The document discusses Supplemental Abbreviated Changes to an Approved Application (SUPAC) guidelines for post-approval changes to pharmaceutical drug products. It defines three levels of changes - minor, moderate, and major - and provides recommendations for documentation and necessary filings based on the level of change for components/composition, manufacturing equipment, processes, batch size, and site changes. Minor changes may only require annual reporting, while major changes involving new excipients, processes, or sites would necessitate prior approval supplements and additional testing.

1. BY SAYEDA SALMA
1ST M PHARM

2. What is supac ?
In the process of developing the new product ,
the batch size used in earliest human studies are
small.
The sizes of the batch is gradually increased(scale
up).
The scale up 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 (supac).

3. SUPAC
The FDA has issued various guidance for supac changes
designated as:
Supac-IR ( for immediate release solid oral dosage
form).
Supac-MR (for modified release solid oral dosage
form).
Supac-SS (for non sterile semisolid dosage form
including creams, ointments, gels and lotions).

4. Supac guidelines-define
Level of
changes
• Minor changes
• Moderate changes
• Major changes
filing
• Annual report
• Changes being affected supplement
• Prior approval supplement
tests
• Application/compendial tests
• In-vitro dissolution/release
• In-vivo

5. Level of changes
Likelihood of impact on formulation quality and performance:
• Level 1: Those changes that are unlikely to have any detectable
impact on formulation quality and performance.
• Example- Changes in the colour, flavours, Changes In the
excipient expressed as percentage (w/w) of total formulation,
less than or equal to the following range .

6. • Level2: Changes are those that could have significant
impact on the formulation quality and performance.
• Example -Changes in the technical grade of excipient
(Avicel PH102 vs Avicel PH200) Changes expressed as
percent (w/w of total formulation) .

7. • Level3:
 Level 3 : changes are those that are likely to have significant
impact on formulation quality and performance.
Example -Any qualitative or quantitative excipient changes a
narrow therapeutic drug beyond the range for level 1 and All
other drug not meeting the dissolution criteria as level 2.

8. These guidelines provide recommdation for post
approval changes in:
• In component or compostion
• The site of manufacture
• The scale up of manufacture
• The manufacturing(process and equipment)

9. Component and composition
changes
SUPAC-IR:
 Focus on changes in the amount of 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.

10. SUPAC-IR ( components
and composition)

11. SUPAC-IR
• 1)Focus on the changes in amount of
excipients in the drug product.
• 2)Not focus on change in the amount of the
drug substance .

12. LEVEL CLASSIFICATION EXCIPIENT
RANGES (%w/w
of total
formulation)
TEST
DOCUMENTATION
FILING
DOCUMENTA
TION
1) • Delition or
partial
delition of an
ingredient
(colour ,
flavor or
change in
ingredient of
the ink).
• -Changes in
excipients,
expressed as
% (w/w) of
total
formulation,
less than or
equal to
excipient.
 Filler
 ±5
Disintegrant
 Starch
 ±1 Binder
 ±0.5 Lubricant
 Calcium
(Ca)or
Magnesium
 (Mg) Stearate
±0.25
 stability
 Application/Co
mpendial
requirements
 Annual report

13. LEVEL CLASSIFICATION EXCIPIENT
RANGES (%w/w of
total formulation)
TEST
DOCUMENTATION
FILING
DOCUMEN
TATION
2)  Change in
technical
grade of
excipient.
 Changes in
excipients,
expressed as
% (w/w) of
total
formulation,
greater than
Level 1
changes.
 Filler
 ±10
Disintegrant
 Starch
 ±6 Other
 ±1 Binder
 ±1 Lubricant
 Calcium (Ca) or
 Magnesium (Mg)
 Stearate ±0.5
 Other
±2 Glidant Talc
±2 Other
±0.2
 -stability
application/co
mpendial
requirements.
 Dissolution
data depends
on solubility,
therapeutic
range and
permeability.
 Case A(hp-hs)
 Case B(lp-hs)
 Case C(hp-ls)
•Prior
approval
supplement
•Annual report

14. LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION
3)  Higher than SUPAC-
IR.
 Level 1 and Level 2
excipient ranges.
 stability
application/compend
ial requirements.
 Case B dissolution
profile (Multi-point
dissolution profile in
the application
/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
•Prior approval
supplement.
•Annual report.

15. SUPAC-MR (components
and composition)

16. SUPAC-MR
Components and composition of non-release controlling
excipient and release controlling excipient.
 Focuses on changes to non-release controlling excipients.
 Changes in components or composition that have the
effect of adding a new excipient or deleting an excipient
are defined at level 3.

17. Non-release controlling excipient
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
1)  Delition or partial
delition of an
ingredient –up to
SUPAC-IR Level 1
excipient ranges.
 stability-
application/compen
dial requirements.
 Annual report

18. LEVEL 2
2)  change in
technical grade
of excipients
 up to SUPAC-IR
Level 2
excipient
ranges
 stability
application/compen
dial requirements.
 Multi-point
dissolution profiles
(15,30,45,60 & 120
min) USP buffer
media at pH 4.57.5
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)
•Prior
approval
supplement.
•Annual report

19. LEVEL 3
3)  Higher than
SUPAC-IR
Level 1 and
Level 2
excipient
ranges.
 -stability
application/compen
dial requirements.
 Biostudy or IVIVC
 Prior approval
supplement

20. SUPAC-MR (release controlling
excipient)
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION
1)  ≤ 5% w/w change
based on total
release
controlling
excipient
content.
 No other changes
 Stability
 application/compendi
al requirements
 Annual report

21. LEVEL 2
2)  change in
technical grade
of excipients.
 ≤ 10% w/w
change based
on total release
controlling
excipient
content.
 stability
application/compendi
al requirements.
 Multi-point dissolution
profiles (15,30,45,60
& 120 min) USP buffer
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 DR release)
 Prior
approval
supplement
 Annual
report

22. SUPAC-SS (components
and composition)

23. SUPAC-SS
• for non sterile semisolid dosage form including
creams , ointments , gels and lotions.

24. SUPAC-SS (Components and
composition)
LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
DOCUMENTATION
1)  Delition or partial
delition of an
ingredient.
 change in supplier or
technical grade of
any other excipient.
 Up to 5 % change in
approved amount of
ingredient
 Stability
 application/
compendial
requirements
 Annual report

25. LEVEL 2
2)  Upto >5 % and ≤ 10
% change in
approved amount of
ingredient.
 Change in particle
size distribution of
the drug substance,
if the drug is in
Suspension.
 change in supplier
or technical grade
of any other
excipient
 stability
application/compe
ndial requirements
 in vitro release
test
 Changes
being
effected
supplement
 Annual
report

26. LEVEL 3
3)  change in approved
amount of
ingredient.
 Change in
crystalline form of
ingredient
 Stability
 application/comp
endial
requirements
 Prior
approval
supplement

27. SUPAC-SS (preservative)
LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
DOCUMENTATION
1) Quantitatively 10% or
less change in the
approved amount of
preservative.
 application/comp
endial
requirements
 Preservative
effectiveness test
at lowest
specified
preservative level
Annual report

28. LEVEL 2
2)  10% -20 % change in
the approved
amount of
preservative
 application/comp
endial
requirements.
 Preservative
effectiveness test
at lowest
specified
preservative level
 Changes
being
effected
supplem
ent
 Annual
report

29. LEVEL 3
3)  > 20% change in
the approved
amount of
preservative
(including
deletion) or use of
a different
preservative.
 application/compen
dial requirements -
executed batch
records.
 For new
preservative,
analytical method
for identification
and assay validation
studies.
 Preservative
effectiveness test at
lowest specified
preservative.
 Prior
approval
supplement
 Annual
report

30. Site changes
It includes the changes in location of the site
of manufacturing facilities for both company
owner and contract manufacturer.
It does not include scale up

31. LEVEL 1
LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
DOCUMENTATION
1)  Site change within a
single facility.
 No change in SOP,
environmental
conditions or
equipment's used.
 Common personnel's
 application/co
mpendial
requirements
Annual report

32. Level 2
2)  Same
continuous
campus
 Common
personnel
 No other
changes
 application/compendial
requirements.
 Notification of Location of
new site
 Updated batch records.
 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)until 80% of
Drug Released.
 Annual
report
 Changes
being
Effected
Supplement

33. LEVEL 3
3)  Different
campus
 Different
personnel
 application/compendial
requirements
 Notification of Location of new
site
 Updated batch record
 SUPAC –IR : Multi-point
dissolution profile in the
application and compendial
medium
 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).
 Annual
report
 Prior
approval
supplement

34. Change in
batch size
(scale up of
manufacture)
Post approval changes in the size of a
batch from the pivotal/pilot scale
biobatch material to larger or smaller
production.
Post
Scale down below 1,00,000 dosage
units is not covered by this guideline.
Scale
down
Scale up changes should be properly
validated and if needed, inspected by
appropriate agency personnel.
Scale
up

35. Level 1
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION
1)  Change in batch
size, up to and
including a
factor of 10
times the size
of the
pilot/biobatch
 Updated batch records
application/compendial
requirements stability
Annual report

36. Level 2
2)  Changes in
batch size
beyond a factor
of ten times the
size of the pilot
or biobatch
 No other
changes
 -Updated batch records -
application/compendial
requirements
 Stability
 SUPAC –IR Multi-point
dissolution profiles.
 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
o Annual
report
o Changes
being
effected
by
suppleme
nt

37. MANUFACTURING CHANGES
(equipment)
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION
1)  Alternate
equipment of
same design and
principles
Automated
equipment's
 Updated batch records
 application/compendial
requirements stability
Annual report

38. LEVEL 2
2)  Change to
equipment of
different design
and principle
 Updated batch records
application/compendial
requirements
 Stability
 SUPAC –IR Multi-point
dissolution profiles in
multiple medias
 SUPAC – MR -Multi-point
dissolution profiles in
multiple medias
 Annual
report
 Changes
being
Effected
Suppleme
nt

39. MANUFACTURING CHANGES
(PROCESS)

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION
1)  Adjustment
of equipment
operating
conditions
(operating
speeds,
mixing times)
 Within
approved
application
ranges
 Updated batch records
 application/compendial
requirements
 Stability
Annual report

40. LEVEL 2
2)  Adjustment of
equipment
operating
conditions
(operating
speeds,
mixing times)
 Beyond
approved
application
ranges
 SUPAC – SS
Change in the
process of
combining two
phases
 -Updated batch records -
application/compendial
requirements
 Stability
 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-SS In vitro release
test Documentation.
 Annual
report
 Changes
being
Effected
Suppleme
nt

41. LEVEL 3
3)  Changes in
the type of
process
used (e.g.
wet
granulation
to direct
compressio
n
 Updated batch records -
application/compendial
requirements -Stability -
Biostudy or IVIVC.
 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)
 Prior
approval
supplement
 Annual
report

42. LIMITATIONS OF SUPAC
• Supac has not been updated ( 1995/97 for main
guidelines )
• Does not discuss multiple changes
• Does not cover modified equipment
• Must be used in conjunction with other references
ex: excipient handbook.