Scale - Up and Post

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

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

Larger Batch SCALE ANDA or A A D A

size UP approved by
FDA
 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.
The SUPAC guidance's define:

1. levels of chemistry, manufacturing, and control change;

2. recommended chemistry, manufacturing, and controls

tests for each level of change;

3. recommended in vitro dissolution and release tests and/or in

vivo bioequivalence tests for each level of change; and

4. recommended documentation that should support the

change for new drug applications and abbreviated new drug
applications
 Scientific Rationale

⚫ To speed up the processes of post approval

changes of drug products

⚫ FDA can assure their safety and

effectiveness.

⚫ Lower the regulatory burden for industry.

 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 semi solid dosage forms
including creams, ointments, gels, and lotions)
 SUPAC GUIDELINES - DEFINE

LEVEL OF CHANGES
• MINOR
• MODERATE
• MAJOR

TESTS
• Application/Compendial Test
• In-vitro dissolution release/in vivo

FILING
• Annual Report
• Changes being made
• Prior approval supplement
LEVELS OF CHANGES
3 levels of changes

level
level 1 2

level 3
 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

9
• 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)

 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

11
 SUPAC - IR
LEVE CLASSIFICAT EXCIPIENT TEST FILING
L I ON RANGES DOCUMENTATI DOCUMENTA
(%w/w of total ON TION
formulation)
-Delition or Filler -stability •Annual
partial delition ±5 -application/ report
of an Disintegrant compendial
ingredient Starch requirements
(colour, flavor ±3
or change in Other
ingredient of ±1
the ink) Binder
-Changes in ±0.5
I excipients, Lubricant
expressed as Calcium (Ca) or
% (w/w) of Magnesium (Mg)
total Stearate
formulation, ±0.25
less than or Other
equal to ±1
LEVE CLASSIFICA EXCIPIENT TEST FILING
L TION RANGES DOCUMENTATION DOCUMEN
(%w/w of total TATION
formulation)
-change in Filler -stability •Prior
technical ±10 application/compendial approval
grade of Disintegrant requirements suppleme
excipients Starch -Dissolution data nt
-Changes in ±6 depends on solubility, •Annual
excipients, Other ±1 theraputic range and report
expressed Binder permeability.
as % (w/w) ±1 Case A : High
of total Lubricant Permeability, High
formulation, Calcium (Ca) or Solubility Drugs
greater than Magnesium (Mg) Single point
II Level 1 Stearate Dissolution profile .
changes. ±0.5 Case B : Low
Other Permeability, High
±2 Solubility Drugs
Glidant Multi point dissolution
Talc profile
±2 Case C :High
Other Permeability, Low
±0.2 Solubility Drugs
LEVEL CLASSIFICATION TEST FILING
DOCUMENTATION DOCUMENTATIO
N

-Higher than -stability •Prior approval

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

-Case B dissolution
profile (Multi-point
dissolution profile in
the application
III /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
 SUPAC – MR
LEVE CLASSIFICATION ipTiEeSnT FILING
L DtsOCUMENTATION
Exc
-Delition or partial -stability •Annual
delition of an -application/compendial report
I requirements
ingredient
-upto SUPAC-IR
Level 1
excipient ranges
-change in -stability •Prior
technical grade of application/compendial approval
excipients requirements supplemen t
-upto SUPAC-IR -Multi-point dissolution •Annual
Level 2 profiles (15,30,45,60 & 120 report
excipient ranges min)
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 -stability •Prior approval
than application/compendial supplemen t
SUPAC-IR requirements
III Level 1 and -Biostudy or IVIVC
Level 2
excipient
ranges.
 SUPAC – MR Release Controlling
LEVE CLASSIFICATION ExTEcSiTpDiOeCnUMtsENTATION FILING
L DOCUMEN-
TATION
-≤ 5% w/w -stability •Annual
change based on -application/compendial report
total release requirements
controlling
I
excipient
content.
-No other
changes
-change in -stability •Prior
technical grade application/compendial approval
of excipients requirements supplement
-≤ 10% w/w -Multi-point dissolution •Annual
change based on profiles (15,30,45,60 & 120 report
II total release min)
controlling USP buffer pH 4.5-7.5 for extended
excipient release) Three different Media (e.g.,
15
content. Water, 0.1N HCl, and USP buffer
media at Ph 4.5 And 6.8 for DR
release)
 SUPAC – SS Components and Composition
LEVE CLASSIFICATION TEST DOCUMENTATION FILING
L
-Delition or partial delition of -stability •Annual
an ingredient -application/ compendial report
-change in supplier or requirements
I technical grade of any other
excipient
-Upto 5 % change in approved
amount of ingredient.
-Upto >5 % and ≤ 10 % change -stability •Changes
in approved amount of application/compendial being
ingredient. requirements effected
-Change in particle size -in vitro release test suppleme
distribution of the drug nt
II substance, if the drug is in •Annual
Suspension report
-change in supplier or
technical grade of any other
excipient

-change in approved amount -stability •Prior

of ingredient. application/compendial approval
-Change in crystalline form requirements suppleme
of
 SUPAC – SS Components and Composition -
LEVE CLASSIFICATION
PrTeESsTeDrvOaCUtiMvEeNTATIO FILING
L
N
Quantitatively -application/compendial •Annual report
10% or less requirements
I change in the -Preservative effectiveness test
approved amount at lowest specified preservative
of preservative level
10% -20 % change -application/compendial •Changes
in the approved requirements being effected
II amount of -Preservative effectiveness test supplement
preservative at lowest specified preservative •Annual
level report
> 20% change in -application/compendial •Prior approval
the approved requirements supplement
amount of -executed batch records •Annual report
preservative -For new preservative:
(including analytical method for
III deletion) or use of identification and assay;
a different validation studies
preservative. -Preservative effectiveness test
at lowest specified preservative
 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.

⚫ currentGood Manufacturing Practice

(CGMP) inspection.
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATI
-ON

-Site change application/compendi •Annual

within a single al requirements report
facility
-No change in
SOP,
I environmental
conditions or
equipments used
-Common
personnels
LEVE CLASSIFICATI TEST DOCUMENTATION FILING
L O N

-Same -application/compendial •Annual report

continuous requirements •Changes
campus -Notification of Location of new being Effected
-Common site Supplement
-Updated batch records
personnel
-No other SUPAC – MR
II changes -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.

22
LEVE CLASSIFICATIO TEST DOCUMENTATION FILING
L N
-Different -application/compendial Annual report
campus requirements Prior approval
-Different -Notification of Location of new supplement
personnel site
-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
 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
24 /100 kg or 10% of a production batch, whichever
LEVE CLASSIFICATI TEST DOCUMENTATION FILING
L ON
I Change in Updated batch records •Annual
batch size, up application/compendial report
to and requirements
including a stability
factor of 10
times the size
of the
pilot/biobatch

II Changes in -Updated batch records •Annual

batch size -application/compendial report
beyond a factor requirements •Changes
of ten times the -Stability being
size of the pilot SUPAC –IR Effected
or biobatch, Multi-point dissolution profiles Suppleme
No other SUPAC – MR nt
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
 Manufacturing Changes
⚫ Changes affecting:
- Equipments
- Manufacturing process

⚫ Appropriate validation studies are

conducted
 Equipments
LEVE CLASSIFICATION TEST DOCUMENTATION FILING
L
-Alternate equipment -Updated batch records •Annual
of same design and -application/compendial report
I principles requirements
Automated stability
equipments
Change to equipment Updated batch records •Annual
of different design and report
principle application/compendial •Changes
requirements being
Stability Effected
SUPAC –IR Supplement
Multi-point dissolution
II profiles in multiple
medias
SUPAC – MR
-Multi-point dissolution
profiles in multiple
medias
 Manufacturing Changes- Process
LEVE CLASSIFICATION TEST DOCUMENTATION FILING
L

I -Adjustment of -Updated batch records •Annual

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

Within approved
application ranges
28
 LEVE CLASSIFICATI TEST DOCUMENTATION FILING
L ON
-Adjustment of -Updated batch records •Annual
equipment -application/compendial report
operating requirements •Changes
conditions -Stability being
(operating Effected
speeds, mixing SUPAC-IR Suppleme
times) Multi-point dissolution nt
profile
Beyond SUPAC-MR
II approved -Multi-point dissolution profiles in
application multiple medias (e.g., USP buffer
ranges media at pH 4.5-7.5 for extended
release) three other media (e.g.,
-SUPAC – Water, 0.1N HCl, and USP buffer
SS media at Ph 4.5 And 6.8 for delayed
Change in the release)
process of
combining two SUPAC-SS
phases In vitro release test Documentation
29
 LEVEL CLASSIFICAT TEST DOCUMENTATION FILING
I ON
III Changes in the -Updated batch records •Prior
(SUPAC- type of -application/compendial approval
IR process used requirements suppleme
SUPAC- (e.g. wet -Stability nt
MR) granulation to -Biostudy or IVIVC •Annual
direct 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)
 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