1. Presented By:-
Sourav Mainan
1st M.Pham
Dept. Of Pharmaceutics.
PES College Of Pharmacy,
Bangalore.
Facilitated By:
Dr. Manjula Talluri
Professor
Dept. Of Pharmaceutics
PES College Of Pharmacy,
Bangalore
2. CONTENTS
DEFINITION OF PAT
INTRODUCTION OF PAT
PURPOSE OF PAT
ADVANTAGE OF PAT
DISADVANTAGE OF PAT
GENERAL AUTOMATIC CONTROL SYSTEM
AUTOMATIC CONTROLLER
3. 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 SUPAC
MAUFACTURING SITE
MANUFACTURING CHANGES
SUPAC LIMITATION
REFERENCES
4. 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.
5. INTRODUCTION
Automation
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
6. 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
7. 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).
8. 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.
9. DISADVANTAGES
Huge 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.
10. 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 be
ccc controlled
Condensate
Valve
Steam
Liquid flow out
11. Type of system in heat exchange process-
Open loop system
Closed loop control system-
Feed back control system
Feed forward control system
12. Open loop system-
Are those in which information about the controlled variable (like
temperature ) is not used to adjust any of the system inputs to
compensate for variation in the processes variables.
13. Closed loop feed back system
In this system, information about the controlled variables is feed back as
the basis for control of a process variable by a human operator (manual
control) 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 is
used to produce a signal proportional to the measured temperature .This
signal is feed to controller which compare it with a preset desired valve
(set point ). If differences exist, the controller changes the opening of the
steam control valve to correct the temperature.
14. 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.
15.
16. 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.
17. 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.
18. 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.
19. PROCESS CONTROL COMPUTER
in the hierarchy of computer control of a process. Four
levels can be identified-
1) unit operation control
2) unit process control
3) plant control
4) 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.
20. Process control computer- analog computer &
Digital computer
1. Analog computer
2. Digital computer
Analog computers- represents the numbers being
manipulated by the magnitude of a physical quantity, such as
volts or pressure. Mathematically operations are carried out in
a continuous manner.
Digital computers- are counting device that operates
directly on numbers to perform the four fundamental
mathematical operation addition, subtraction, multiplication,
and division.
23. 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.
24. 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 devices
1-Visual types
2- Float actuated types
3- Displacer type.
4- Head devices.
5- miscellaneous.
25. 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.
28. 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.
29. MATERIAL HANDLING
BASIC PRINCIPLE
1. Short distances
2. Short terminal times
3. Two way pay load
4. Avoid partial loads
5. Avoid manual handling
6. Move scrap cheaply.
7. Gravity is cheapest power
8. Move in straight lines
9. Unit loads
10. Label thoroughly
31. Examples of material handling improvement
Granulation and tableting sections of the computer controlled
tablet manufacturing process by Merck Sharp & Dohme (MSD)
and Eli lily and company.
32. Advantages Of Material Handling
1. No human handling of material
2. 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.
33. Processing step combination or elimination
Wet granulation (standard processing steps)
Standard processing steps -Load processer Weigh
ingredients Mix, mass, agglomerate, dry lubricate
Transfer ,Continuous batch powder mixing and massing
equipment.
E.g. Dionsa mixer & granulator is a high – shear powder
mixer and processor.
34.
35. 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.
36. 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.
37. 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).
38. 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.
39. 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………….
40. 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.
41. TTS III: - have advanced sampling & microprocessor
technology.
Functional feature of TTS III
1. 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.
42. ROTARY TABLET PRESS
Involve use of computer technology. Using a microprocessor , the
pharma control units corrects automatically for weight variation
, monitor, means & individual tablets values , control the discard
of faulty tablets and may include a quick –stop controls that is
put into operation when certain tolerances are exceeded .
This system also monitor optimal speed, help to optimize tool
use, evaluating tableting data, record errors and conduct
statistical evaluation during the run.
Fette perfecta 2000 cooltex – a tablet press system
It enables compression of system at low temperature by
connecting an appropriately constructed press to a cooling unit
which can supply coolant so that -6 c is attainable on the press.
43. COATING PROCESS IMPROVEMENT
Coating 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.
Advantages
1. 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.
44.
45. 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.
47. 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.
48. The purpose of Supack guidelines
The guidelines provide recommendation of the sponsors of
New Drug Application (NDA’S)
Abriviated new drug application (ANDA’S)
Abriviated antibiotic application (AADA’S)
49. The guidance came into being due to
the following efforts
A workshop on scale-up of immediate release of the drug
products conducted by The American Association Of
Pharmaceutical Sciences (AAPS) in conjugation with the
United States Pharmacopoeial convention and the food and
drug administration (FDA).
Research conducted by the university of Maryland at Baltimore
on the chemistry manufacturing and the controls of the
immediate release drug products under the FDA/University Of
Maryland Manufacturing research contract.
The drug categorization research conducted at the University Of
Michigan and the University of Uppsala on the permeability of
drug substances.
50. 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
51. 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
52. 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.
53. 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
54. LEVEL OF CHANGES
Likelihood 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.
55. 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.
56. 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).
57. 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)
58. 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 .
59. SUPAC-IR EXCEPIENTS
LEVEL CLASSIFICATION EXCIPIENT
RANGES
(%w/w of total
formulation)
TEST
DOCUMENTATIO
N
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 ±5
Disintegrant
Starch ±3
Other ±1
Binder
±0.5
Lubricant
Calcium (Ca) or
Magnesium (Mg)
Stearate
±0.25
Other ±1
Glidant
Talc ±1
Other ±0.1
Film Coat ±1
stability
-application/
compendial
requirements
Annual report
60. 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 ±10
Disintegrant
Starch ±6
Other ±1
Binder ±1
Lubricant
Calcium (Ca) or
Magnesium (Mg)
Stearate ±0.5
Other ±2
Glidant
Talc ±2
Other ±0.2
Film Coat ±2
stability
application/compend
ial requirements
-Dissolution data
depends on solubility,
therapeutic range
and permeability.
Case A : High
Permeability, High
Solubility Drugs
Single point
Dissolution profile .
Case B : Low
Permeability, High
Solubility Drugs
Multi point
dissolution profile
Case C :High
Permeability, Low
Solubility Drugs
Multi point and multi
media dissolution
profile
•Prior approval
supplement
•Annual report
61. LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
DOCUMENTATION
III Higher than
SUPAC-IR Level 1
and Level 2
excipient ranges.
stability
application/compendi
al 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
62. SUPAC – MR Non Release Controlling
ExcipientsLEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
I -Delition or partial
delition of an ingredient
-up to SUPAC-IR Level 1
excipient ranges
stability
application/compend
ial requirements
Annual report
II change in technical
grade of excipients
-up to SUPAC-IR Level 2
excipient ranges
stability
application/compendial
requirements
-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
63. SUPAC – MR Release Controlling
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATI
ON
I -≤ 5% w/w change based on
total release controlling
excipient content.
-No other changes
stability
application/compendial
requirements
Annual report
II change in technical grade
of excipients
-≤ 10% w/w change based
on total release
controlling excipient
content.
stability
application/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.
stability
application/compendial requirements
-Biostudy or IVIVC
stability
application/compe
ndial
requirements
-Biostudy or IVIVC
64. SUPAC – SS Components and Composition
LEVEL 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 in
Suspension
-change in supplier or technical grade of
any other excipient
stability
application/compendial
requirements
-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
stability
application/compendial
requirements
-in vitro release test
-in vivo bioequivalence test.
•Prior approval
supplement
•Annual report
65. 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.
66. 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/com
pendial
requirements
Annual report
67. LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
II Same continuous
campus
-Common
personnel
-No other changes
application/compendial
requirements
-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
68. LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
III Different campus
-Different
personnel
-application/compendial
requirements
-Notification of Location of new site
-Updated batch record
SUPAC –IR
Multi-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 report
Prior approval
supplement
69. 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.
71. Manufacturing Changes - Equipments
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
I Alternate
equipment of same
design and
principles
Automated
equipments
Updated batch records
-application/compendial requirements
stability
Annual
report
II Change to
equipment of
different design
and principle
Updated batch records
application/compendial requirements
Stability
SUPAC –IR
Multi-point dissolution profiles in multiple
medias
SUPAC – MR
-Multi-point dissolution profiles in
multiple medias
SUPAC-SS
In vitro release test Documentation
•Annual
report
•Changes
being
Effected
Supplement
72. Manufacturing Changes- Process
LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
I Adjustment of
equipment operating
conditions (operating
speeds, mixing times)
Within approved
application ranges
Updated batch
records
application/compen
dial requirements
-stability
Annual report
CONT……..
73. LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
II Adjustment of
equipment
operating
conditions
(operating
speeds, mixing
times)
Beyond approved
application
ranges
-SUPAC – SS
Change in the
process of
combining two
Updated batch records
-application/compendial requirements
-Stability
SUPAC-IR
Multi-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-SS
In vitro release test Documentation
•Annual
report
•Changes
being
Effected
Suppleme
nt
74. 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 references
eg. excipient handbook
