Based on the legislatively defined sets of "basis for change" documents, changes in the definition of a Medicinal Product - Preparation Production Chain related to the Manufacture of the Medicinal Product initiate the following variations that have to be reported to the competent Health Authorities:

• B.II.b.1 Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product
  

  • a) Secondary packaging site

  • b) Primary packaging site

  • c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes

  • d) Site which requires an initial or product specific inspection

  • e) Site where any manufacturing operation(s) take place, except batch-release, batch control, primary and secondary packaging, for non-sterile medicinal products

  • f) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for sterile medicinal products (including those that are aseptically manufactured) excluding biological/immunological medicinal products

• B.II.b.2 Change to importer, batch release arrangements and quality control testing of the finished product

  • a) Replacement or addition of a site where batch control/testing takes place

  • b) Replacement or addition of a site where batch control/testing takes place for a biological/immunological product and any of the test methods performed at the site is a biological/immunological method

  • c)   Replacement or addition of a manufacturer responsible for importation and/or batch release

    • 1. Not including batch control/testing

    • 2. Including batch control/testing

    • 3. Including batch control/testing for a biological/immunological product and any of the test methods performed at that site is a biological/immunological/immunochemical method

• B.II.b.3 Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product

  • a) Minor change in the manufacturing process

  • b) Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product

  • c) The product is a biological/immunological medicinal product and the change requires an assessment of comparability

  • d) Introduction of a non-standard terminal sterilisation method

  • e) Introduction or increase in the overage that is used for the active substance

  • f) Minor change in the manufacturing process of an aqueous oral suspension

• B.II.b.4 Change in the batch size (including batch size ranges) of the finished product

  • a) Up to 10-fold compared to the originally approved batch size

  • b) Downscaling down to 10-fold

  • c) The change requires assessment of the comparability of a biological/immunological medicinal product or the change in batch size requires a new bioequivalence study

  • d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes

  • e) More than 10-fold increase compared to the originally approved batch size for immediate release (oral) pharmaceutical forms

  • f) The scale for a biological/immunological medicinal product is increased/decreased without process change (e.g. duplication of line)