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SUPAC: A REGULATORY APPROACH FOR HIGH QUALITY
DOCUMENTATION IN CHEMISTRY, MANUFACTURING AND
CONTROL (CMC)
Balasubramanian J.1*
, P. Naveena2, S. Hari Ram
2, Chenchu Teja Varma Y.
4, Eknath
Babu5
1Navitas LLP, Shriram "The Gateway SEZ", Dept of Regulatory Operations, Chennai -600
063.
2Mesmer Pharmaceuticals, Alathur, Tamil Nadu – 603 110.
3Annamacharya College of Pharmacy, Dept. of Regulatory Affairs, Andhra Pradesh – 516
115.
4Caplin Point, Dept of Regulatory Affairs, Thiruvallur (District) – 601 201.
ABSTRACT
SUPAC is the guidance about the level of changes, recommended
chemistry, manufacturing and control tests for each level of change.
CMC changes are inevitable due to many reasons including changing
needs, new findings and continuous improvement. Therefore,
regulations require that all changes be evaluated carefully and follow
the proper regulatory path for implementation, regardless of whether it
is an investigational or a commercial product. Failure to comply with
regulatory requirements for post approval CMC changes can
potentially lead to ―misbranded or adulterated‖ status for a given
product. This should be taken very seriously for marketed products
because of the potential safety/efficacy impact for the vast number of patients as well as
legal, regulatory and business impact for the sponsor. This retrospective approach provides a
clear path for SUPAC in various parameters such as change in components, composition,
batch size of the formulation, manufacturing site, manufacturing equipment, process as per
USFDA norms.
KEY WORDS: Chemistry Manufacturing Control, SUPAC – Scale up and post approval
changes, USFDA – United States of Food and Drug Administration.
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.421
Volume 7, Issue 5, 437-452 Review Article ISSN 2278 – 4357
*Corresponding Author
Balasubramanian J.
Navitas LLP, Shriram "The
Gateway SEZ", Dept of
Regulatory Operations,
Chennai -600 063.
Article Received on
28 Feb. 2018,
Revised on 20 March 2018,
Accepted on 11 April 2018,
DOI: 10.20959/wjpps20185-11500
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1. INTRODUCTION
The acronym "SUPAC" stands for "Scale-Up and Post-Approval Changes". It refers to the
FDA-recommended testing and filing actions to be taken by a pharmaceutical firm when it
changes the manufacturing processes of a drug product that has been approved via a New
Drug Application (NDA), an Abbreviated New Drug Application (ANDA), or an
Abbreviated Antibiotic Drug Application (AADA). The Agency has provided its
recommendations to industry in the form of Guidance’s.
On November 30, 1995, the Scale-up and Post-Approval Changes Guidance for Immediate
Release Products (SUPAC-IR) was published. Since then a number of questions have arisen
in interpreting the Guidance as it applies to specific situations encountered or that could be
encountered in the pharmaceutical industry. The purpose of this letter is primarily to share
with you the questions that have been asked most frequently or that we consider the most
significant. Also included are the Centre’s responses to these questions. The responses were
developed and concurred with by the Office of New Drug Chemistry and Office of Generic
Drugs, Centre for Drug Evaluation and Research (CDER).[1]
As you may be aware, 21 CFR 314.70 already provides instructions for how changes to
approved manufacturing process should be reported to the Agency. Specifically, depending
on the magnitude of the change and the possibility that the change could negatively affect the
product, the Code provides that notification should be accomplished in one of three ways:
1. A supplement that requires approval by the FDA prior to implementation of the change.
2. A supplement that does not require approval by the FDA prior to implementation of the
change ("changes being effected");
3. An annual report.[2]
The chemistry, manufacturing and controls (CMC) section is a very important part of any
clinical trial or marketing application. Drugs can be denied marketing approval if the quality
of the product and the manufacturing process cannot be shown to be of a sufficiently high
standard to satisfy regulators.
Chemistry and Manufacturing Control (CMC) is the FDA term used globally to describe the
data for the manufacture and testing of a medicinal product. In Europe, the ICH term, Module
3 Quality, is more commonly used. The two terms are interchangeable.
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The CMC aspects of the regulatory submission will cover
Characterisation of the active substance
Composition of the dosage form
Raw materials used to manufacture the active substance and finished dosage form
Description of the product and process development
Description of the manufacturing processes
Release and stability testing data for both the active substance and the dosage form
Analytical methods and specifications used for testing and release of raw materials
In-process controls
Container and closure systems
CMC is an integral part of drug development, a regulatory submission and the on-going
marketing and life cycle management of a medicinal product. As drug development of the
dosage form moves from concept to commercialisation, the breadth and depth of CMC
documentation required in submissions increases in parallel. All regulatory submissions
require CMC data
e.g.:-
IND
CTA
MAA
Variations
NDA
Annual reports[3]
2. Scientific & Regulatory Rational for SUPAC
Authorities Regulations like FDA (U.S. Food and Drug Administration), the European
Commission, the Agencia Nacional de Vigilancia Sanitaria (ANVISA) (in English the
National Health Surveillance Agency — Brazil, and others require the pharmaceutical
industries in respective countries to follow guidelines on scale- up and post approval
changes (SUPAC) to maintain the quality of the pharmaceutical produced.
3. SUPAC & FDA
The SUPAC guidance published by the FDA defines various levels of change and for each
level of change specifies the:
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3.1. Recommended chemistry, manufacturing and control tests.
3.2. In-vitro dissolution testing and/or in-vivo bioequivalence tests and
3.3. Documentation that the FDA requires to be filed in the NDA, ANDA or AADA to
Support the change.[4]
SUPAC is that it is not regulation, but only guidance. It relates only to drug manufacturing
and it’s only available for certain dosage forms: immediate release solid oral dosage forms
including tablets, capsules, and soft gelatine capsules; modified release solid oral dosage
forms including delayed release and extended release; and topical semi-solid dosage forms
including creams, ointments, suspensions, emulsions and gels.
SUPAC is a very valuable tool in the scale-up process and the guidance does reflect the
FDA’s current thinking. The guidance defines: levels of change; recommended chemistry,
manufacturing and controls tests for each level of change; in vitro dissolution tests and/or in
vivo bioequivalence tests for each level of change; and documentation that should be
submitted to support the change.[5]
4. Chemistry Manufacturing Control
The Manufacturing Technical Committee of the Product Quality Research Institute provides
information on the common, best practices in use today in the development of high-quality
chemistry, manufacturing and controls documentation. Important topics reviewed include
International Conference on Harmonization, in-vitro in-vivo correlation considerations,
quality-by-design approaches, process analytical technologies and current scale-up, and
process control and validation practices. It is the hope and intent that this whitepaper will
engender expanded dialog on this important subject by the pharmaceutical industry and its
regulatory bodies.[6]
The SUPAC guidance published by the FDA define various levels of change and for each
level of change specifies the: a) Recommended chemistry, manufacturing, and control tests;
b) In-vitro dissolution testing and/or in-vivo bioequivalence tests; and c) Documentation that
the FDA requires to be filed in the NDA, ANDA, or AADA to support the change.[7]
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5. FDA Finalizes Guidance on Drug CMC Post approval Changes And Allows More
To Be Submitted in Annual Reports, Instead of Supplements
Over the years, the number of chemistry, manufacturing, and controls (CMC) post approval
drug manufacturing supplements for NDAs and ANDAs submitted to FDA has continued to
increase. These are required for ―major‖ or ―moderate‖ manufacturing changes:
Major. If a manufacturing change is considered to be major, an applicant must submit
and receive FDA approval of a prior-approval supplement (PAS) before the drug product
made with the change is distributed.
Moderate. If a manufacturing change is considered to be moderate, an applicant must
submit a supplement at least 30 days before the drug product is distributed (a CBE-30
supplement) or, in some cases, submit a supplement at the time of distribution (a CBE-0
supplement). ―CBE‖ means ―changes-being-effected‖.
The increasing number of supplements – combined with FDA’s goal of implementing a more
cooperative, efficient, and risk-based approach for regulating pharmaceutical manufacturing
– has resulted in the agency examining the types of changes that historically have been
submitted as CMC post approval manufacturing supplements (PAS, CBE-30, and CBE-0).
As a result, FDA concluded that many of the changes being reported present low risk to the
quality of the product and can therefore be documented in a company’s annual report (i.e.,
notification of a change after implementation) rather than in a supplement. SUPAC involves
in the following CMC areas related to product specification, change in batch size (Scale up
and scale down), manufacturing site, process and equipment’s refer fig.1.[8]
Fig No.1: SUPAC role in CMC.
SUPAC
Specifications
Components and
Compositions
Changes in
Batch size
Site Changes
Manufacturing
Process
Manufacturing
Equipment’s
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6. SUPAC-Implementation
• Federal register notice - June 13, 1997
• Industry training - May 29, 1997
Applies to non-sterile semi-solid preparations, e.g., creams, gels, and ointments, solid dosage
forms of IR/MR.[9]
Scale-up and Post-approval Changes (SUPAC) Guidance Documents give recommendations
to the pharmaceutical manufacturer in case of changes with respect to
Specifications
Site changes
Manufacture equipment’s
Manufacturing process
Composition and Ingredients
Batch size
Manufacturing site[10]
7. Chemistry Manufacturing and Control as per SUPAC
This is a guidance document that comes under Chemistry manufacturing and controls section
of USFDA. During formulation development, initially, development process is carried out in
small batch sizes generally in the multiples of 10X i.e., small scale or lab scale. The batch
size is then increased to multiples of 100X i.e., medium scale or pilot scale. In production
scale or large scale, manufacturing is carried out in large numbers usually multiples of 1000X
depending upon the requirement. This increase in batch sizes is termed as scale up.
Sometimes, batch sizes need to be reduced depending upon the market requirements. This is
termed as Scaled down. Quantities of active ingredients, excipients, equipment’s, formulation
parameters differ from lab scale to manufacturing scale. Submission of all this data including
excipients, their purpose and quantities to FDA is required for marketing approval by the
agency. A need may arise to change the excipient or composition of excipients, batch size,
manufacturing site, equipment on due course depending upon the market requirements. These
needs are classified as components and composition, site changes, changes in batch size
(scale up/scale down) levels under this guidance to avoid resubmission whenever a change
has been taken place.
7.1 A level 1 change is the one assumed to be that such change will not have any significant
effect on product's performance or quality. FDA has given the limits up to which an excipient
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can be changed. For example, quantity of filler can be used more or less 5 per cent of the
proposed amount during submission.
Level 1 requires
Chemistry documentation application/compendia release requirements
Notification of change and submission of updated batch records in annual report
One batch on long-term stability reported in annual report
No dissolution or in vivo testing
Filing documentation: annual report (long-term stability commitment)
7.2 A level 2 change is assumed to have significant change on quality on product quality and
it depends on therapeutic range, solubility and permeability of drug. Change in the technical
grade of an excipient comes under this category.
Level 2 requires
One batch with 3 month ACC and 1 batch with long term stability data.
Dissolution documentation: Case B testing
Filling documentation: Prior approval supplement annual report.
Level 2 additionally requires
7.3 A level 3 change also will have significant impact on product's quality and performance
and those changes must be done according to the guideline. Guidelines are given for the site
change, manufacturing equipment changes, process changes. In summary, SUPAC guideline
is a regulatory relaxation to industries that avoids resubmission of data for every small
change. Changes can be made subject to the guidelines given in the document.[11]
The impact of
(a) Formulation or compositional changes,
(b) Process variable changes,
(c) Process scale changes, and
(d) Process site changes on the finished quality parameters of these products.
Each area of change was further divided to reflect a hierarchy of ―significance‖ and hence
aided in establishing post-approval change filing documentation. In the case of the extended-
release dosage forms, the potential need for the conduct of one or more pivotal
bioavailability/bioequivalence (BA/BE) studies was recognized and, as a result, included a
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recommended decision tree to determine when a BE study would be needed to prove
equivalence.[12]
8. Components and Composition IR, MR and SS
This section of the guidance focuses on changes in excipients in the drug product. Changes in
the amount of drug substance are not addressed by this guidance. Changes in components or
composition that have the effect of adding a new excipient or deleting an excipient are
defined at another level. In level 3 changes are those that are likely to have a significant
impact on formulation quality and performance. Tests and filing documentation vary
depending on the following three factors: therapeutic range, solubility, and permeability.
Regarding the changes in components and composition refer table 1 and 2.[13]
Table 1: Level 1 & Level 2 Changes.
Table 2: Components and Composition SS.
Level 1 Level 2 Level 3
• Detectable change in
formulation.
• Significant impact and
formulation.
• Significant impact and
formulation.
• Change in before 5%
Addictive effect 5%.
• Total additive effect not
more than 10%.
• Total additive effect not more
than 10%.
• Total additive effect not more
than 10%.
• Change in supplier or
technical grade, particle
size distribution.
• Change in crystal uniform of
drug substance.
• Chemistry documents In-vivo
& In vitro documentation.
• Chemistry documents In-
vivo documentation
• Chemistry documents In-vivo
documentation.
•Annual report long term
stability.
ACC and long term
stability data.
ACC and long term stability
data.
EXCIPIENT Level 1 Level 2
Filler ±5 ±10
Disintegrant
Starch
Other
±3
±1
±6
±2
Binder ±0.5 ±1
Lubricant
Calcium (Ca) or Magnesium
(Mg) Stearate
Other
±0.25
±1
±0.5
±2
Glidant
Talc
Other
±1
±0.1
±2
±0.2
Film Coat ±1 ±2
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9. SUPAC Equipment Information
This guidance combines and supersedes the following scale-up and post-approval changes 18
(SUPAC) guidance for industry: (1) SUPAC-IR/MR: Immediate Release and Modified 19
Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum, and (2) SUPAC-SS
No sterile Semisolid Dosage Forms, Manufacturing Equipment Addendum.[14]
10. Manufacturing Process, Batch Size, and Equipment
10.1. The following process changes
10.1.1. Addition of a sieving step(s) for aggregates removal if it occurs under non aseptic
conditions.
10.1.2. Changes in mixing times (for blending powders, granules) for immediate-release solid
oral dosage forms and solution products.
10.1.3. Changes in drying times for immediate-release solid oral dosage forms.
10.1.4 Manufacturing batch size or scale change that results from combining previously
separated batches (or lots) of in-process material to perform the next step in the
manufacturing process if all combined batches meet the approved in-process control limits,
the next step remains unaffected, and appropriate traceability is maintained.
10.2. For equipment used in aseptic manufacturing processes (e.g., new filling line, new
lyophilizer), replacement of equipment with that of the same design and operating principle,
when there is no change in the approved process methodology or in-process control limits.
10.3. Addition of identical processing lines that operate parallel to each other in the drug
substance and drug product manufacturing process with no change in in-process control
limits or product specification.
10.4. For sterile drug products, addition of, deletion of, or change in a reprocessing protocol
for refiltrations to control bio burden because of filter integrity test failures.
10.5. Decrease in the number of open handling steps or manual operation procedures, when it
reduces risk to product and there is no other change to the process (e.g., implementation of
aseptic connection devices to replace flame protection procedures).
10.6. For sterile drug products, changes to the ranges of filtration process parameters (such as
flow rate, pressure, time, or volume, but not pore size) that are within currently validated
parameters ranges and therefore would not warrant new validation studies for the new ranges.
10.7. In the manufacture of sterile drug products, change from a qualified sterilization
chamber (ethylene oxide (EtO), autoclave) to another of the same design and operating
principle for the preparation of container/closure systems, sterilization of ―change parts‖ for
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processing equipment, and terminal sterilization of product, when the new chamber and load
configurations are validated to operate within the previously validated parameters. This does
not include situations that change the validation parameters.[15]
10.8. Changes in the processing equipment’s leads to change the product quality which leads
to major changes in various areas refer table 3 to 16.
SUPAC EQUIPENT (IR/MR) INFORMATION
Table 3: Particle size Reduction/Separation.
Fluid Energy Mills Impact Mills Screening
Mills Tumbling Separators
-Loop/Oval -Hammer Air
Swept
-Rotating
impeller -Ball media
-Vibratory/
shaker
-Opposed Jet -Hammer
Conventional
-Rotating
screen -Rod media -Centrifugal
-Opposed Jet with
Dynamic Classifier -Pin/Disc
-Oscillating
bar -Vibrating
-Fluidized Bed -cage
-Fixed Target
-Moving Target
-High Pressure
Homogenizer
NOTE: Cutting and Compression mills are not applicable for IR/MR formulation
equipment’s.
Table 4: Blending and Mixing.
Diffusion Mixers (Tumble) Convection Mixers
-V-blenders -Ribbon Blenders
-Double Cone Blenders -Orbiting Screw Blenders
-Slant Cone Blenders -Planetary Blenders
-Cube Blenders -Forberg Blenders
-Bin Blenders -Horizontal Double Arm Blenders
-Horizontal/Vertical/Drum Blenders -Horizontal High Intensity Mixers
-Static Continuous Blenders -Vertical High Intensity Mixers
-Dynamic Continuous Blenders -Diffusion Mixers (Tumble) with
Intensifier/Agitator
NOTE: Pneumatic mixers are not applicable for IR/MR formulation equipment’s.
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Table 5: Granulation.
Dry
Granulator
Wet High-
Shear
Granulator
Wet Low-
Shear
Granulator
Low-Shear
Tumble
Granulator
Extrusion
Granulator
Rotary
Granulator
-Slugging
-Vertical (Top
or Bottom
Driven)
-Planetary -Slant cone -Radial or
Basket -Open
-Roller
Compaction
-Horizontal
(Side Driven) -Kneading
-Double
cone -Axial
-Closed
-Screw -V-blender -Ram
-Roller, Gear, or
Pelletizer
NOTE: Fluid bed, Spray dryer, Hot-melt granulators are not applicable for IR/MR
formulation equipment’s.
Table 6: Drying.
Direct Heating, Static
Solids Bed
Direct Heating, Moving
Solids Bed
Indirect Conduction
Heating, Moving Solids Bed
-Tray & truck -Rotating Tray -Paddle
-Belt -Horizontal -Vibrating
Conveyor -Rotary (Tumble)
-Agitation
NOTE: Direct Heating, Fluidized Solids Bed (Fluid Bed Dryer), Direct Heating, Dilute
Solids Bed, Spray Dryer, Direct Heating, Dilute Solids Bed, Flash Dryer, Indirect
Conduction Heating, Static Solids Beds, Indirect Conduction, Lyophilization, Gas Stripping,
Indirect Radiant Heating, Moving Solids Bed (Microwave Dryer)’s are not applicable for
IR/MR formulation equipment’s.
Table 7: Unit Dosing.
Tablet Press Encapsulator Powder Filler
-Gravity -Auger -Vacuum
-Power Assisted -Vacuum -Auger
-Centrifugal -Vibratory
-Compression Coating -Dosing Disk
-Dosator
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Table 8: Soft gelatin capsule.
Mixers and
Mixing Vessels
De
aggregators De aerators
Holding
Vessels Encapsulators Inspection/Sorting
-Low Energy
Mixer -Rotor/Stator
-
VacuumVessel
-Jacketed
vessel with
and without
mixing system
-Positive
Displacement
Pump
-Belt
High Energy
Mixer
Planetary
-Roller -Off Line/In
Line
-Gravity or
Force Fed -Vibratory
-Jacketed Vessel
With and
Without Vacuum
-Cutting
Mills -Roller
-Stone Mills -Rotary Table
-Tumbling
Mills Electromechanical
Table 9: Coating/Printing/Drilling.
Pan Coating Gas Suspension Ink based printing Laser etching
(printing)
-Non perforated
coating system
-Fluidized bed with
bottom spray
mechanism
Offset Ink Jet
-Perforated coating
system
-Fluidized bed with
tangential spray
mechanism
-Fluidized bed with
top spray mechanism
-Fluidized bed with
Wurster column
NOTE: Vacuum film coating, Dip coating, Electrostatic coating, Compression coating, Laser
etching (printing), Drilling’s are not applicable for IR/MR formulation equipment’s.
SUPAC EQUIPENT (SS) INFORMATION
Table 10: Mixing.
Convection Mixers, Low Shear Convection Mixers, High Shear
-Anchor or sweep gate -Dispersator
-Impeller -Rotor stator
-Planetary
NOTE: Roller Mixers (Mills) and Static Mixers are not applicable for SS formulation
equipment’s.
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Table 11: Emulsification.
High Shear Emulsifiers
-Dispersator
-Rotor stator
-Valve or pressure homogenizer
NOTE: Low Shear Emulsifiers are not applicable for SS formulation equipment’s.
Table 12: De aeration.
De aerators
-Off-Line or in-line
-Vacuum vessel
Table 13: Transfer.
Low Shear High Shear
-Diaphragm -Centrifugal or turbine
-Gravity -Piston
-Peristaltic -Rotating gear
-Piston
-Pneumatic
-Rotating lobe
-Screw or helical screw
Table 14: Packaging.
Holders Fillers Sealers
-Auger -Auger -Heat
-Gravity -Gear pump -Induction
-Pneumatic (nitrogen, air, etc.) -Orifice -Microwave
-Peristaltic pump -Mechanical or crimping
-Piston -Torque
BATCH SIZE FOR IR, MR AND SS
Table 15: Batch Size.
LEVEL 1 LEVEL 2
1.Equipment Vary in Capacity
2.Batches as per GMP
3. Same Standard operating procedure may be
used.
4. Full scale production batches are used.
1. Batch size is beyond a factor of ten times size
of pilot/bio batch
2. Equipment of same design and operating
principle
3. Manufacturing Batches as per CGMP
4. Same SOPS, Formulation, Manufacturing
procedure on test and full- scale production
batches.
1.Equipment Vary in Capacity
2.Batches as per GMP
3. Same Standard operating procedure may be
1. Batch size is beyond a factor of ten times size
of pilot/bio batch
2. Equipment of same design and operating
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used.
4. Full scale production batches are used.
principle
3. Manufacturing Batches as per CGMP.
4. Same SOPS, Formulation, Manufacturing
procedure on test and full- scale production
batches.
1. Equipment Vary in Capacity
2. Batches as per GMP
3. Same Standard operating procedure may be
used.
4. Full scale production batches are used.
1.Batch size is beyond a factor of ten times size
of pilot/bio batch
2. Equipment of same design and operating
principle.
3. Manufacturing Batches as per CGMP.
4. Same SOPS, Formulation, Manufacturing
procedure on test and full- scale production
batches.
SITE CHANGES FOR IR, MR AND SS
Table 16: Site Changes.
Sr.no LEVEL 1 LEVEL 2 LEVEL 3
1
Site changes within a
single facility where the
same equipment, standard
operating procedures,
environmental conditions
and controls.
Site changes within a
single facility where the
same equipment, standard
operating procedures,
environmental conditions
and controls.
Changes consist of site changes
within a single facility where the
same equipment, standard
operating procedures,
environmental conditions and
controls.
2
Level 1 change consists of
site changes within a
single facility where the
same equipment, SOPs,
environmental conditions.
Level 2 changes consist of
site changes within a
contiguous campus, or
between facilities in
adjacent city blocks,
where the same
equipment, SOPs,
environmental conditions.
Level 3 changes consist of a
change in manufacturing site to a
different campus. A different
campus is defined as one that is
not on the same original
contiguous site or where the
facilities are not in adjacent city
blocks.
3
Level 1 changes consist of
site changes within a
single facility where the
same equipment, standard
operating procedures,
environmental conditions
and controls.
Level 2 changes consist of
site changes within a
contiguous campus, or
between facilities in
adjacent city blocks,
where similar equipment,
standard operating
procedures, environmental
conditions.
Level 3 changes consist of a site
change in manufacturing site to a
different campus. A different
campus is defined as one that is
not on the same original
contiguous site or where the
facilities are not in adjacent city
blocks.
CONCLUSION
Scale-up is an inevitable part of the product life cycle of every successful drug, and each time
it is required, a meticulous process must be followed to ensure that the end result is identical
to the product formulation as originally devised. Among the things you should know about
SUPAC (Scale-Up and Post-Approval Changes) is that it is not regulation, but only guidance.
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It relates only to drug manufacturing and it’s only available for certain dosage forms. That
being said, it’s a very valuable tool in the scale-up process related to chemistry
manufacturing and control.
ACKNOWLEDGMENT
The Author wish to thank the management of Navitas LLP (Take solutions Enterprises) and
the staff members such as Mr. Mallikaarjunan R (General Manager) and Mr. Prabhu
(Manager) of Regulatory Operations for their constant support. Further I am greatly thanking
Mr. J. Jeyaseelan, Mrs. Bernitta Sugirtha (Managing Director) for providing the greatest
opportunity in the field of RA in Sai Mirra Innopharm Pvt Ltd. I am personally thanking Mr.
Davendiran (Managing Director), Mr. G. Sivaramakrishnan (General Manager) Mesmer
Pharmaceuticals, Mr. S. Suresh (Executive Director) Aeon Formulations Pvt Ltd.
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solutions/chemistry-manufacturing-controls-cmc/)
4. .(1) Mendapara VP SN, Purohit PV, Sanghavi G, Ashara KC. SUPAC of Immediate
Release Solid Oral Dosage Form-Eplerenone. Inventi Rapid: Pharm Tech. 2013; 3: 1-7.
5. (http://www.wellspringcmo.com/blog/introduction-to-scale-up-and-post-approval-
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