SCALE UP PROCESS APPROVAL

CHANGES (SUPAC)
INTRODUCTION
 In the process of developing the new product the
batch size used in the earliest human studies are
small.
 The size of the batch is gradually increased
(scale up)
 The scale up and the changes made after
approval in the composition manufacturing
equipment and change of site have become
known as scale up and post approval changes
(SUPAC)
CURRENTLY FINALIZED SUPAC
GUIDANCE ARE AS BELOW
 SUPAC – IR ( Immediate Release ) – Nov.1995.
 SUPAC – IR Questions and Answer – Feb.1997.

 PAC-ATLS ( Post Approval Changes – Analytical

testing Laboratories changes )- Apr.1998
 SUPAC – MR (Modified Release ) – Sep.1997.

 SUPAC-SS (Semisolid – Non sterile ) –May 1997

COMPONENT AND COMPOSITION
CHANGES

Focus on the changes in amount of excipients

in the drug product

Not focus on change in the amount of the

drug substance
LEVEL 1 CHANGES
Definition of level
 These are unlikely to have any detectable impact on
formulation quality and performance
 Examples : a. Deletion or partial deletion of an
ingredient intended to affect the color or flavor of the
drug product; or change in the ingredient of the printing
ink to another approved ingredient.
 b. Changes in excipient, expressed as percentage
(w/w) of total formulation.

Cont…..
TEST DOCUMENTATION
 Chemistry documentation Stability testing (long
term data)
 Dissolution Documentation None

 InVivo Bioequivalence Documentation none

Filling Documentation
 Annual report(long) term stability data.
LEVEL 2 CHANGES
Definition of level
 They have a significant impact on formulation quality
and performance.
 Level 2 changes vary depending on three factors:

 I. Therapeutic range II. Solubility III. Permeability

 Examples: a. Change in the technical grade of an

excipient: Avicel PH102 vs. Avicel PH200
b. Changes in excipient, expressed as percentage
(w/w) of total formulation:
Cont…..
 TEST DOCUMENTATION
Chemistry Documentation
Level 1 + 1 batch with 3 month accelerated stability study

Dissolution Documentation
Case A – High permeability, High solubility
Case B –Low permeability, High solubility
Case C- High permeability, Low solubility
In Vivo Bioequivalence Documentation None
Filling Documentation As level 1 + Accelerated stability study
LEVEL 3 CHANGES
Definition of level
They have a significant impact on formulation quality and
performance.
Level 3 changes vary depending on three factors :
I. Therapeutic range
II. Solubility
III. Permeability.

Cont......
TEST DOCUMENTATION
a. Chemistry Documentation:
Level 1 + 1 month accelerated stability of 1 batches or
3
b. Dissolution Documentation:
Case B –Low permeability, High solubility
c. In Vivo Bioequivalence Documentation: Full
bioequivalence study. Except IVIVIC verified.
Filling Documentation
As level 1 + Accelerated stability study
SITE CHANGES
It includes the changes in location of the
site of manufacturing facilities for both
company owned and contract
manufacturer

It do not include scale up.

LEVEL 1 CHANGES
Definition of level
 Site change within a single facility where same
equipment, Standrad Operating Procduer (SOP),
Environment condition and common personnel
Test Documentation
 Chemistry, dissolution are according to
compendial and vivo BE not required.
 In Vivo Bioequivalence Documentation: None.

 Filling Documentation Annual report.

LEVEL 2 CHANGES
Definition of level
 Site change within a contiguous campus or between
facilities in adjacent city blocks.

Test Documentation
 Level 1 + one batch long term stability in chemistry

Filling Documentation
 Annual report
LEVEL 3 CHANGES
Definition of level
Site change to different campus.
Test Documentation:
Chemistry Documentation: One batch for accelerated
stability (3month)+One batch for long term stability for
SBOIA or 3 batches for accelerated and long term
stability (SBOINA)
Dissolution testing – Case B.
 No be required

Filling Documentation – Annual report

CHANGE IN BATCH SIZE
Post approval changes in the size of a batch from the pilot scale biobatch
material to larger or smaller production.

Scale down below 1,00,00 dosage units is not covered by this guideline.

Scale up changes should be property validated and if needed, inspected by

appropriate agency personnel.
LEVEL 1 CHANGES
Definition of level
Changes in the batch size up to and including
factor of 10 times the size of the pilot/ biobatch
where The equipment is of same design and
principle. Both manufacture, According to the
Current good manufacturing practice (CGMP)
compliance. Same Standrad Operating Procduer
(SOP) followed.
Test Documentation Level 1 + one batch
long term stability in chemistry
Filling Documentation Annual report
LEVEL 2 CHANGES
Definition of level
Changes in the batch size up to and including
factor of 10 times the size of the pilot/ biobatch
where The equipment is of same design and
principle. Both manufacture, According to the
Current good manufacturing practice (CGMP)
compliance. Same Standrad Operating Procduer
(SOP)followed.
Test Documentation
As per level 1 + one batch with three month
accelerated stability + Case B dissolution testing.
MANUFACTURING CHANGES

EQUIPMENT CHANGES

PROCESS CHANGES
EQUIPMENT CHANGES
LEVEL 1 LEVEL 2
• Change from non- Change in equipment to a
automated or vice versa to different design
more ingredients. •Test and filing
• Change to alterative documentation.
equipment of same design
and the operating principle
of the same or different • As per level 3 of the site
capacity. change except Case C
• Test and filling dissolution of Case B
documentation- as per level
1 batch size change 22
SUPAC
PROCESS CHANGES
Level 1 Level 2 Level 3

• This changes includes • This changes includes •Change in the type of

process changes like process changes like the process used in the
mixing time and mixing time and manufacture of the
operating speed within operating speed outside product, such as a
application/validation the change in from the wet
range. application/validation granulation to the direct
• Test and filing range. compression of dry
document as per level 1 • Test and filing powder.
of site change. documentation – as per • Documentation – As
the level 2 changes in per the level 3 changes
site changes. of component and
composition changes.
THANK YOU