill.htm&h=303&w=226&sz=11&tbnid=cioUoK4wCYTAPM:&tbnh=116&tbnw=87&prev=/images%3Fq%3Dmulti%2Bmill&zoom=1&q=multi+mill&hl=en&usg=__8H91wP5SEJFVuGsVyJ1PIYQoFg8=&sa=X&ei=w5MgTezTA8r8nAfKnMDbDQ&ved=0CBkQ9QEwAw


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ManufacturingInstructionslubr icat ion

Lubrication SOP No.:


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


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
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

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

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


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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


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

f


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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

January 18-21, 2012


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Satish Mallya January 20-22 201029| h nks

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1-7 Manufacturing Basics.ppt