SUPAC (Scale Up and Post

Approval Changes)
GUIDELINES…
BY;
Sachinkumar B
1st [Link]
Pharmaceutics.
SCP Mangalore
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Content
Introduction
Purpose of the Guidance
SUPAC documents
Level of changes
Components and composition
-SUPAC-IR
-SUPAC-MR
-SUPAC-SS
Manufacturing Site changes
Batch Size changes (Scale up)
Manufacturing change :Process & Equipment
Limitations of SUPAC
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 Introduction;

Control of changes in process, method, machine &

system is important part of GMP.

Some times we need to change the informations given to

the FDA in approved application.

These changes done after the FDA approval is called Post

Approval Changes.

The scale-up process and the changes made after

approval in the composition, manufacturing process,
manufacturing equipment, and change of site together known as
Scale-Up and Post approval Changes, or SUPAC.

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Purpose of the guidance;

This guidance provides recommendations to sponsors of

new drug applications(NDA’s), abbreviated new drug
applications (ANDA’s) who intend to change (during the post
approval period);

[Link] components or the composition

2. The site of manufacture
3. The batch size
[Link] manufacturing(process or equipment).

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What are SUPAC documents
 A series of documeissued by US FDA (CDER) to help
applicants with post-approval [Link]

 Currently finalized SUPAC guidance are as below

 SUPAC-IR(immediate release) -Nov 1995.
 SUPAC-IR Ques and Answers- Feb 1997.
 PAC- ATLS(Analytical testing laboratories)- Apr 1998.
 SUPAC –MR(modified release)- Sep 1997.
 SUPAC SS(non sterile semisolid)- May 1997.

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SUPAC

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 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

excipients expressed as percentage (w/w) of total formulation,
less than or equal to the following range.

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 Level-2
• 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) .

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 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.

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These guidelines provide recommendation for the post approval
changes in:

• In component or composition

• The site of manufacture

• The scale up of manufacture

• The manufacturing(process and equipment)

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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 preservatives.

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SUPAC-IR (Components and
Composition)

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SUPAC-IR

• Focus on the changes in amount of excipients in the drug

product.

• Not focus on change in the amount of the drug substance.

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SUPAC-MR (Components and
Composition)

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 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 detecting an excipient are defined at
level 3.

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 Non-release controlling excipient

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

1) Deletion or partial Stability- Annual report

deletion of an ingredient Application/compendi
-up to SUPAC-IR Level 1 al requirements.
excipient ranges.

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2) Change in Stability •Prior approval
technical grade of application/compendia supplement.
excipients l requirements.
Up to SUPAC-IR •Annual report
Level 2 excipient  Multi-point
ranges dissolution profiles
(15,30,45,60 &
120min) 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)

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3)  Higher than Stability Prior
SUPAC-IR Level 1 and application/comp approval
Level 2 excipient endial supplement
ranges. requirements.

Bioassay or
IVIVC

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SUPAC-MR (release controlling
excipient)

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Level 2

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SUPAC-SS (Components and
Composition)

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 SUPAC-SS

• for non-sterile semisolid dosage form including creams,

ointments, gels and lotions.

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SUPAC-SS (components and composition)

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Level-2

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Level-3

3) change in approved Stability Prior

amount of ingredient. approval
Application/c supplement
Change in crystalline ompedial
form of ingredient requirements

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SUPAC-SS (Preservative)

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Level-2

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Level-3

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 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.

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Level-1

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Level-2

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Level-3

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 Batch Size Change (Scale UP)
Changes in the size of a batch from the pivotal/pilot scale bio-
batch material to larger production batches

No change in SOP, formulation and manufacturing procedures

or equipments used

All scale-up charges should be properly validated

The minimum batch size for the pivotal clinical trial batch or
bio-batch be at least 1,00,000 dosage units /100 kg or 10% of a
production batch, whichever is larger.

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LEVEL 1 CHANGES

Test documentation
Chemistry documentation
• None beyond application/compendial product release
requirements.
• Notification of the change and submission of the updated
executed batch records.

Other documentation remains same as non release controlling

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LEVEL 2 CHANGES

 This category includes process changes involving adjustments

of equipment operating conditions such as mixing times and
operating speeds outside of original approved application
ranges.

Other documentation remains same as non-release controlling

excipient

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 LEVEL 3 CHANGES

This category includes change in the type of process used in

the manufacture of the product, such as change from wet
granulation to direct compression of dry powder.

Other documentation remains same as non-release controlling

excipient.

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LIMITATIONS OF SUPAC

• Supac has not been updated (1995/97 for main guidelines)

• It does not discuss multiple of changes

• Does not cover modified equipment

• Must be used in conjunction with other references

ex: excipient handbook.

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 REFERENCES:
1. Lachman leon and Schwartz .B. Joseph Pharmaceutical
dosage forms: Tablets. Vol 3, edition 2. P.P 1-74.

2. Savant D.A. Pharma Pathway Industrial and applied

pharmacy: 8th edition. 2.308-23.

3. Nash R.A, Wachter A.H. Pharmaceutical Process Validation:

3rd edition. 705-46.

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Thank You

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