SUPAC GUIDELINES

(Scale-Up and Post Approval Changes)

(Part –I Introduction)
By
Dr. Krishnananda Kamath K. M. Pharm, Ph.D
Professor, Department of Pharmaceutics
Srinivas College of Pharmacy,
Mangalore 574143
E mail: medhakkamath@gmail.com
Mobile: 9742227045
CONTENTS
• Part I
– Introduction
– Definition
– SUPAC Documents
– SUPAC Guidelines
• Part II
– Levels of Change
– Components and composition
– Manufacturing change : Process & Equipment
– Limitations of SUPAC
– Summary
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Introduction
• Earlier days in house “change control procedure”
and scope is limited to plant level only.
– Determining the importance of various changes and
impact on product quality. (Proposal and Approval Part)
• How can we update or change the information
given to FDA approved Applications.
– After approval if any changes, done called Post
Approval changes.
• FDA issued clear guidance Nov 1999 (21CFR
314.70 Changes to Approved applications)
– Recommended reporting changes for component and
composition changes.
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Quality Assessment
Manufacturing science
– Pharmaceutical engineering/pharmaceutical technology
(production methods and systems, facilities, equipment)

Pharmaceutical sciences
 Pharmaceutical chemistry (organic, inorganic, physical,
biochemical, analytical (e.g. methodology, validation,
spectral analysis)) SAR, and study of drug design
• Pharmaceutics (study of drug formulation)
Other fields: Math/statistics, microbiology, GMP
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What is SUPAC
• In the process of developing a new drug product,
the batch sizes used in the earliest human studies
are small (bio-batch).
• SU: Scale-up during original dossier assessment.
Note that this is not SU during development.
• The size of the batches is gradually increased (SU).
• The scale-up process and the changes made after
approval.
• Issued by: Center for Drug Evaluation and Research
(USFDA)
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 SUPAC Guidelines
• Guidance provides recommendations to sponsors of
– New Drug Applications (NDA's),
– Abbreviated New Drug Applications (ANDA's),
– Abbreviated Antibiotic Drug Applications (AADA's)
• who intend, during the post approval period, to
change in the :
1) components or composition;
2) site of manufacture;
3) scale-up/scale-down of manufacture;
4) manufacturing (process and equipment).
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 Srinivas College of Pharmacy,
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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 as supporting documents:
– to understand the significance of changes
– to assist in decision-making
• Nothing substitutes for critical thinking-Chemistry,
Manufacturing and controls
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 NDA/ANDA/AADA

AFTER APPROVAL

PILOT SIZE COMMERCIAL SIZE

LEVEL I CHANGE

changes LEVEL II CHANGE

LEVEL III CHANGE

Batch size Changes in Changes in Changes in

manufacturing site Changes in
equipment raw material
process
supplier

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SUPAC documents for quality assessment are
1. SUPAC IR (for immediate-release solid oral dosage forms) –Nov 1995

2. SUPAC MR (for modified-release solid oral dosage forms)-Sep. 1997

3. SUPAC IR Q&A (Question and Answers)-Feb. 1997

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

creams, ointments, gels, and lotions).-May 1997

5. PAC ATLS-(Analytical testing Lab. changes)- Apr. 1998

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Introduction to SUPAC IR guidance
• Prepared by SUPAC expert working group
(CDER)
• Result of:
– scale-up workshop by American Association of
Pharmaceutical Scientists/USP convention/FDA
– Research from universities of Maryland,
Michigan
– International Society of Pharmaceutical
Engineering (equipment addenda)
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 Introduction to SUPAC IR guidance
SUPAC IR guidelines define:
1. Levels of change
2. Recommended chemistry, manufacturing and
controls (CMC) for each level of change
3. In-vitro and/or in-vivo requirements for each
level of change
4. Required documentation to support the change

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 SUPAC GUIDELINES
(Scale-Up and Post Approval Changes)
(Part –II Levels of Change)
By
Dr. Krishnananda Kamath K. M. Pharm., Ph.D
Professor, Department of Pharmaceutics
Srinivas College of Pharmacy,
Mangalore 574143
E mail: medhakkamath@gmail.com
Mobile: 9742227045
 Introduction to SUPAC IR guidance
SUPAC IR guidelines define:
1. Levels of change
2. Recommended chemistry, manufacturing and
controls (CMC) for each level of change
3. In-vitro and/or in-vivo requirements for each
level of change
4. Required documentation to support the change

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 Two key areas:
► Changes to
Components and composition

► Changes to
Manufacturing (Equipment, Process)

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 Components and composition
• Level 1 changes: quantitative only (colour, flavour, ink Change)
• Level 2 changes: quantitative > Level 1, plus any change in
excipient grade (change in excipient specifications).
• Level 3 changes: quantitative > Level 2, plus addition or
deletion of an excipient .
LEVEL 1 LEVEL 2 LEVEL 3
Unlikely to have detectable Could have significant Likely to have significant impact
impact. impact on the quality of the product.

Eg: changes in the color, Eg: change in the Eg: addition/ deletion of any
flavor. technical grade of the excipient.
excipients.

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 Composition – Level 1 Changes
Level 1 changes
• Addition or deletion of a colour or flavour, or
change in an ink excipient (or preservative
(MR))
• Changes less than the following table level 1
column (expressed as percentage of the total
formulation):
[Note that total additive effect should not
exceed 5% of total target FPP weight.]

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 Composition – Level 2 Changes
Level 2 changes
• Changes greater than level 1 but less than the
following table (level 2 column).
• Changes in the technical grade of an excipient
e.g. Avicel PH102 vs Avicel PH200
• BEWARE TRADE NAME CHANGES – some are
actually qualitative changes, not just grade
changes
[Note that total additive effect should not
exceed 10%of total target FPP weight.]
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 Composition – Level 1/2 Changes
Excipient % Excipient
L1 L2
Filler ±5 ±10
Disintegrants
Starch ±3 ±6
Other ±1 ±2
Binder ±0.5 ±1
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 Composition – Level 1/2 Changes
Excipient % Excipient
Lubricant L1 L2
Calcium (Ca) or
Magnesium (Mg) Stearate ±0.25 ±0.5
Other ±1 ±2
Glidant
Talc ±1 ±2
Other ±0.1 ±0.2
Film Coat ±1 ±2
Total Additive Effect 5% 10%

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 Composition – Level 3 Changes
• Any change beyond level 2 OR:
• Any level 2 change for a BCS Class 4 (low
solubility and low permeability) or narrow
therapeutic drug
• Drugs not meeting the level 2 dissolution testing
• For both level 2 and level 3 changes, the
therapeutic range, solubility and permeability
are factors to be consider.

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Recommended documentation – level 1
• Stability testing: One batch on long-term
stability data reported in annual report.
• Supportive dissolution data: none
• Supportive in-vivo bioequivalence
testing: none

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Recommended documentation – level 2
• Requirements for level 2
• include stability testing, dissolution testing
and possibly an in-vivo study (depending on
the results of dissolution testing).
• IR guideline: the dissolution testing required
depends on the BCS class of the API.
• MR guideline: the dissolution testing depends
on the type of release of the FPP (Finished
Pharmaceutical Product).

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 Recommended documentation – level 3
• Requirements For Level 3 Include
• Stability Testing,
• Dissolution Testing
• An In-vivo Study.

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 FILING
COMPOSITION TIME LINE DOCUMENTATION REQUIRED
METHOD
LEVEL 1 Annual No delay, allows 1. Stability testing: one batch on long-
Report. immediate term stability data
implementation. reported in annual report.
2. Dissolution Documentation-NO.
3. In Vivo Bioequivalence –NO.

LEVEL 2 Change Being Generally a 60 day Stability testing-1 batch with 3 months
Effected. wait for FDA accelerated stability data in
review. supplement and 1 batch on long-term
stability.
Dissolution testing and possibly an in-
vivo study (depending on the results
of dissolution testing).

LEVEL 3 Prior Implementation Stability testing, dissolution testing

Approval. only after FDA and an in-vivo study.
approval may be
as long as 18
months.
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 CHANGES TO MANUFACTURING
(EQUIPMENT, PROCESS)

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 Manufacturing – Process Changes
• Level 1: changes to parameters
– (e.g. mixing times, operating speeds) within
application/validation ranges
• Level 2: changes to parameters
– (e.g. mixing times, operating speeds) outside
application/validation ranges
• Level 3: change in the type of process,
– such as from granulation technique to direct
compression of dry powder
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 Manufacturing – Process Changes
Changes Level Recommended documentation

Manufacturing – Level 1: one batch on long-term stability

Process Changes data reported in annual report.

Level 2: Stability, dissolution

Level 3: Stability, dissolution, and BE study

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 Manufacturing – Equipment Changes

Equipment is categorized according to

• Class: operating principle
• Subclass: design characterization

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 Manufacturing – Equipment Changes
Divided by unit operation:
• Blending and mixing
• Drying
• Particle size reduction/separation
• Granulation
• Unit dosing (tabletting, encapsulating, powder filling)
• Coating and printing
• Soft gelatin capsule encapsulation
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 Example class/subclass:
Blending and Mixing
Class: Diffusion (tumble) mixers:
Subclasses:
• V-blenders
• Double Cone Blenders
• Slant Cone Blenders
• Shell like Blendes
• Cube Blenders
• Bin Blenders
• Horizontal/Vertical/Drum Blenders
• Static Continuous Blenders
• Dynamic Continuous Blenders

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 Example class/subclass: Blending and
Mixing

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 Manufacturing – Equipment Changes
• Level 1:
– 1) change from non-automated or non-
mechanical equipment to automated or
mechanical equipment to move ingredients; and
– 2) change to alternate equipment of the same
design and operating principles of the same or
of a different capacity.
• Level 2:
– change to equipment of different design and
different operating principles
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 Manufacturing – Equipment Changes
Recommended documentation:
Level 1:
• One batch on long term stability
Level 2:
• Stability, dissolution

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 CHANGE LEVEL 1 LEVEL 2 LEVEL 3
Change in the technical
Addition or deletion of
grade of an Changes in addition or
color or flavor.
Component & excipient.Total additive deletion of any
Total additive effect
Composition effect should not excipient.(except color
should not exceed 5%
exceed 10% of FPP or flavor)
of FPP weight.
weight.

Manufacturing Same facility, may be Same campus,

Different campus.
Site different room. different building.
Scale up beyond 10x
Scale up to 10x batch
Scale Up/Down size of pilot batch.
batch size of pilot NA
batch.
Complete change of
Changes in process Changes in process
Manufacturing process
within validation range outside validation
Process Eg: wet granulation-
eg: mixing speeds ranges.
direct compression
Change in equipment
Change in equipment
for different design,
Equipment same operating
to different design,
NA
operating principle.
principle. Srinivas College of Pharmacy,
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SUPAC limitations

SUPAC: has not been updated (1995/97 for main

guides, 1998/99 for equipment addenda)
does not discuss multiple changes
does not directly cover same class, different subclass
for equipment
does not cover modified equipment
must be used in conjunction with other references,
e.g. Excipient handbook

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References
• Drugs, Guidance, Compliance & Regulatory Information
www.fda.gov (Accessed on 30/07/2020)
• Mounica NVN, Sharmila RV, Anusha S, Evangeline L,
Nagabhushanam MV. Scale up and postapproval changes
(SUPAC) guidance for industry: A regulatory note. Int J of Drug
Regulatory Affairs; 2017, 5(1); 13-19.
• Savant DA, Ambulge JK. Pharma Pathway Industrial and
Applied Pharmacy. 14th edition. January 2016; 308-323

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 Thank You
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