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  • SUPAC Guidelines – Scale-Up and Post-Approval Changes

    The SUPAC guidelines are prepared by the American Association of Pharmaceutical Scientists (AAPS) in association with the United States Food & Drug Administration (FDA) and the United States Pharmacopeia (USP).

    The guideline looks into manufacturing procedures, and compositional modification changes during scale-up and post-approval in drug production.

    In pharmaceutical technology, the transfer of a pharmaceutical product from small scale (research) to the production scale – an increase in batch size from small scale to large scale – is termed scale-up with an increase in simultaneous production outputs. In general, the process of increase in batch size is termed scale-up. This process is required for in-depth study and knowledge about the product which needs to be manufactured at a larger scale.

    The scale-up process and the changes made after approval in the manufacturing process, equipment, composition, and change in the site are known as scale-up and post-approval changes or SUPAC. It is important to make sure that the applied process is capable enough to manufacture an appropriate quality product and as well as to know that the product after scale-up doesn’t suffer any changes in the physical and chemical properties of the product. 

    What are the SUPAC guidelines?

    SUPAC, which stands for Scale-up and Post Approval Changes, refers to guidelines that govern changes made during the post-approval phase of drug manufacturing. These guidelines apply when there are changes in:

    • Manufacturing procedures or equipment.
    • Specifications.
    • Composition or components.
    • Manufacturing site.
    • Scale-up or scale-down of batch size.

    These changes may arise due to either anticipated or unanticipated requirements. They can involve alterations in the process, raw materials, equipment, manufacturing site, or batch size, all of which may potentially impact the quality attributes of the drug or the finished drug product.

    Therefore, it’s crucial to anticipate and evaluate the impact of any such changes on the final quality of a drug or drug product. We must carry out appropriate investigations and submissions to ensure compliance. Therefore, we should authorize these actions as per the regulations of the New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Abbreviated Antibiotic Applications (AADA’s).

    This guidance gets together and replaces the below-mentioned scale-up and post-approval changes guide for the pharmaceutical industry:

    1. SUPAC-IR/MR: Immediate-release tablets, capsules, soft gelatine capsules, and modified-release oral solid dosage forms which include delayed-release (DR) and extended-release (ER); Manufacturing equipment addendum.
    2. SUPAC-SS: Nonsterile semisolid dosage forms include creams, ointments, gel, suspensions, emulsions, and Manufacturing equipment addendum.

    The systematic aspect of SUPAC guidelines for pharmaceuticals

    The SUPAC guidance summaries it identifies different levels of change. Each level of change describes as per the below points:

    1. Proposed chemistry, manufacturing, and control (CMC) assessment,
    2. In-vitro dissolution analysis or in-vivo bioequivalence analysis,
    3. The supporting documents required by the FDA are to be filed in the NDA, ANDA, or AADA.

    Applying SUPAC guide to your annual report

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

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

    Drug products manufactured with the proposed changes are 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 a different level of changes

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

    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 pharmaceutical drug products which can require an increase or decrease in the batch size. It reduces the time of manufacturing, improves yield, and reduces cost.

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    FAQ’s

    What is SUPAC’s full form?

    SUPAC’s full form is Scale-up and Post-Approval Changes.

    What is SUPAC?

    It is not a guideline it is just a guidance document. This guidance states that when there is any change during the post-approval phases, such as manufacturing procedures or equipment, specifications, compositional or components change, change in manufacturing site, or scale-up or scale-down of batch size.

    What is SUPAC-IR/MR?

    SUPAC-IR/MR: Immediate-release tablets, capsules, soft gelatine capsules, and modified-release oral solid dosage forms which include delayed-release (DR) and extended-release (ER); manufacturing equipment addendum.

    What is SUPAC-SS?

    SUPAC-SS: Non-sterile semisolid dosage forms include creams, ointments, gel, suspensions, emulsions, and Manufacturing equipment addendum.

    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.