supac: a regulatory approach for high quality

www.wjpps.com Vol 7, Issue 5, 2018.

437

Balasubramanian et al. World Journal of Pharmacy and Pharmaceutical Sciences

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


1. Batch size is beyond a factor of ten times size

of pilot/bio batch



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used.


principle

3. Manufacturing Batches as per CGMP.



batches.

1. Equipment Vary in Capacity

2. Batches as per GMP


used.


1.Batch size is beyond a factor of ten times size

of pilot/bio batch


principle.

3. Manufacturing Batches as per CGMP.



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





and controls.

Changes consist of site changes

within a single facility where the



environmental conditions and

controls.

2

Level 1 change consists of

site changes within a


same equipment, SOPs,

environmental conditions.

Level 2 changes consist of


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







and controls.



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.


451


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.

REFERENCES

1. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm124

826.htm

2. (http://www.regulatory.com/forum/clinic/clin0797.html)

3. (https://consult2deliver.co.uk/regulatory-strategy-borderline-products/regulatory-

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-

changes-supac-part-2).

6. (http://pqri.org/wp-content/uploads/2015/08/pdf/White%20Paper.pdf)

7. 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.

8. https://www.hlregulation.com/2014/03/07/fda-finalizes-guidance-on-drug-cmc-

postapproval-changes-and-allows-more-to-be-submitted-in-annual-reports-instead-of-

supplements/

9. (Azeem S and Sharma S, et al. Immediate release drug delivery systems: a review. Int J

Biopharm Toxicol Res. 2011; 1(1): 24-46).

10. (https://www.gmp-compliance.org/gmp-news/change-control-new-supac-guidance-

published)

11. (http://www.pharmainfo.net/sailesh/blog/scale-and-post-approval-changessupac)

https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm124826.htm

https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm124826.htm

http://www.regulatory.com/forum/clinic/clin0797.html

https://consult2deliver.co.uk/regulatory-strategy-borderline-products/regulatory-solutions/chemistry-manufacturing-controls-cmc/

https://consult2deliver.co.uk/regulatory-strategy-borderline-products/regulatory-solutions/chemistry-manufacturing-controls-cmc/

http://www.wellspringcmo.com/blog/introduction-to-scale-up-and-post-approval-changes-supac-part-2

http://www.wellspringcmo.com/blog/introduction-to-scale-up-and-post-approval-changes-supac-part-2

http://pqri.org/wp-content/uploads/2015/08/pdf/White%20Paper.pdf

https://www.hlregulation.com/2014/03/07/fda-finalizes-guidance-on-drug-cmc-postapproval-changes-and-allows-more-to-be-submitted-in-annual-reports-instead-of-supplements/



https://www.gmp-compliance.org/gmp-news/change-control-new-supac-guidance-published

https://www.gmp-compliance.org/gmp-news/change-control-new-supac-guidance-published

http://www.pharmainfo.net/sailesh/blog/scale-and-post-approval-changessupac


452


12. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037495/)

13. (https://www.fda.gov/downloads/drugs/guidances/ucm070636.pdf)

14. (https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan

ces/ucm346049.pdf)

15. https://www.fda.gov/downloads/Drugs/.../Guidances/UCM217043.pdf)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037495/

https://www.fda.gov/downloads/drugs/guidances/ucm070636.pdf

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm346049.pdf

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm346049.pdf

https://www.fda.gov/downloads/Drugs/.../Guidances/UCM217043.pdf