BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 333

fermentation/cell culture, sterilizing the medium to be employed, sterilizing the
fermenter/biorecator vessel, sterilizing all materials to be added during the pro-
cess, and maintaining aseptic conditions during fermentation and cell culture
process. Clean-in-place (CIP) and sterilization-in-place (SIP) processes should
be qualified and/or validated where required. The extent to which these proce-
dures need to be adopted is determined by the risk of contamination and the
nature of the consequences.
Facilities and Equipment The maintenance of aseptic conditions during fermen-
tation/cell culture and the design of suitable fermentation/bioreactor equipment
are critical for the fermentation/cell culture process. The main function of a
fermenter/bioreactor is to provide a controlled environment for the growth of
microorganisms or mammalian cells used for obtaining the desired product. As
such, the fermentation/bioreactor vessel should be capable of being operated
aseptically for a number of days and should be reliable in long-term operations.
Significantly, it should also provide adequate aeration and agitation to meet the
metabolic needs of the microorganisms and cells and should not cause damage
to the microorganisms/cells during mixing and agitation.
Scale-Up The challenge of developing a process from a laboratory to the pilot
scale and subsequently to the industrial scale is also an important consideration
during fermentation/cell culture. Additional details on scale-up considerations are
provided in Section 12.3.5.
12.3.4 Downstream Processing
12.3.4.1 Process Overview Downstream processing refers to the recovery and
purification of biotechnology products from the recombinant culture or plant
tissue or fermentation broth. The purification of biotechnology-derived products
can be difficult, resource intensive, and expensive. Therefore, the main goal of
the recovery and purification process is to obtain a sufficient quantity of good
quality product and to do that as quickly and efficiently as possible. In general,
downstream processing steps can be broadly categorized into four main groups:
• Removal of insolubles involves the recovery of the product as a solute and
removal of large particulates and/or cell debris.
• Product isolation involves the removal of those components whose prop-
erties vary markedly from that of the desired product, for example, viral
inactivation.
• Product purification is done to separate those contaminants that resemble
the product very closely in physical and chemical properties.
• Product polishing involves the final processing steps to obtain a concentrated
and pure product and ends with packaging/storing of the product in a form
that is stable and transportable.