SUPAC Guideline

SUPAC Guideline

SUPAC Guideline

  • After a pharmaceutical product is approved, its sponsor and manufacturer must work to meet ever-changing manufacturing standards, as well as demand for the drug
  • Though the drug product itself is still approved, a manufacturer must show to the FDA that each change it makes to its manufacturing process (e.g. new production lines, the use of new equipment, or new processes) will have no effect on the safety, efficacy or quality of the approved medicine
  • Technology transfer of a pharmaceutical product from research to the production floor with a simultaneous increase in production outputs is commonly known as scale –up
  • Scale-up is an inevitable part of the product life cycle of every successful drug, and each time it is required, a meticulous process must be followed to ensure that the end result is identical to the product formulation as originally devised

SUPAC guideline

  • In simple terms, the process of increasing batch size is termed a scale-up
  • Conversely, scale-down refers to a decrease in batch size in response to reduced market requirements
  • Depending on the magnitude of the proposed changes, the FDA permits sponsors to make them in a variety of different ways
  • For minor changes, companies can either make note of those changes in their Annual Reports or notify FDA at the time a change is made using the Changes Being Effected (CBE) process
  • For most manufacturing changes, however, sponsors must notify the FDA of the change using the Prior Approval Supplement (PAS) (21 CFR 314.70) and await the FDA’s approval of the change before implementation.
  • Determining which change notification process to use—and knowing which documentation FDA needs to determine if a change is appropriate—can be difficult
  • FDA’s latest guidance, SUPAC: Manufacturing Equipment Addendum, is dedicated to creating a holistic set of recommendations about how to support proposed manufacturing changes using proper documentation

SUPAC guidelines- History

  • In  1991-92,  two  workshops  were  held  by  the  American Association  of  Pharmaceutical  Scientists  (AAPS),  the  U.S. Food & Drug Administration (FDA) and the United States Pharmacopeia (UPS) to explore principles for making process and/or compositional changes in drug products post approval
  • These changes ultimately included formulation or compositional changes, process changes, process scale changes and process site or campus changes
  • The proceedings of these workshops were ultimately published as a guidance by the FDA titled “Scale-Up and Post-Approval Changes” or SUPAC
  • The scale-up process and the changes made after approval in the composition, manufacturing process, manufacturing equipment, and change of site have become known as scale-Up and Post-approval Changes, or SUPAC

SUPAC guidelines

This guidance combines and supersedes the following scale-up and post-approval changes (SUPAC) guidances for the industry:

(1) SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum, and

(2)SUPAC-SS Nonsterile Semisolid Dosage Forms – Manufacturing Equipment Addendum. It removes the lists of manufacturing equipment that were in both guidances and clarifies the types of processes being referenced

This draft SUPAC addendum should be used in conjunction with the following SUPAC guidances for industry:

(1) 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,

(2)  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, and

(3)  SUPAC-SS:  Nonsterile Semisolid Dosage Forms, Scale-Up, and Post Approval Changes: Chemistry Manufacturing and Controls; In Vitro Release Testing and In Vivo Bioequivalence

What You Should Know about SUPAC?

SUPAC Guideline is not regulation, but only guidance

  • It relates only to drug manufacturing and it’s only available for certain dosage forms: immediate-release solid oral dosage forms including tablets, capsules, and soft gelatin capsules; modified-release solid oral dosage forms including delayed-release and extended-release; and topical semi-solid dosage forms including creams, ointments, suspensions, emulsions, and gels


SUPAC Guideline provides recommendations to sponsors of new drug applications (NDA’s), abbreviated new drug applications (ANDA’s), and abbreviated antibiotic applications (AADA’s)

What does SUPAC means in the drug industry?

SUPAC guidance provides recommendations to sponsors of new drug applications (NDA’s), abbreviated new drug applications (ANDA’s), and abbreviated antibiotic applications (AADA’s) who intend, during the post-approval period, to change:

1)   The components or composition;

2)   The site of manufacture

3)   The scale-up/scale-down of manufacture; and/or

4)   The manufacturing (process and equipment) of an immediate-release oral formulation

What does the guidance define???

1) Levels of change

2) Recommended chemistry, manufacturing, and controls tests for each level of change

3) In-vitro dissolution tests and/or in vivo bioequivalence tests for each level of change

4) Documentation that should support the change.

Levels of Change

  • Changes in the size of a batch from pilot scale to small or large production batches after approval of a new drug application (NDA) or abbreviated new drug application (ANDA) require submission of additional information
  • All scale-up changes should be properly validated and, where needed, inspected by appropriate agency personnel


The FDA divides scale-up into two levels:-

  • Level 1 is defined as a: Change in batch size, up to and including a factor of 10 times the size of the pilot batch
  • Level 2 discusses Changes in batch size beyond a factor of 10 times the size of the pilot batch. Otherwise, the requirements of level 2 are similar to level 1 requirements

Level 1 requirements

  1. Chemistry documentation application/compendia release requirements
  2. Notification of change and submission of updated batch records in annual report
  3. One batch on long-term stability reported in annual report
  4. No dissolution or in vivo testing
  5. Filing documentation: annual report (long-term stability commitment)

Level 2 additional requirements

  1. Stability testing: one batch with three months accelerated stability data and one batch on long-term stability
  2. Dissolution documentation: Case B testing
  3. Filing documentation: prior approval supplement; annual report

Dissolution Testing

Case A

Dissolution of Q = 85% in 15 minutes in 900ml od 0.1N HCL, using the
USP <711> apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM

Case B

Multi point dissolution profile in the application/compendial medium
at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for
proposed and currently accepted formulation.

Case C

Multi point dissolution profiles performed in water, 0.1N HCL, and
USP buffer media at ph 4.5, 6.5, and 7.5 (five separate profile) for the
proposed and currently accepted formulation. Adequate sampling should be
performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from
the drug product is dissolved or an asymptote is reached.

A surfactant may be used with appropriate justification.




Test Documentation



Quantitatively 10% or less change in the approved amount of

– Application/compendial requirement

– Preservative effectiveness test at lowest specified preservative

– Annual Repot


10-20% change in the approved amount of preservative

– Application/compendial requirement

– Preservative effectiveness test at lowest specified preservative

– Changes being effected supplement

– Annual eport


> 20% change in the approved amount of preservative ( including
deletion) or use of different preservative

– Application/compendial requirement

– Executed batch record

– For new preservative: analytical method for identification and
assay; validation studies

– Preservative effectiveness test

– Prior approval supplement

– Annual report

SUPAC Guideline FAQs

What is SUPAC?

SUPAC stands for Scale-Up and Post-Approval Changes. It is a regulatory guideline that governs how pharmaceutical companies can make changes to their products while maintaining safety and efficacy.

How does SUPAC affect pharmaceutical manufacturing?

SUPAC provides a framework for making changes to manufacturing processes, formulations, and packaging while ensuring product quality and safety are upheld.

What are the key considerations in SUPAC compliance?

Key considerations include conducting thorough testing, documenting changes, and ensuring that modifications do not compromise product quality or safety.

Can SUPAC apply to biopharmaceuticals?

Yes, SUPAC can apply to biopharmaceuticals. The guidelines are adaptable to various types of drug products, including biologics.

What are the benefits of adhering to SUPAC guidelines?

Adhering to SUPAC guidelines ensures that pharmaceutical companies can make necessary changes to their products while maintaining product quality, safety, and efficacy, ultimately benefiting both the company and the patients they serve.

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