SUPAC Guidelines

1. SUPAC GUIDELINES
Dr. Vinod M. Thakare
NAGPUR COLLEGE OF PHARMACY
WANADONGARI, HINGNA ROAD,
NAGPUR

2. Contents
Introduction
History of SUPAC
Purpose of SUPAC Guidelines
SUPAC documents
Needs for SUPAC
Level of changes
Limitations
References

3. SUPAC Guidelines
SUPAC stands for scale up and post approval changes
Defination:- The scale up process and changes made after the
approval in composition, manufacturing process, manufacturing
equipment and change of site is collectively called as SUPAC.
It is the guideline that comes under Chemistry Manufacturing
and controls section of USFDA.
During a stage of F&D , initially, development process is carried
out in small batch sizes are generally in the multiples of 10X i.e
(small scale or lab scale)

4. Then this batches are increased to multiples of 100X i.e (medium
scale or pilot scale).
While in production scale or large scale, manufacturing is carried
out in large numbers usually multiples of 1000X depending upon
the requirement.
This increase in batch size is termed as scale up.
Sometimes, batch sizes need to be reduced depending upon the
market requirements. This is termed as (Scaled down).
During such a changes the quantities of active ingredients,
excipients, & formulation parameters differ from lab scale to
manufacturing scale.

5. • Hence while making such a changes from lab scale to pilot scale ar
to plant scale, submission of all this data including excipients, their
purpose and quantities to FDA is necessary for getting the
marketing approval.

6. History of SUPAC
FDA regulations
1962-1974
1974-1985
1985-1999
These three sets of regulations defined and handled PAC’s in different ways
The SUPAC task force, established by the centre for Drug evaluation and
research Chemistry manufacturing and control coordinating committee.

7. Purpose of the guidance
This guidance provides recommendations to sponsors of new drug
applications(NDA’s), abbreviated new drug applications (ANDA’s)
who intend during the post approval to change (during the post
approval period)
1.The components or the composition
2. The site of manufacture
3. The scale up/scale down of manufacture
4.The manufacturing(process or equipment)

8. Need for SUPAC Guideline
To expedite the processes of post approval changes of drug
products FDA can assure their safety and effectiveness.
Lower the regulatory burden for industry

9. SUPAC documents
List of document issued by FDA for help applicant with post
approval changes.
Documents are divided into IR (immediate release), MR
(modified release), SS (non-sterile semisolid dosage form like
creams, ointments and etc)
Various types of changes are required
1) Components and compositions of drug product
2) Manufacturing process and equipment
3) Batch size
4) Manufacturing site change

10. SUPAC Guideline defines
• Level of changes minor changes
moderate changes
major changes
• Filling annual report
changes being affected
prior approval supplement
supplement
• Tests application/compendial tests
in-vitro dissolution/ release
in-vivo studies

11. Level of changes
Level 1 ( minor):-
Likelihood of impact on formulation quality and performance:
1) Those changes that are unlikely to have any detectable impact on
formulation quality and performance
2) Example- Changes in the color, flavors.

12. Level-2 (moderate)
1) Changes are those that could have significant impact on the formulation
quality and performance.
2) Example –Changes in the technical grade of excipient (Avicel pH102 vs
Avicel pH200) changes expressed as percent (w/w of total formulation) .
 Level-3(major)
1) Changes are those that are likely to have significant impact on formulation
quality and performance.
2) 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.

13. (A)Component and composition changes
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 .

14. Level 1 changes
Ex –
• Deletion or partial deletion of an ingredient which affect the colour and flavor
of product.
• Change in ingredient of the printing ink to another approved ingredient.
• Changes in excipients.
• Total additive effect of all excipient changes should not be more than 5%.
Test documentation
• Chemistry documentation
Application/compendial release requirements stability testing
Stability testing:-one batch on long term stability data reported in annual report.

15. Dissolution Documentation
None beyond the compendial requirements
In vivo bioequivalence documentation None
Filling documentation
Annual report

16. Level 2 changes
Test and filling documentation vary depending upon three factors
1. Therapeutic range: narrow or non- narrow
2. Solubility: determined in PH range (1-8) and temp(37+0.50c)
3. Permeability: low or high
Test Documentation
• Chemistry documentation
Stability testing : 1 batch with 3 month accelerated stability data
in supplement and 1 batch on long term stability.

17. Dissolution documentation
Case A – High permeability, High solubility
Case B – low permeability, High Solubility
Case C – High permeability, Low Solubility Drugs
 In vivo Bioequivalence documentation -None
Filing documentation – prior approval supplement( Accelerated stability study)
annual report(long term stability data)

18. Level 3 changes
Test documentation
• Chemistry Documentation – 1 batch with 3 months(SBOIA) or 3
batches with 3 months (SBOINA)
(Significant body for information available)
• Dissolution documentation – Case B
• In vivo Bioequivalence – Full bioequivalence study.
Filing documentation – prior approval supplement ,
annual report

19. (B)Manufacturing changes
A. Equipment
Level 1
• This consist of Change from non-automated to automated
equipment or vice versa to move ingredients
• Change to alternative equipment of same design and the operating
principle of the same or different capacity
Test and filing documentation
• Chemistry documentation
• Dissolution documentation

20. Level 2
 Change in equipment to a different design
Test and filing documentation as per level 3 of the site change
except Case C dissolution instead of Case B.

21. B. Process changes
Level 1
• This changes includes process changes like mixing times and
operating speed within application/validation range
• Test and filing document as per level 1 of site change
Level 2
• This changes includes process changes like mixing times and
operating speed outside the application/validation range
• Test and filing documentation – as per the level 2 changes in site
changes

22. Level 3
Change in the type of the process used in the manufacture of the
product, such as a change in from the wet granulation to the direct
compression of dry powder.
Documentation – prior approval supplement ,
annual report

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

24. Level 1
Level Classification Test
Documentation
Filling
Documentation
I • Changes in the batch size up
to and including factor of 10
times the size of the pilot /
bio batch where
• The equipment is of same
design and principle
• Both manufacturer.
According to the CGMP
compliance.
• Same SOP’s followed
• Chemistry
documentation
• Dissolution
documentation
• In-vivo
bioequivalence
documentation
Annual
report(changes being
affected supplement;
annual reprt (long
term stability test
data)

25. Level 2
Level Classification Test
Documentation
Filling
Documentation
II • Changes in the batch size
beyond factor of 10 times
the size of the pilot /
biobatch where
• The equipment is of same
design and principle
• Both manufacturer.
According to the CGMP
compliance.
• Same SOP’s followed
• Chemistry
documentation
• Dissolution
documentation
• In-vivo
bioequivalence
documentation
Annual
report(changes being
affected supplement;
annual reprt (long
term stability test
data)

26. (D)Site changes
Site changes consists of changes in location of the site of
manufacture for both company owned and contract manufacturing
facilities
Scale-up is addressed in section V of this guidance
New manufacturing location should have a satisfactory current
Good Manufacturing Practice (CGMP) inspection.

27. Level 1
Level Classification Test
Documentation
Filling
Documentation
I • Consists of site changes within
single facility
• No change in SOPs, equipment,
environmental conditions(e.g
temperature and humidity) and
controls
• Common personnel
• No change in manufacturing batch
record, except for administrative
information and location of facility
• Chemistry
documentation
• Dissolution
documentation
• In-vivo
bioequivalence
documentation
• Annual
report(changes being
affected supplement;
annual reprt (long
term stability test
data)

28. Level 2
Level Classification Test
Documentation
Filling
Documentation
II • Changes within a contiguous
campus
• Or between facilities in adjuscent
city blocks where same SOPs,
equipment, environmental
conditions(e.g temperature and
humidity) ,controls and personnels
are used
• No change in manufacturing batch
record, except for administrative
information and location of facility
• Chemistry
documentation
• Dissolution
documentation
• In-vivo
bioequivalence
documentation
• Annual
report(changes
being affected
supplement;
annual reprt
(long term
stability test
data)

29. Level 3
Level Classification Test
Documentation
Filling
Documentation
III • Different campus
• Different personnel
1) Chemistry documentation:
• Location of new site
• updated batch records
• Application/ compendial release
requirements
1) Dissolution documents:
• Multipoint dissolution profile in application/
compendia medium at 15, 30, 45, 60 and 120
min USB buffer media at 4.5-7.5 for
(extended release)
• Three different media (e.g water, 0.1 N
HCL, and USB buffer media at PH 4.5 and
6.8 for (delayed release)
• Annual
report(changes
being affected
supplement;
annual reprt (long
term stability test
data)

30. SUPAC Guidelines Limitation
1. Has not been updated(1995/97) for main guide
2. Does not discuss multiple changes.
3. Does not cover modified equipment.
4. Must be used in conjunction with other references e.g excipient
handbook.

31. Thank you