ABSTRACT
Adventitious agents represent undesirable contaminants of exogenous origin that are introduced during the production of biopharmaceuticals. Microbial adventitious agents include viruses, bacteria, fungi, and mycoplasma. Transmissible spongiform encephalopathy (TSE) agents are also potential adventitious contaminants. Raw materials may contain adventitious agents. Adventitious agents can be introduced during establishment of cell lines, cell culture/fermentation, capture and downstream processing steps, formulation/Œlling, and even during drug delivery. Therapeutic biotechnology products have an excellent safety record. However, the potential introduction of adventitious agents must continually be evaluated. The testing that
6.1 Introduction .................................................................................................. 141 6.2 Viruses .......................................................................................................... 143
6.2.1 Raw Materials ................................................................................... 144 6.2.2 Cell Banks ........................................................................................ 144 6.2.3 Unprocessed Bulk ............................................................................. 145 6.2.4 Summary of Viral Safety Issues ....................................................... 149
6.3 Bioburden: Bacteria and Fungi ..................................................................... 149 6.3.1 Assays ............................................................................................... 149 6.3.2 Cell Banks and Unprocessed Bulk ................................................... 150 6.3.3 In-Process Raw Materials ................................................................. 151 6.3.4 Final Product .................................................................................... 151 6.3.5 The Positives and Negatives ............................................................. 152
6.4 Mycoplasma .................................................................................................. 152 6.4.1 Test Methods ..................................................................................... 153
6.5 Transmissible Spongiform Encephalopathies ............................................... 153 6.6 Summary ...................................................................................................... 154 References .............................................................................................................. 155
is performed for this purpose is addressed in regulatory documents that include International Conference on Harmonization (ICH) guidelines, US Points to Consider, and European (Ph. Eur.), US Pharmacopoeia (USP), and Japanese Pharmacopoeia (JP) documents. In some cases, 9 CFR (US Code of Federal Regulations) and 21 CFR 211 and 610 are applicable. Table 6.1 lists some of the regulatory documents that describe testing requirements.
