General
Article 71
1. This chapter applies to active substances or intermediates thereof manufactured by cell culture or fermentation using natural or recombinant organisms. 2. This Chapter applies as from the point at which a vial of the cell bank is retrieved for use in the manufacturing of an active substance or intermediates thereof. 3. For active substances or intermediates manufactured by means of cell culture or fermentation, the control of bioburden, viral contamination and endotoxins during the manufacture as well as monitoring of the process at appropriate stages may be necessary depending on the source, method of preparation and the intended use of the active substance or intermediate thereof. 4. Appropriate equipment and environmental controls shall be used to minimise the risk of contamination. The acceptance criteria for environmental quality and the frequency of monitoring shall depend on the step in the production and the production conditions (open, closed or contained systems). 5. Process controls shall take into account: (a) maintenance of the working cell bank, where appropriate; (b) proper inoculation and expansion of the culture; (c) control of the critical operating parameters during fermentation or cell culture; (d) monitoring of the process for cell growth, viability (for most cell culture processes) and productivity, where appropriate; (e) harvest and purification procedures that remove cells, cellular debris and media components while protecting the active substances or intermediates thereof from contamination (particularly of a microbiological nature) and from loss of quality; (f) monitoring of bioburden and, where needed, endotoxin levels at appropriate stages of production; (g) viral safety concerns as described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q5A Guideline ( 8 ) , where appropriate. 6. Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities or contaminants shall be demonstrated.