Introduction to Scale-Up and Post-Approval Changes (SUPAC)

Posted by Norm Fong

Scale-Up Blog Series, Part 2

[Editor’s note: 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. This is part 2 of an in-depth, multi-part series on product scale-up. Visit our blog page to read part 1.]

First, a little 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. Today SUPAC can refer to a variety of publications on this theme.

What You Should Know

Among the things you should know about SUPAC is that it 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.

Assuring-Pharmaceutical-Technology-Transfer-Success-eBookThat being said, it’s a very valuable tool in the scale-up process and the guidance does reflect the FDA’s current thinking. The guidance defines: levels of change; recommended chemistry, manufacturing and controls tests for each level of change; in vitro dissolution tests and/or in vivo bioequivalence tests for each level of change; and documentation that should be submitted to support the change.

Changes in Batch Size

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/biobatch, where:

  1. The equipment used to produce the test batch(es) is of the same design and operating principles
  2. The batch(es) is (are) manufactured in full compliance with cGMPs
  3. The same standard operating procedures and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es)

Level 2 discusses Changes in batch size beyond a factor of 10 times the size of the pilot/biobatch. Otherwise, requirements of level 2 are similar to level 1 requirements.

Level 1 requires: 

  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 additionally requires:

  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

Changes in process or formulation that go beyond straightforward scaling may require costly clinical and  bioclinical studies to prove safety and efficacy and a prior approval statement from the FDA, which notifies you that the agency has accepted your changes. Although this may take six months or more, it may be possible to delay process validation while waiting on the results of a stability program and use the time pending FDA approval for developing validation and commercial launch or supply plans.

Next Time: Part 3 — Scale-Up Checklist

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Topics: scale-up, Pilot Batch, Process Development, SUPAC, batch, Documentation, Stability Testing

Norm is the technical transfer manager, business development, for WellSpring. He has over 21 years in the pharmaceutical manufacturing industry and has held development, transfer and commercial manufacturing positions over the course of his career with Patheon, Global Pharm (formally Pharmacia Upjohn) and Genpharm (owned by Merck). Norm is responsible for overseeing technology transfer and all validation activities in the organization.

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