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

• B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier

  • a) The proposed manufacturer is part of the same pharmaceutical group as the currently approved manufacturer

  • b) Introduction of a manufacturer of the active substance supported by an ASMF

  • c) The proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability

  • d) New manufacturer of material for which an assessment is required of viral safety and/or TSE risk

  • e) The change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product

  • f) Changes to quality control testing arrangements for the active substance-replacement or addition of a site where batch control/testing takes place

  • g) Introduction of a new manufacturer of the active substance that is not supported by an ASMF and requires significant update to the relevant active substance section of the dossier

  • h) Addition of an alternative sterilization site for the active substance using a Ph.Eur. method

  • i) Introduction of a new site of micronisation

  • j) Changes to quality control testing arrangements for a biological active substance: replacement or addition of a site where batch control/testing including a biological/immunological/immunochemical method takes place

  • k) New storage site of Master Cell Bank and/or Working Cell Banks

• B.I.a.2 Changes in the manufacturing process of the active substance

  • a) Minor change in the manufacturing process of the active substance

  • b) Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product

  • c) The change refers to a biological/immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological substance, which may have a significant impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol

  • d) The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production

  • e) Minor change to the restricted part of an Active Substance Master File

• B.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance

  • a) Up to 10-fold increase 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 active substance

  • d) More than 10-fold increase compared to the originally approved batch size

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