Textual Amendments
The description of the active substance manufacturing process represents the applicant's commitment for the manufacture of the active substance. To adequately describe the manufacturing process and process controls, appropriate information as laid down in guidelines published by the Agency shall be provided.
All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided.
Raw materials shall be listed and their quality and controls shall also be documented.
The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided.
For biological medicinal products, the following additional requirements shall apply.
The origin and history of starting materials shall be described and documented.
Regarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate that the active substance complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.
When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond.
Seed materials, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials from which they are derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and/or inactivation, and this shall be validated.
Whenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed. In addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed; if this proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection, transportation and storage of the starting material shall be described and documented in accordance with provisions laid down in Part III of this Annex.
The manufacturing facilities and equipment shall be described.
Tests and acceptance criteria carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies shall be provided as appropriate.
If the presence of potentially pathogenic adventitious agents is inevitable, the correspondent material shall be used only when further processing ensures their elimination and/or inactivation and this shall be validated in the section dealing with viral safety evaluation.
A description and discussion of the significant changes made to the manufacturing process during development and/or manufacturing site of the active substance shall be provided.]