Cell culture or fermentation
Article 73
1. Where aseptic addition of cell substrates, media, buffers and gases is needed, closed or contained systems shall be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there shall be controls and procedures in place to minimise the risk of contamination. 2. Where the quality of the active substance can be affected by microbial contamination, manipulations using open vessels shall be performed in a biosafety cabinet or similarly controlled environment. 3. Personnel shall be appropriately gowned and take special precautions handling the cultures. 4. Critical operating parameters (e.g. temperature, pH, agitation rates, addition of gases, pressure) shall be monitored to ensure compliance with the established process. Cell growth, viability (for most cell culture processes), and where appropriate, productivity shall also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (e.g. cell viability) may not need to be monitored. 5. Cell culture equipment shall be cleaned and sterilised after use. As appropriate, fermentation equipment shall be cleaned and sanitised or sterilised. 6. Culture media shall be sterilised before use where appropriate to protect the quality of the active substance. 7. Appropriate procedures shall be in place to detect contamination and to determine the course of action to be taken. Those procedures shall include instructions on how to determine the impact of the contamination on the product and to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes shall be identified as appropriate and the effect of their presence on product quality shall be assessed, if necessary. The results of those assessments shall be taken into consideration in the disposition of the material produced. 8. Records of contamination events shall be maintained. 9. Use of shared (multi-product) equipment shall be based on a risk assessment and may warrant additional testing after cleaning between product campaigns, as appropriate, to prevent the risk of cross-contamination.