SUPAC

Scale - Up and Post Approval

Changes

1 Presented By:- Sonia P. Nagvenkar

 Index
Definition
Scientific Rational
SUPAC Guidelines SUPAC IR, SUPAC MR, SUPAC SS
Levels of Change
Components and composition
Manufacturing Site Changes
Batch size change (Scale up)
Manufacturing change : Process & Equipment
Limitations of SUPAC

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

Bioequivalent to the
Generic Drug FDA reference listed
Product drug (RLD)product

ANDA or
Larger Batch size SCALE UP
AADA approved
by FDA
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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.
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.

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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.

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 The FDA has issued various guidances 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),
and
C. SUPAC-SS (for non-sterile semisolid dosage forms
including creams, ointments, gels, and lotions).

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 SUPAC GUIDELINES - DEFINE

Minor change
Level of Moderate change
Changes Major change

Application / Compendial Tests

Tests In Vitro Dissolution / Release
In Vivo

Annual Report
Filing Changes Being Effected
Supplement
Prior Approval Supplement

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 Levels of change
Likelihood of impact on formulation quality and
performance

Level 1: unlikely to have detectable impact

Level 2: could have significant impact
Level 3: likely to have significant impact

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 These guidelines provide recommendations for
post approval changes in
(1) the components or composition,
(2) the site of manufacture,
(3) the scale-up of manufacture, and
(4) the manufacturing (process and equipment)

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 Components & Composition
This section focuses on changes in excipients in the drug
product
SUPAC-MR: Excipient critical or non critical to the drug
release.
- Changes in non release controlling excipients
- Changes in release controlling excipients
SUPAC-SS: Changes in preservative

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 SUPAC - IR
LEVEL CLASSIFICATION EXCIPIENT RANGES TEST FILING
(%w/w of total DOCUMENTATION DOCUMENTAT
formulation) ION
-Delition or Filler 5 -stability Annual
partial delition Disintegrant -application/ report
of an ingredient Starch 3 compendial
(colour, flavor Other 1 requirements
or change in Binder
ingredient of 0.5
the ink) Lubricant
I -Changes in Calcium (Ca) or
excipients, Magnesium (Mg)
expressed as % Stearate 0.25
(w/w) of total Other 1
formulation, less Glidant
than or equal to Talc 1
excipient % Other 0.1
ranges Film Coat 1
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LEVEL CLASSIFICATI EXCIPIENT RANGES TEST DOCUMENTATION FILING
ON (%w/w of total DOCUMEN
formulation) TATION
-change in Filler 10 -stability Prior
technical Disintegrant application/compendial approval
grade of Starch 6 requirements supplement
excipients Other 1 -Dissolution data depends Annual
-Changes in Binder 1 on solubility, theraputic report
excipients, Lubricant range and permeability.
expressed as Calcium (Ca) or Case A : High
% (w/w) of Magnesium (Mg) Permeability, High
total Stearate 0.5 Solubility Drugs
II formulation, Other 2 Single point Dissolution
greater than Glidant profile .
Level 1 Talc 2 Case B : Low Permeability,
changes. Other 0.2 High Solubility Drugs
Film Coat 2 Multi point dissolution
profile
Case C :High Permeability,
Low Solubility Drugs
Multi point and multi
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media dissolution profile
 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION

-Higher than SUPAC- -stability Prior approval

IR Level 1 and Level 2 application/compendial supplement
excipient ranges. requirements Annual report

-Case B dissolution profile

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

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 SUPAC MR Non Release Controlling Excipients
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

-Delition or partial delition of -stability Annual

an ingredient -application/compendial report
I
-upto SUPAC-IR Level 1 requirements
excipient ranges
-change in technical grade of -stability Prior
excipients application/compendial approval
-upto SUPAC-IR Level 2 requirements supplement
excipient ranges -Multi-point dissolution profiles Annual
(15,30,45,60 & 120 min) report
II
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)
-Higher than SUPAC-IR Level -stability Prior
1 and Level 2 excipient application/compendial approval
III ranges. requirements supplement
-Biostudy or IVIVC Annual
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report
 SUPAC MR Release Controlling Excipients
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMEN-
TATION
- 5% w/w change -stability Annual report
based on total -application/compendial requirements
I release controlling
excipient content.
-No other changes
-change in -stability Prior approval
technical grade of application/compendial requirements supplement
excipients -Multi-point dissolution profiles Annual report
- 10% w/w change (15,30,45,60 & 120 min)
II
based on total USP buffer pH 4.5-7.5 for extended
release controlling release) Three different Media (e.g.,
excipient content. Water, 0.1N HCl, and USP buffer media
at Ph 4.5 And 6.8 for DR release)
-> 10% w/w change -stability Prior approval
based on total application/compendial requirements supplement
III
release controlling -Biostudy or IVIVC Annual report
15 excipient content.
 SUPAC SS Components and Composition
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

-Delition or partial delition of an -stability Annual

ingredient -application/ compendial report
-change in supplier or technical requirements
I
grade of any other excipient
-Upto 5 % change in approved
amount of ingredient.
-Upto >5 % and 10 % change in -stability Changes
approved amount of ingredient. application/compendial being
-Change in particle size requirements effected
distribution of the drug -in vitro release test supplement
II
substance, if the drug is in Annual
Suspension report
-change in supplier or technical
grade of any other excipient
-change in approved amount of -stability Prior
ingredient. application/compendial approval
III -Change in crystalline form of the requirements supplement
drug substance, if the drug is in -in vitro release test Annual
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suspension -in vivo bioequivalence test. report
 SUPAC SS Components and Composition - Preservative
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

Quantitatively 10% -application/compendial Annual report

or less change in the requirements
I
approved amount of -Preservative effectiveness test at
preservative lowest specified preservative level
10% -20 % change in -application/compendial Changes being
the approved requirements effected
II amount of -Preservative effectiveness test at supplement
preservative lowest specified preservative level Annual report

> 20% change in the -application/compendial Prior approval

approved amount of requirements supplement
preservative -executed batch records Annual report
(including deletion) -For new preservative: analytical
III
or use of a different method for identification and assay;
preservative. validation studies
-Preservative effectiveness test at
lowest specified preservative level
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 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.

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 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATI-
ON

-Site change within application/compendial Annual report

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

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LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

-Same continuous -application/compendial Annual report

campus requirements Changes being
-Common -Notification of Location of new site Effected
personnel -Updated batch records Supplement
-No other changes
SUPAC MR
-Multi-point dissolution profiles
II
(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.

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LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
-Different campus -application/compendial Annual report
-Different requirements Prior approval
personnel -Notification of Location of new site supplement
-Updated batch record

SUPAC IR
Multi-point dissolution profile in the
application/compendial medium
III
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.
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 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.

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 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
I Change in batch Updated batch records Annual
size, up to and application/compendial requirements report
including a stability
factor of 10 times
the size of the
pilot/biobatch
II Changes in batch -Updated batch records Annual
size beyond a -application/compendial requirements report
factor of ten -Stability Changes
times the size of SUPAC IR being
the pilot or Multi-point dissolution profiles Effected
biobatch, SUPAC MR Supplement
No other changes -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
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 Manufacturing Changes
Changes affecting:
- Equipments
- Manufacturing process

Appropriate validation studies are conducted

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 Manufacturing Changes - Equipments
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
-Alternate equipment of -Updated batch records Annual report
same design and -application/compendial
I
principles requirements
Automated equipments stability
Change to equipment of Updated batch records Annual report
different design and application/compendial Changes
principle requirements being Effected
Stability Supplement
SUPAC IR
Multi-point dissolution
II profiles in multiple medias
SUPAC MR
-Multi-point dissolution
profiles in multiple medias
SUPAC-SS
In vitro release test
25 Documentation
 Manufacturing Changes- Process

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

I -Adjustment of -Updated batch records Annual

equipment -application/compendial report
operating requirements
conditions -stability
(operating speeds,
mixing times)

Within approved
application ranges

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 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

-Adjustment of -Updated batch records Annual

equipment -application/compendial report
operating requirements Changes
conditions -Stability being
(operating Effected
speeds, mixing SUPAC-IR Supplement
times) Multi-point dissolution profile

Beyond approved SUPAC-MR

II
application -Multi-point dissolution profiles in
ranges multiple medias (e.g., USP buffer media
at pH 4.5-7.5 for extended release)
-SUPAC SS three other media (e.g., Water, 0.1N HCl,
Change in the and USP buffer media at Ph 4.5 And 6.8
process of for delayed release)
combining two
phases SUPAC-SS
In vitro release test Documentation
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 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

III Changes in the -Updated batch records Prior

(SUPAC-IR type of process -application/compendial approval
SUPAC-MR) used (e.g. wet requirements supplement
granulation to -Stability Annual
direct -Biostudy or IVIVC report
compression
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)

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 Dissolution Profile Comparison Using
Similarity Factor, f2
FDA has placed more emphasis on a dissolution profile
comparison in the area of post-approval changes
Among several methods investigated for dissolution
profile comparison, f2 is the simplest.
f2 = 50 + log {[1+ (1/n) t=1 * n (Rt-Tt)2]-0.5 *100}
(where Rt and Tt are the cumulative percentage
dissolved at each of the selected n time points of the
reference and test product respectively.
When the two profiles are identical, f2=100. FDA has
set a public standard of f2 value between 50-100 to
indicate similarity between two dissolution profiles.

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 SUPAC limitations
SUPAC:
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, e.g.
excipient handbook

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 Thank You

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