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4. Batch size changes
Level 1 change
Level 2 change
5 . Manufacturing changes
Manufacturing equipment changes
Manufacturing process changes
6. Reference
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y NDA
y ANDA
y AADA
y changes
The components
or compositions
Manufacturing(Process and
equipment) of an
immediate release
dosage form
The site of
manufacture
The scale up/down of
manufacture
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SUPAC guidance covers
y Component and composition change
y Manufacturing site change
y Batch size changey Manufacturing process and equipment change
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y SUPAC IR
y SUPAC-SS
y SUPAC-MR
SUPAC industry perspective:
It is based on interviews with 6 companies in the firsthalf of1997.
Shorter waiting times for site transfers.More rapid implementaion of process and equipment
changes.
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y Production of fewer unmarketable stability batches
y Reduced administration costs for documentation ofchanges by the regulatory affairs departments.
y Estimated saving $51.2 million/year.
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Level 1 changesy Level 1 changes are those that are unlikely to have any
detectable impact on formulation quality and
performance.
Examplesy deletion of color or flavor
y excipient change with total additive effect of up to 5%
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Nonrelease controlling
excipient
Percent excipient (w/w) of
total formulation, less than
or equal to the followingpercent ranges
Filler 5
Disintegrants
Starch
Other
3
1
Binder 0.5
Lubricant
Ca or Mg Stearates
Other
0.25
1Glidant
Talc
Other
Film Coat
1
0.1
1
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IR SS
(Semisolid)
MR (nrc) MR (rc)
Chemistry
documentation
Application/co
mpendial
release
requirement*
same same same
Stability
testing
One batch
with long term
stability testing
( 1 LT)
1 st batch with
LT
Same as SS Same as SS
Dissolution
Documentation
None none none none
In vivo None none none none
Filling
documentation
Annual report
(all information
including LT)
same same same
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y Level 2 changes are those that could have a significantimpact on formulation quality and performance.
y Tests and filing documentation for a level 2 changevery depending on three factors:
y therapeutic range
y solubility
y permeability
Examples:y change in technical grade of excipient
y excipient change with total additive effect of up to 10%
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Excipient % W/W out of total target dosage for
weight
Filler 10
Disintegrant
Starch 6
Other 2
Binder 1
Lubricant
Calcium or magnesium stearate 0.5
Other 2
Glidant
Talc 2
Other 0.2
Film Coat 2
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IR SS MR (nrc) MR (rc)
Chemistry
documentation
Release and
batch record
Release and
executed batch
record
release and
executed batch
record
release and
executed batch
record
Stabilitydocumentation
1 batch with 3month accel and
1 batch LT*
same same Same
Dissolution Yes- depends
on Permeability
and solubility@
Yes- Compare Yes- compare Yes- compare
In vivo None none none Non for non-
narrowtherapeutic
index (T.I.) AND
Single dose for
narrow T.I.
Filing
documentation
PA (accel stab)
AR (LT stab)
CBE (accel
stab)
AR (LT stab)
Same as IR Same as IR
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Case AHP,
HS
Dissolution of 85 % in 15 min. in 900 ml 0f 0.1 N HCl.
If drug product fails to meet the criteria then go for
the Case B, C
Case BLP,HS
Multi point dissolution profile according thecompendial medium at 15, 30, 45, 60 and 120 min.
Case CHP,
LS
Dissolution profile comparison in water, 0.1 N HCl,
pH 4.5, 6.5 and 7.5. adequate sampling at 15, 30,
45, 60 and 120 minute or until either 90 % of drug
from the drug product is dissolved.
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IR SS MR (nrc) MR (rc)
Chemistry
documentation
Release and
batch record
Release and
executed batch
record
Release and
executed batch
record
Release and
executed batch
record
Stability
documentation
1 batch with 3
months accel
1 LT
Same and first
three batches
with LT
Same as SS Same as SS
Dissolution Same as Level
2
Not required Extended and
delayed*
Extended and
delayed*
In vivo Bioequivalence
needed
Same Same Same
File PA (accel stab)
AR (LT stab)
Same Same Same
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A. Manufacturing site Level I changes
y Level I changes is defined as changes in manufacturingsite
y within a single facility where the same equipment,SOPs, environmental conditions and controls, andpersonnel common to both sites are used
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IR SS MR
Chemistry
documentation
Release Same Same
Dissolution Release none Release
In vivo None none None
File AR AR AR
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y Level 2 changes may be defined as the changes in themanufacturing site
y within a contiguous campus, or between facilities inadjacent city blocks, where same equipment, SOPs,environmental conditions and controls, and personnelcommon to both sites are used
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IR SS MR
Chemistry
documentation
Release;
Notification of
location of new
site and updated
batch record
Same as IR Release;
Notification of
location of new
site and updated
executed batchrecord
Stability testing 1 LT 1 st LT 1 batch w/3
months accel.
1 st LT*
Dissolution Release none Extended and
delayedIn vivo None none None
File CBE
AR (LT stab)
CBE
AR (LT stab)
CBE (accel stab)
AR (LT stab)
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y A change in manufacturing site to a different campuswhere the same equipment, SOPs, environmentalconditions and controls are used
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IR SS MR
Chemistry
documentation
Release; Notification of
change and updated
batch record
Release;
same
Release;
same
Stability testing
SBI (significant body of
information available) *
1 batch w/3 months
acel.
Upto 3 batch with LT
Same; 1 st three batch
LT
Same;
1 st three batch LT
NSBI (significant body
of information is not
available) *
Upto 3-3 months accel.
Upto 3 LT*
Three batch with 3
months accel.
Three batch with LT
Three batch with three
months accel.
1 st three production
batches with LT
Dissolution As per low permeability
and high solubility
comparison Extended and delayed
In vivo None none Single dose
bioequivalence
File CBE (accel stab)
AR (LT stab)
Same as IR PA (accel stab)
AR (LT stab)
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y change to larger or smaller production batch
y < 100,000 unit scale down not covered
y scale up validation needed
y may need inspection
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y A change up to and including a factor of10 times thepilot/biobatch where cGMPs, SOPs and controls,formulation and manufacturing procedures are the
same.
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IR SS MR
Chemistry
documentation
Release; Notification
of change and
updated batch
record
Release; Notification
of change and
updated batch
record
Release; Notification
of change and
executed batch
record
Stability study 1 LT 1 st LT 1 st LT
Dissolution Release none Release
In vivo none none None
File AR (LT stab) same Same
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y Defined as a change in batch size beyond a factor of10times the pilot / bio batch where cGMPs, equipment,SOPs and controls, formulation and manufacturing
procedures are same.
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changes that may affect equipment
changes that may affect the manufacturing process
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y A. Equipment Level 1 change
A change to automated or mechanical equip. to move
ingredients, a change to alternative equipment of samedesign and operating principle, a change to differentcapacity equipment.
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IR SS MR
Chemistry Release; Notification
of change and
updated batch
record
Release; Notification
of change and
updated batch
record
Release; Notification
of change and
updated batch
record
Stability testing 1 LT 1 LT 1 LT
Dissolution Release None Release
In vivo None none None
File AR (LT stab) same Same
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y Examples include: Changes in equipment to a differentdesign or different operating principle or a change inthe type of mixing equipment.
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IR SS MR
Chemistry
documentation
Release;
Notification of
change and
updated batch
record
Release;
Notification of
change and
updated batch
record
Release;
Notification of
change and
updated
executed batch
record
Stability testing
SBD One batch with 3
months
accelerated
stability study
1 LT
Same
1 st LT
Same
Three batch with
long term stability
study
Dissolution Yes (Case C) comparision Extended and
delayedIn vivo None none none
File PA (accel stab)
AR (LT stab)
CBE (accel stab)
AR (LT stab)
PA (accel stab)
AR (LT stab)
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y A. Manufacturing Process Level 1 ChangeThis category includes process changes including changes such as
mixing times and operating speeds within application/validationranges.
IR SS MR
Chemistry
documentation
Release release Release;
Notification of
change and
updated
executed batch
record
Dissolution Release None Release
In vivo None none None
File AR AR AR
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y This category includes process changes includingchanges such as mixing times and operating speedsoutside of application/validation ranges
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IR SS MR
Chemistry
documentation
Release; Notification
of change and
updated batch
record
Same same
Stability testing 1 LT One batch with 3
months accel.
1 st LT
Stability: SBD 1-3 mos accel *
1 st LT
Stability: NSBD 3-3 mos accel @
Dissolution Yes (case B) comparision Extended and
delayed)File CBE (accel stab)
AR (LT stab)
same same
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y This category includes change in the type of processused in the manufacture of the product, such as achange from wet granulation to direct compression ofdry powder.
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IR SS MR
Chemistry
documentation
Release; Notification of
change and updated
batch record
No level 3 Release; notification of
change and updated
executed batch record
Stability testing Three batch with 3
months accelerated
stability study1 st 3 LT @
Stability: SBD One batch with 3
months accel.
1 LT
Stability: NSBD Upto 3-3 mos accel.
Upto 3 LT *
Dissolution Yes (Case B) Extended and delayed
In vivo Study needed Single dose
File PA (accel stab)
AR (LT stab)
same
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