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Scale-up Process in Pharmaceutical Industry


As per SUPAC (Scale-Up and Post-approval Changes) guideline,

Post-approval changes in the batch size from the pivotal/pilot scale bio-batch material to larger or smaller production batches call for submission of additional information in the application. Here we discuss about immediate release solid oral dosage forms.


Scale-down below 100,000 dosage units is not covered by this guidance. All scale-up changes should be properly validated and, where needed, inspected by appropriate agency personnel. There are two level changes:


Level 1 Changes

Change in batch size, up to and including a factor of 10 times the size of the pilot/bio-batch, 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 CGMP's; and 

3) the same standard operating procedures (SOP's) 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).


Required Documentation for Level 1 Changes

  • Chemistry Documentation: Application/compendial release requirements. Notification of change and submission of updated batch records in annual report. One batch on long-term stability reported in annual report.
  • Dissolution Documentation: None beyond application/compendial release requirements.
  • In Vivo Bioequivalence: None.
  • Filing Documentation: Annual report (long-term stability data).


Level 2 Changes

Changes in batch size beyond a factor of ten times the size of the pilot/bio-batch, 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 CGMP'S; and 

3) the same SOP's 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).


Required Documentation for Level 2 Changes

  • Chemistry Documentation: Application/compendial release requirements. Notification of change and submission of updated batch records.
  • Stability testing: One batch with three months accelerated stability data and one batch on long-term stability.
  • Dissolution Documentation: 

- For immediate release product: Case B testing. (Multi-point dissolution profile in the application/compendial medium at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the proposed and currently accepted formulation.)

- For extended release product: In addition to application/compendial release

- requirements, multipoint dissolution profiles should be obtained in three

- other media, for example, in water, 0.1N HCl, and USP buffer media at pH

- 4.5, and 6.8 for the changed drug product and the biobatch or marketed

- batch (unchanged drug product). Adequate sampling should be performed,

- for example, at 1, 2, and 4 hours, and every two hours thereafter until

- either 80% of the drug from the drug product is released or an asymptote is

- reached. A surfactant may be used with appropriate justification.

  • In Vivo Bioequivalence: None.
  • Filing Documentation: Changes being effected supplement; annual report (long-term stability data).


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