Overview of Scale-Up and Post-Approval Changes

(SUPAC)

Introduction:
The development of increase in batch size from small scale to large scale is termed as scale-
up. This process is required in-depth study and knowledge about the product which need to
be manufactured at a large scale. It’s important to make sure that the applied process is
capable enough to manufacture appropriate quality product. It is important to know that the
product after scale-up don’t have any changes in physical as well as chemical properties of
the product.
The detail guidance document prepared by the group of American Association of
Pharmaceutical Scientists (AAPS) in association with United States Food & Drug
Administration (FDA) and the United States Pharmacopeia (USP) to look into the basic of
manufacturing procedure, compositional modifications changes during scale-up and post
approval in the drug product.

What is SUPAC?
SUPAC full form is Scale-up and Post Approval Changes. It is not a guideline; it is just a
guidance document. This guidance states that when there is any change during post approval
phase, such as:
i) Manufacturing procedure or equipment’s,
ii) Specifications,
iii) Compositional or components change,
iv) Change in manufacturing site,
v) Scale-up or Scale-down of batch size
The firm must ensure to take appropriate investigation and submission action which has been
authorised by New Drug Application (NDA). by Abbreviated New Drug Application
(ANDA) or by Abbreviated Antibiotic Applications (AADA's). This guidance gets together
and replaces the below mentioned scale-up and post approval changes directives for the
pharmaceutical industry:
1. SUPAC-IR/MR: Immediate release tablets, capsules, and soft gelatine capsules and
modified release oral solid dosage forms which includes delayed release (DR) and
extended release (ER); Manufacturing equipment addendum,
2. SUPAC-SS Nonsterile semisolid dosage forms which includes creams, ointments, gel,
suspensions and emulsions, Manufacturing equipment addendum.

Systematic aspect of SUPAC:

As per the SUPAC guidance its summaries different level of changes, each level change
describes as per below points:
i. Proposed chemistry, manufacturing and control (CMC) assessment,
ii. In-vitro dissolution analysis or in-vivo bioequivalence analysis,
iii. The supporting documents required by the FDA to be filed in the NDA, ANDA or
AADA.

The post approval changes in the drug CMC for ‘moderate’ and ‘major’ allowed to be
submitted in the annual report.

A. Moderate: In case of moderate changes, applicant must submit an addendum prior to

30 day before the supply of drug product i.e. Change being effected (CBE)-30
supplement or in some cases addendum can be submit at the time of supply i.e. CBE-
0 supplement.
B. Major: In case of major changes, applicant must submit and receive FDA approval of
a prior approval supplement (PAS) before the distribution of drug product.

Drug product manufactured with the proposed changes as per below:

1. Change in components or composition,
2. Change in manufacturing site,
3. Scale up and scale down of manufacture
4. Change in manufacturing process and equipment

SUPAC guidance defines different level of changes as asper below:

1. Proposed chemistry,
2. Manufacturing and controls tests for each level change,
3. In-vitro dissolution testing and/or In-vivo bioequivalence tests for each level of
change and
4. Required documents to support for filing.
Conclusion:

SUPAC guidance is important considering the scale-up process related to chemistry

manufacturing and control. Scale-up is an important and expected stage of manufacturing of
pharmaceutical drug product it either requires to increase or decrease the batch size. It
reduces the time of manufacturing, improve yield and reduce cost.

References:

1. Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-
Up and Post-approval Changes: Chemistry, Manufacturing, and Controls; In Vitro
Dissolution Testing and In Vivo Bioequivalence Documentation, U.S. Department of
Health and Human Services Food and Drug Administration, Centre for Drug Evaluation
and Research (CDER) September 1997,
2. Guidance for Industry Immediate Release Solid Oral Dosage Forms Scale-Up and Post-
approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation, U.S. Department of Health and
Human Services Food and Drug Administration, Centre for Drug Evaluation and
Research (CDER) November 1995,
3. Shah V P, Skelly J P, Barr W H, Malinowski H, and Amidon G L. "Scale-up of
Controlled Release Products - Preliminary Considerations," Pharmaceutical Technology.
1992,
4. Mendapara VP SN, Purohit PV, Sanghavi G, Ashara KC. SUPAC of Immediate Release
Solid Oral Dosage Form-Eplerenone. Inventi Rapid: Pharm Tech. 2013,
5. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.
T. Rhodes.