Biomedical Engineering Reference
In-Depth Information
studies utilizing appropriate viral agents (e.g., generic as well as specific types of
virus particles). The above-mentioned strategies along with testing for absence of
infectious agents at appropriate stages during the purification process are typically
used to minimize this critical risk to the product.
Endotoxins (Pyrogens) Endotoxins are lipopolysaccharides found in the cell
membranes of gram-negative bacteria, which are released during cell division,
cell growth, and cell death. Because of their high toxicity in vivo and in vitro ,
their removal is essential for a safe parenteral administration. Ideally, in cell cul-
ture supernatants the endotoxin level should be zero, which is not always the case
because endotoxins can be found virtually everywhere (e.g., the process water
used in cell culture). Methods used for decontamination of water, such as ultra-
filtration, have little effect on endotoxin levels in protein solutions. Therefore, to
reduce the risk of endotoxins, removal techniques tailored to meet specific prod-
uct requirements must be built into the purification process. The standard protein
purification process often includes an ion exchange step, a hydrophobic interac-
tion step, and some sort of size-based separation to remove risk of endotoxin
contamination. These three steps frequently are adequate for endotoxin removal,
but the product should be tested at appropriate stages for their absence.
12.3.5 Scale-Up of Production Process
12.3.5.1 Process Overview Scale-up is a standard aspect of product devel-
opment and/or life cycle management. Typically, material requirements increase
significantly from clinical trial stage to product launch, and the increase in product
demand drives the decision to increase the scale of production. A successful scale-
up strategy requires identifying parameters that should either remain constant or
need to be scaled appropriately when transferred to large-scale manufacturing.
Therefore, an understanding of the cellular mechanisms that regulate cell physiol-
ogy, the physicochemical characteristics of the product, and the basic engineering
design principles of equipment and process parameters is essential. In addition, at
the completion of a process scale-up operation, it is important that a comparison
of the laboratory and large-scale operation should be performed and documented.
The comparison report would typically focus on the process performance, pro-
cess design, and product quality aspects between the two manufacturing scales,
and is important to demonstrate comparability (or noncomparability) of a pro-
cess/product.
This section presents a brief overview of some of the typical unit operations
that are scaled up during upstream and downstream manufacturing operations of
biotechnology products.
Scale-Up of Upstream Operations
MEDIUM PREPARATION While it may be feasible to use custom, completely
liquid media for production runs at the laboratory scale and pilot scale, com-
mercially available powdered media or liquid concentrate media is typically
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