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

• B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material/intermediate/reagent used in the manufacturing process of the active substance

  • a) Tightening of specification limits for medicinal products subject to Official Control Authority Batch Release

  • b) Tightening of specification limits

  • c) Addition of a new specification parameter to the specification with its corresponding test method

  • d) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)

  • e)Deletion of a specification parameter which may have a significant effect on the overall quality of the active substance and/or the finished product

  • f) Change outside the approved specifications limits range for the active substance

  • g) Widening of the approved specifications limits for starting materials/intermediates, which may have a significant effect on the overall quality of the active substance and/or the finished product

  • h) Addition or replacement (excluding biological or immunological substance) of a specification parameter with its corresponding test method as a result of a safety or quality issue

  • i) Where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State for the active substance, a change in specification from in-house to a non-official Pharmacopoeia or a Pharmacopoeia of a third country