BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 328

authorities as an integral part of Biologic License Applications (BLAs) before
approval. For more information, refer to EP 5.1.7 Viral Safety [14], FDA's 1993
Points to Consider in the Characterization of Cell Lines Used to Produce Bio-
logicals [15], and ICH Q5A (R1) [11].
The presence of bacterial endotoxins should also be monitored and levels
controlled throughout the production process to ensure that the downstream
purification process is not overloaded with this contaminant. In vitro bacterial
endotoxin testing and in vivo pyrogenicity testing are critical for demonstrat-
ing that the manufacturing appropriately reduces, removes, or inactivates these
hazards. Mycoplasma are the simplest, smallest, self-replicating organisms. Pro-
duction culture contamination usually originates from components of cell culture
medium (e.g., serum) or from an infected person working in production. Tests
such as direct fluorescent assay or PCR can be employed to readily detect
mycoplasma contamination.
Facilities, Equipment, and Personnel For all areas in which cell banking opera-
tions are performed, precautions should be taken to prevent contamination. Gen-
erally, GMP banks need to be prepared in well-controlled facilities where rooms
are appropriately classified to demonstrate control in quality of air, movement of
equipment (clean and dirty), and segregation of activities. In addition, thorough
personnel training and control of work practices are necessary to ensure that the
preparation and maintenance of cell banks are free from cross-contamination.
Inappropriate preparation and handling of the cells for banking is one of the
common reasons for contaminated cell lines.
Documentation Inappropriate or inadequate documentation of proper control
procedures used during the assembling, preparation, and storage of the cell banks
is a risk because it does not provide assurance regarding the true identity of the
components and the absence of introduced contamination. The results of all test
performed on the MCB, WCB, and EOP cells have to be appropriately docu-
mented and filed with regulatory agencies to demonstrate the safety and quality
of the genetic source material for the biopharmaceutical product. Inadequate
documentation can be a significant problem for companies because according
to the FDA, per 21 CFR 601.2(a), the Agency can refuse to file a submitted
BLA/NDA because of “ ... insufficient description of source material (including
characterization of relevant cell banking systems) ... ” [16].
Storage Finally, the appropriate and reliable storage of cell banks is also critical
for ensuring the availability and the quality of the genetic source material. Cell
banks have to be maintained in a suitable and controlled environment (typically
in the vapor phase of liquid nitrogen) to ensure viability, stability, absence of
contamination, and their availability. Therefore, the selection of the appropri-
ate cell banking conditions and facilities is important in minimizing risk to the
integrity of the MCB and WCB banks.