QP FORUM 2018 QP DECISION MAKING

SCENARIO 1 The Process Drug A is a monoclonal antibody produced through mammalian cell culture in a 12,500L bioreactor, and followed by a series of downstream purification processes including chromatography, buffer exchange and filtration, yielding a low bioburden bulk drug product solution. The mammalian cell culture used in manufacturing is cultured from a 1ml vial, and scaled up through a series of flasks and then fermenters up to the final 12,500L fermenter where the monoclonal antibody is expressed. The 12,500L fermentation is 15 days long with periodic media and antifoam additions throughout the fermentation. In-process samples are taken at the end of each scale up stage to check for cell viability and absence of contamination. Additional samples are taken as follows: The 6,000L bioreactor (which is used to inoculate the 12,500L bioreactor) is sampled just prior to being transferred to the 12,500L bioreactor and tested for mycoplasma The 12,500L bioreactor is sampled at day 13, 14 and 15 (the end of the fermentation) and tested for mycoplasma. A separate sample is taken on day 15 for sterility testing. The day 15 mycoplasma and sterility tests are licensed in-process specifications The Issue Following testing of the day 15 samples from the 12,500L bioreactor for batch X, the samples for mycoplasma testing were found to be contaminated with other bacteria (not mycoplasma) with the result that there was no in-process mycoplasma result. The sterility samples were negative for growth. Questions What information needs to be considered for the disposition of Batch X? As the in process mycoplasma test is a licenced in process specification, does the QP have the discretion to release the batch? Is Board of Health notification required?

SCENARIO 2 The Process Product B is a monoclonal antibody produced through mammalian cell culture in a 12,500L bioreactor. Feed media additions are made periodically during the fermentation via a sterilising filter. The 12,500L bioreactor is tested for sterility just prior to being transferred to the harvest stage. Upon completion of the cell culture, the culture is harvested, filtered to remove cells/cell debris and then purified through a series of Ultrafiltration (UF)/Diafiltration (DF) steps and chromatography steps (bind and elute). At the harvest stage and at each of the purification steps, the product is tested for bioburden and endotoxin. The Issue For Batch Z, the harvest sample had an endotoxin result of 200EU/ml, the in process control limit is 25EU/ml. The sterility test on the bioreactor was negative and subsequent bioburden results were within limits. The investigation determined that the feed media to the bioreactor was contaminated with Gram negative organisms, but the bioreactor was not contaminated as media additions are made via a sterilising filter. However, the harvest pool has a high level of endotoxin. Questions What do you need to consider for the disposition of Batch Z So if the final Drug Substance meets specification and limits – would you release the batch?