Neue EU-Verordnung Nr. 722/2012

Abstract

Requirements by regulatory agencies and due to scientific rationale are discussed for the manufacture of pathogen safe final biologicals products derived from plasma as coagulation factor concentrates, immunoglobulins and inhibitors or from cell lines as recombinant proteins, monoclonal antibodies, and vaccines as well as advanced therapies (gene therapy and somatic cell/tissue therapy).The risk of transmitting pathogens by the application of biologicals to patients is mitigated by complementary approaches, primarily by●selection and, if feasible, testing of starting and raw materials of human or animal origin,●releasing defined product intermediates for further processing only when non-reactive in virus tests,●inactivation and removal of potentially present viruses and prions (causative agent of transmissible spongiform encephalopathies) by the manufacturing process.A high margin of pathogen safety is achieved by implementing these approaches in the manufacturing process of biologicals performed per cGMP.The overall manufacturing process of biologicals starts with the selection of starting and raw materials, which must be of high quality and safety. Regarding pathogen safety, material of animal origin has to be selected based on the health of animals (fit for human consumption) and tested for species specific pathogens, if feasible; material of human origin, especially plasma for the production of plasma derived medicinal products, and cells/tissues for advanced therapy medicinal products has to be collected from healthy donors and each donation has to be tested at least according to regulatory requirements for the absence of a predefined panel of blood-borne viruses; cell lines used for the production of recombinant proteins and monoclonal antibodies as well as vaccines have to be free of human infectious and pathogenic viruses.Furthermore, the starting material of plasma derived medicinal products, the plasma pools for fractionation, and of recombinant proteins/monoclonal antibodies, the unprocessed bulk of fermenter harvests, is released for further manufacturing based on non-reactivity in sensitive assays to detect human pathogenic viruses. Despite testing, these starting materials may contain a low concentration of viruses, due to detection limits inherent in each assay, or may contain viruses not tested for. Therefore, production steps have to be integrated into the manufacturing process of biologicals to reduce (inactivate and/or remove) viruses; the capacity of the manufacturing step to reduce viruses is demonstrated in virus validation studies. For live attenuated vaccines and products for advanced therapies, usually such manufacturing steps for virus reduction cannot be implemented as the quality and clinical safety and efficacy of the final product must remain untampered. The reduction of prions will also be covered. Microorganisms and parasites are removed very effectively by sterile filtration; therefore, conventional biologicals, applied parenterally, meet the Sterility Assurance Level defined by pharmacopoeias worldwide. Furthermore, effective methods to clean and sanitize equipment and material used during the production of biologicals to avoid cross-contamination and to establish batch-to-batch segregation are presented.Finally, the risk to transmit viruses and prions to patients due to the application of biologicals is assessed based on the efficacy of these combined complementary approaches.