Presented By:-

Sourav Mainan

1st M.Pham

Dept. Of Pharmaceutics.

PES College Of Pharmacy,

Bangalore.

Facilitated By:Dr. Manjula TalluriProfessorDept. Of PharmaceuticsPES College Of Pharmacy,Bangalore

CONTENTS

DEFINITION OF PAT

INTRODUCTION OF PAT

PURPOSE OF PAT

ADVANTAGE OF PAT

DISADVANTAGE OF PAT

GENERAL AUTOMATIC CONTROL SYSTEM

AUTOMATIC CONTROLLER

PROCESS CONTROL COMPUTER PROCESS MEASUREMENT LEVEL MEASUREMENT PHYSICAL PROPERTY MEASUREMENT PROCESS CHEMICAL COMPOSITION ANALYZER ELECTRO ANALYTICAL INSTRUMENTS AUTOMATION IN TABLET MANUFACTURING TABLETING IMPROVEMENT SUPAC LEVEL OF CHANGES TYPES OF SUPACMAUFACTURING SITEMANUFACTURING CHANGES SUPAC LIMITATION REFERENCES

DEFINITION

PROCESS AUTOMATION TECHNOLOGY (PAT) is considered to be a technology for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

INTRODUCTIONAutomation Means the use of machines and the equipments for the performing

physical and menatal operation in a production processing place of human being.

Is a system of doing work where material handling , production process and product design are integrated through mechanism of thoughts and effort to achieve a set regulating and control system.

Is the result of industrialization, driven by the need to increase productivity and to archive consisting quality product.

It can be done various levels of manufacturing system-

Handling of raw materials , semi finished goods and finished goods

During the production process(efficient machine are used)

In inspection and quality control operation

PURPOSE OF PAT

To Increase Productivity

Reliving from heavy work load

Improve quality of products & reduce waste

For safe handling of Hazardous

substances

To reduce the cost

Pharmaceutical industry is hybrid of both process and discrete manufacturing .Process automation system applies in the primary

manufacturing of API(Active Pharmaceutical Ingredients)

Both process and discrete automation are applied in the secondary manufacturing formulation and packing(i.e. in compounding , filling and packing).

ADVANTAGES It provides better quality of goods and service.

It minimizes the total cost ,in direct labor cost.

It provides effective control in operation.

Greater accuracy, more output and greater speed are induced.

It can improve a better working condition.

Safety of workers is improved.

Minimal of wastage is done.

The quality of product improves as human input is minimized.

DISADVANTAGESHuge capital investment is required.

The maintenance cost is very high because maintenance labor of high caliber is required.

It can create unemployment.

Continuous power supply is required.

Large inventories are required.

Any breakdown, anywhere lead to the complete break down.

There are restrictions in designing and construction of the building.

GENERAL AUTOMATIC CONTROL SYSTEM-

In heat exchange process-

In this process, the in flowing liquid is to be heated to the required

temperature steam flowing through heating coils.

The temperature of exit flow is affected by the processes variable such

as-temperature and flow rate of the flowing liquid, temperature and flow

rate of the steam, heat capacity of the fluids, and heat loss from the

vessel and mixer speed.

Liquid to be heated Mixer Temperature to beccc controlled

Condensate

Valve

Steam

Liquid flow out

Type of system in heat exchange process-

Open loop system

Closed loop control system-

Feed back control system

Feed forward control system

Open loop system-Are those in which information about the controlled variable (like

temperature ) is not used to adjust any of the system inputs tocompensate for variation in the processes variables.

Closed loop feed back system

In this system, information about the controlled variables is feed back asthe basis for control of a process variable by a human operator (manualcontrol) or by use of instruments (automatic control).

In manual control system an operator periodically measures the

temperature of liquid. If for example, the temperature is below the

desired value, he increases the steam flow by opening the valve slightly.

For automatically controlled system a temperature sensitive device isused to produce a signal proportional to the measured temperature .Thissignal is feed to controller which compare it with a preset desired valve(set point ). If differences exist, the controller changes the opening of thesteam control valve to correct the temperature.

Closed loop feed forward control

In this process disturbances are measured and compensated

without waiting for a change in the controlled variable to

indicate that a disturbance has occurred.

This type of control is useful when the final controlled variable

can not be used.

AUTOMATIC CONTROLLERS

Industrial automatic process controller varies from simple on off device to

special purpose computing instruments.

Four general type of controllers-

1) Self operated controller-

On off controllers

Proportional controller

2) Electronic controller

3) Pneumatic controller

4) Miscellaneous controller – Hydraulic, fluidic and special response controller.

1)Self operated controllers- Some control systems obtain the power require to operate the error detector and final control element from the controller medium of the process by way of the sensing element .such controller are self operated controller , used for temperature and pressure controller .

There are two type of self operated controller –

On off controller – in this controller, the amount of control action applied at the process input is either zero or the maximum available.

Proportional controllers- The action of a proportional controller is smooth and continuous over the operating range.

For example In a steam-heated process vessel, if the temperature to be controlled increase above the set point, the controller output well increase a proportional amount. This output may reduce the amount of heat being added.

2) Electronic controllers- Are extensively used for process control .

The reason for their increase usage are-

solid state circuit

Easier servicing

Smaller particle size

can easily be linked with process control computer

cost completive compare to pneumatic controller

may be more accurately tuned.

3) Pneumatic controllers- Its basic purpose is to supply compressed air to a pneumatic valve actuator in response to an error signal, based on the deviation of measured variable from the set point.

PROCESS CONTROL COMPUTER

in the hierarchy of computer control of a process. Four levels can be identified-1) unit operation control2) unit process control3) plant control4) Departmental and corporate control level of a company.

Without computer control at the plant or unit process level, the study state plant operating period tend to become several days.

Process control computer- analog computer & Digital computer

1. Analog computer

2. Digital computer

Analog computers- represents the numbers beingmanipulated by the magnitude of a physical quantity, such asvolts or pressure. Mathematically operations are carried out ina continuous manner.

Digital computers- are counting device that operatesdirectly on numbers to perform the four fundamentalmathematical operation addition, subtraction, multiplication,and division.

PROCESS MEASUREMENT

Instrument for Measuring Vacuum :

Compression gauge- Simple manometer.

Thermal conductivity (Pirani type) gauge.

Ionization gauge

Diaphragm gauges

Radiometer gauges

TEMPERATURE MEASUREMENT

THERMOCOUPLES

RESISTANCE THRMOMETERS

FILLED IN THERMOMETERS

BIMETAL THERMOMETER

LIQUID IN GLASS THERMOMETERS

PYROMETER

PRESSURE MEASUREMENT DEVICES

THREE TYPES

Based on measurement of height of liquid column.

Based on measurement of the distortion of an elastic

pressure chamber.

Electrical sensing devices.

LEVEL MEASUREMENT This may be defined as the determination of the location of the

interface between two fluids separated by gravity, with respect to a fixed datum plate .the most common level measurement is that of the interface between a liquid & gas.

Types of devices1-Visual types2- Float actuated types3- Displacer type.4- Head devices.5- miscellaneous.

PHYSICAL PROPERTY MEASUREMENT these include measurement of

1. Density & specific gravity.2. Viscosity & consistency.3. Refractive index.4. Thermal conductivity.5. Boiling point.6. Flash point.

PROCESS CHEMICAL-COMPOSITION ANALYZERS

1. Chromatographic analyzers.2. Infrared analyzers.3. U.V. & visible radiation analyzers.4. Turbid metric analyzer.5. Paramagnetic & nephelometric analyzer.

ELECTRO ANALYTICAL INSTRUMENTS1. Conductometric analysis.2. Oscillometric analysis.3. Potentiometric analysis.4. Measurement of pH.5. Polar graphic analysis.

AUTOMATION IN TABLET MANUFACTURING

Benefits of automation in tablet production

Improve material handling.

Improve specific unit operation- Unit operations in tablet manufacturing-

Particle size reduction

Sieving

Mixing.

Particle size enlargement.

Drying.

Compression.

Sorting.

Coating.

Packaging.

Eliminate or combine processing steps.

Incorporate automated process control of unit operation and processes.

MATERIAL HANDLINGBASIC PRINCIPLE

1. Short distances2. Short terminal times3. Two way pay load4. Avoid partial loads5. Avoid manual handling6. Move scrap cheaply.7. Gravity is cheapest power8. Move in straight lines9. Unit loads10. Label thoroughly

MATERIAL HANDLING

RISKS-:

1.Customer dissatisfaction.2. Increased product cost.3. Employee safety liabilities.

Examples of material handling improvementGranulation and tableting sections of the computer controlled tablet manufacturing process by Merck Sharp & Dohme (MSD) and Eli lily and company.

Advantages Of Material Handling

1. No human handling of material2. The system is built in 3 story building which incorporate vertical drops to utilize gravity whenever possible and uses pumps, vacuum, bucket conveyors to move material upward whenever necessary.

Processing step combination or elimination

Wet granulation (standard processing steps)

Standard processing steps -Load processer Weighingredients Mix, mass, agglomerate, dry lubricateTransfer ,Continuous batch powder mixing and massingequipment.

E.g. Dionsa mixer & granulator is a high – shear powdermixer and processor.

Fluid -bed spray granulators

• A suction fan generates air flow necessary for fluidization of powder.

• Air heater to heat the air to desired temperature.• Air is drawn through pre filter to remove any impurities• Material to be processed kept in container just below the spray

inlet.• The liquid granulating agent is pumped from its container & is

sprayed as a fine mist through a spray head onto a fluidized powder.

• Exhaust filters are mounted above the product retainer to retain

dust and fine particles.

Advantages of Fluid-spray Granulator

capable of processing approximately 200Kg per batch.

Rapid wet massing, agglomeration, & drying within one unit.Process can be completed within 60-90 min.

Direct compression (new process)

1. Raw materials.

2. Weighing and measuring (automatic weigher and recording system).3. Gravity feeding.4. Compression (high speed rotary press).5. Aqueous coating (Hi coater).

TABLETING IMPROVEMENT

Thomas Tablet Sentinel (TTS)-: is an automatically controlled tablet production unit with an online control & monitoring of tablet weight.This unit utilizes commonly available strain gage technology. strain gage placed on a tablet machine monitor the strain that is incurred during the compression step on the machine.The amount of pressure or compression force developed at each station is dependent upon the amount of powder that was contained in each corresponding die.Measurement of this compression force is thus an indirect method of monitoring the tablet weight.

Latest monitoring system TTS II –element of this unit

1. The sensing system.2. The weight control system.3. The reject control system.4. A tablet counting system.5. A defective tablet counter.6. Printer for recording.

CONTINUED………….

The weight control system of TTS-II is equipped with an audible signal to alert the operator when a machine drift out of present limits, as well as automatic press shutdown after a chosen no. of rejected tablet have been observed by the system.

CAPACITY-: To compress up to 12000 tablets per minute .If the rejection system is used then maximum rate of tablet preparation is 8000.The printing unit records time and tablet count & if tablet are rejected , the rejection appear in red print rather than the normal black print.

TTS III: - have advanced sampling & microprocessor technology.

Functional feature of TTS III1. Maintaining compression forces within preset limits.2. Automated adjustment.3. Reading and setting fill depth.4. Activating rejects dates.5. Stopping the press.6. Displaying compression force for each station in real time.7. Printing all CRT displays.8. Providing statistical data for machine performance analysis.

ROTARY TABLET PRESSInvolve use of computer technology. Using a microprocessor , thepharma control units corrects automatically for weight variation, monitor, means & individual tablets values , control the discardof faulty tablets and may include a quick –stop controls that isput into operation when certain tolerances are exceeded .

This system also monitor optimal speed, help to optimize tooluse, evaluating tableting data, record errors and conductstatistical evaluation during the run.

Fette perfecta 2000 cooltex – a tablet press system

It enables compression of system at low temperature byconnecting an appropriately constructed press to a cooling unitwhich can supply coolant so that -6 c is attainable on the press.

COATING PROCESS IMPROVEMENTCoating of tablets and pills using coating pan is entirely operator

dependent.

Typical Accela cota- : for aqueous or solvent film coating. This is a

side vented or perforated coating pan.

Advantages1. One way flow of air through the tablet bed and out the perforation of the pans. These greatly reduces or eliminate the bounce back of atomized spray and particle spray drying of the spray droplets that occurs especially with solvent based coating with conventional pans.2. It benefits coating because the greater air flow through the bed facilitates drying.3. Used for continuous coating of film and sugar systems.

BASIC PROCESS CONTROL DEVICES

• Sensors -: it is a device to measure the variable of the process which must be considered in making control decisions.• I-O devices-: transforms the signals from the sensors into signal that are usable by the computer.• Computer-:programmable controller• Microcomputer• Minicomputer• Activators -: take the command from the computer via the I-O devices and turn them into action in the process.

SUPAC GUIDELINESScale – Up

and

Post Approval Changes

Guidelines

What is SUPAC In the process of developing a new drug product, the batch sizes

used in the earliest human studies are small.

The size of the batches is gradually increased (Scale - up).

The scale-up process and the changes made after approval in the composition, manufacturing process, manufacturing equipment, and change of site have become known as Scale-Up and Post approval Changes or SUPAC.

The purpose of Supack guidelinesThe guidelines provide recommendation of the sponsors of

New Drug Application (NDA’S)

Abriviated new drug application (ANDA’S)

Abriviated antibiotic application (AADA’S)

The guidance came into being due to the following efforts

A workshop on scale-up of immediate release of the drugproducts conducted by The American Association OfPharmaceutical Sciences (AAPS) in conjugation with theUnited States Pharmacopoeial convention and the food anddrug administration (FDA).

Research conducted by the university of Maryland at Baltimoreon the chemistry manufacturing and the controls of theimmediate release drug products under the FDA/University OfMaryland Manufacturing research contract.

The drug categorization research conducted at the University OfMichigan and the University of Uppsala on the permeability ofdrug substances.

GUIDANCE FOR INDUSTRY Scale-up and post approval changes for immediate release

solid oral dosage forms includes

Chemistry, Manufacturing & Controls.

In Vitro Dissolution Testing

In Vivo Bioequivalence Documentation

DIAGRAMATIC PROCESS OF SUPAC

New Drug Application (NDA) approved by FDA SCALE-UP

Larger Batch size

Generic Drug Product

Bioequivalent to the FDA reference listed drug (RLD)product

Larger Batch size

Scientific Rationale to expedite the processes of post approval changes of drug

products.

FDA can assure their safety and effectiveness.

lower the regulatory burden for industry.

SUPAC GUIDELINES - DEFINE

• Minor change

• Moderate change

• Major change

• Application / Compendial Tests

• In Vitro Dissolution / Release

• In Vivo

• Annual Report

• Changes Being Effected

Supplement

• Prior Approval Supplement

LEVEL OF CHANGESLikelihood of impact on formulation quality and performance

Level 1:

If a scale-down of the production batch to 2 or 1/10 the size is

needed, operating parameters that would fall within the range

established for manufacture of the test batch and the first three

production batches (i.e., validation batches) will be regarded as a

level 1 change.Those changes that are unlikely to have any

detectable impact on formulation quality and performance. Example

Changes in the colour, flavours Changes in the excipient express as

the percentage (w/w) of total formulation, less than or equal to the

following range.. If they fall outside the validation ranges the change would be permitted under SUPAC as a level 2 change.

Level 2:Changes are those that could have significant impact on the formulation quality and performance .Example Changes in the technical grade of excipient (Avicel PH102 vs. Avicel PH200) Changes expressed as percent (w/w of total formulation) Level 2 Change to Level3.

Level 3:Changes are those that are likely to have significant impact on formulation quality and performance. Example Any qualitative or quantitative excipient changes to a narrow therapeutic drug beyond the range for level 1. All other drug not meeting the dissolution criteria as level 2.

The FDA has issued various guidance's for SUPAC changes designated as

A.SUPAC-IR (for immediate-release solid oral dosage forms)

B.SUPAC-MR (for modified-release solid oral dosage forms)

C.SUPAC-SS (for non-sterile semisolid dosage forms including

creams, ointments, gels, and lotions).

SUPAC

These guidelines provide recommdation for post approval changes in

(1) the components or composition

(2) the site of manufacture

(3) the scale-up of manufacture

(4) the manufacturing (process and equipment)

1.Component and composition changes

Focus on the changes in amount of excipients in the drug product, not focus on change in the amount of the drug substance .

SUPAC-IR EXCEPIENTSLEVEL CLASSIFICATION EXCIPIENT

RANGES(%w/w of total formulation)

TEST DOCUMENTATION

FILING DOCUMENTATION

I -Delition or partial delition of an ingredient (colour, flavor or change in ingredient of the ink)-Changes in excipients, expressed as % (w/w) of total formulation, less than or equal to excipient %ranges

Filler ±5DisintegrantStarch ±3Other ±1Binder ±0.5LubricantCalcium (Ca) orMagnesium (Mg) Stearate ±0.25Other ±1GlidantTalc ±1Other ±0.1Film Coat ±1

stability-application/ compendial requirements

Annual report

LEVEL CLASSIFICATION EXEPIENTS RANGES%W/W OF TOTAL FORMULATION

TEST DOCUMENTATION

FILING DOCUMENTATION

II change in technical grade of excipients-Changes in excipients, expressed as % (w/w) of total formulation, greater than Level 1 changes.

Filler ±10DisintegrantStarch ±6Other ±1Binder ±1LubricantCalcium (Ca) orMagnesium (Mg) Stearate ±0.5Other ±2GlidantTalc ±2Other ±0.2Film Coat ±2

stabilityapplication/compendial requirements-Dissolution data depends on solubility, therapeutic range and permeability.Case A : High Permeability, High Solubility DrugsSingle point Dissolution profile .Case B : Low Permeability, High Solubility DrugsMulti point dissolution profileCase C :High Permeability, Low Solubility DrugsMulti point and multi media dissolution profile

•Prior approval supplement•Annual report

LEVEL CLASSIFICATION TEST DOCUMENTATION

FILING DOCUMENTATION

III Higher than SUPAC-IR Level 1 and Level 2 excipient ranges.

stabilityapplication/compendial requirements-Case B dissolution profile (Multi-point dissolution profile in the application /compendial medium at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the proposed and currently accepted formulation.)-Biostudy or IVIVC

•Prior approval supplement•Annual report

SUPAC – MR Non Release Controlling ExcipientsLEVEL CLASSIFICATION TEST

DOCUMENTATIONFILING

I -Delition or partial delition of an ingredient-up to SUPAC-IR Level 1 excipient ranges

stabilityapplication/compendial requirements

Annual report

II change in technical grade of excipients-up to SUPAC-IR Level 2 excipient ranges

stabilityapplication/compendialrequirements-Multi-point dissolution profiles (15,30,45,60 & 120 min)USP buffer media at pH 4.5-7.5 for extended release) Three different Media (e.g., Water, 0.1N HCl, and USP buffer media at Ph 4.5 And 6.8 for delayed release)

•Prior approval supplement•Annual report

III Higher than SUPAC- stability •Prior approval

SUPAC – MR Release Controlling

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING DOCUMENTATION

I -≤ 5% w/w change based on total release controlling excipient content.-No other changes

stabilityapplication/compendialrequirements

Annual report

II change in technical grade of excipients-≤ 10% w/w change based on total release controlling excipient content.

stabilityapplication/compendial requirements-Multi-point dissolution profiles (15,30,45,60 & 120 min)USP buffer pH 4.5-7.5 for extended release) Three different Media (e.g., Water, 0.1N HCl, and USP buffer media at Ph 4.5 And 6.8 for DR release)

•Prior approval supplement•Annual report

III > 10% w/w change based on total release controlling excipient content.

stabilityapplication/compendial requirements-Biostudy or IVIVC

stabilityapplication/compendialrequirements-Biostudy or IVIVC

SUPAC – SS Components and CompositionLEVEL CLASSIFICATION TEST DOCUMENTATION FILING

I -Delition or partial delition of an ingredient -change in supplier or technical grade of any other excipient-Upto 5 % change in approved amount of ingredient.

stability-application/ compendial requirements

Annual report

II -Upto >5 % and ≤ 10 % change in approved amount of ingredient.-Change in particle size distribution of the drug substance, if the drug is inSuspension-change in supplier or technical grade of any other excipient

stabilityapplication/compendialrequirements-in vitro release test

•Changes being effected supplement•Annual report

III change in approved amount of ingredient.-Change in crystalline form of the drug substance, if the drug is in suspension

stabilityapplication/compendialrequirements-in vitro release test-in vivo bioequivalence test.

•Prior approval supplement•Annual report

2.Manufacturing Site Changes

changes in location of the site of manufacture, packaging operations and/or analytical testing laboratory.

do not include any scale-up changes, changes in manufacturing (including process and/or equipment), or changes in components or composition.

current Good Manufacturing Practice (CGMP) inspection.

LEVELS OF MANUFACTURING SITE

LEVEL CLASSIFICATION TEST DOCUMENTATION

FILING DOCUMENTATI-ON

I Site change within a single facility-No change in SOP, environmental conditions or equipments used-Common personnels

application/compendial requirements

Annual report

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

II Same continuous campus-Common personnel-No other changes

application/compendialrequirements-Notification of Location of new site-Updated batch records

SUPAC – MR-Multi-point dissolution profiles (15,30,45,60 & 120 min)USP buffer media at pH 4.5-7.5 for extended release) Three different Media (e.g., Water, 0.1N HCl, and USP buffer media at Ph 4.5 And 6.8 for delayed release)until 80% of Drug Released.

•Annual report•Changes being Effected Supplement

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

III Different campus-Different personnel

-application/compendial

requirements-Notification of Location of new site-Updated batch record

SUPAC –IRMulti-point dissolution profile in the application/compendial medium

SUPAC – MR-Multi-point dissolution profiles (15,30,45,60 & 120 min)USP buffer media at pH 4.5-7.5 for extended release) Three different Media (e.g., Water, 0.1N HCl, and USP buffer media at Ph 4.5 And 6.8 for delayed release) untill 80 % of drug released.

Annual reportPrior approval supplement

3.Batch Size Change (Scale Up)

changes in the size of a batch from the pivotal/pilot scale biobatch material to larger production batches

compliance with CGMP's

No change in SOP, formulation and manufacturing procedures or equipments used

All scale-up changes should be properly validated

the minimum batch size for the pivotal clinical trial batch or biobatch be at least 100000 dosage units /100 kg or 10% of a production batch, whichever is larger.

4.Manufacturing Changes Changes affecting:

- Equipments

- Manufacturing process

Appropriate validation studies are conducted

Manufacturing Changes - EquipmentsLEVEL CLASSIFICATION TEST DOCUMENTATION FILING

I Alternate equipment of same design and principlesAutomated equipments

Updated batch records-application/compendial requirementsstability

Annualreport

II Change to equipment of different design and principle

Updated batch recordsapplication/compendial requirementsStabilitySUPAC –IRMulti-point dissolution profiles in multiple mediasSUPAC – MR-Multi-point dissolution profiles in multiple mediasSUPAC-SSIn vitro release test Documentation

•Annual report•Changes being Effected Supplement

Manufacturing Changes- Process

LEVEL CLASSIFICATION TEST DOCUMENTATION

FILING

I Adjustment of equipment operating conditions (operating speeds, mixing times)

Within approved application ranges

Updated batch recordsapplication/compendial requirements-stability

Annual report

CONT……..

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

II Adjustment of equipment operating conditions (operating speeds, mixing times)

Beyond approved application ranges

-SUPAC – SSChange in the process of combining two

Updated batch records-application/compendial requirements-StabilitySUPAC-IRMulti-point dissolution profile

SUPAC-MR-Multi-point dissolution profiles in multiple medias (e.g., USP buffer media at pH 4.5-7.5 for extended release) three other media (e.g., Water, 0.1N HCl, and USP buffer media at Ph 4.5 And 6.8 for delayed release)

SUPAC-SSIn vitro release test Documentation

•Annual report•Changes being Effected Supplement

SUPAC LIMITATIONS

► has not been updated (1995/97 for main guides)

► does not discuss multiple changes

► does not cover modified equipment

► must be used in conjunction with other referenceseg. excipient handbook

REFERENCES :1- Lachman Leon and Schwartz .B. Joseph Pharmaceutical dosage

forms: Tablets. Vol 3, edition 2. P.P 1-74.

2- Sambhamurti B.S., pharmaceutical engineering.

3- http://www.slideshare.net/bdvfgbdhg/scale-up-and-post-approval-changessupac.

4- http://www.authorstream.com/Presentation/sumit_191-1991896-supac-guidelines/

5- http://www.authorstream.com/Presentation/voravipul-1010787-supac/

6- http://www.authorstream.com/Presentation/ravikeshari-1419792-automation/

7-http://www.pharmainfo.net/og/pharmindia/automation-pharmaceutical-manufacturing