BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 342

process parameters (e.g., temperature, oxygen dissolved concentration, pH etc.)
is essential to ensure a successful operation. Inadequate or inefficient process
monitoring and/or process controls pose a significant risk for large-scale produc-
tion. Therefore, it is important to perform optimization experiments at a small
scale, and identify relevant analytical techniques and issues during small-scale
production so that they can be integrated into the large-scale manufacturing pro-
cess. A deficiency in understanding and control of critical process parameters
could significantly impact the validation campaign. For example, during inoculum
development, it is important to know the oxygen requirements for the cell cultures
because culture flasks used during large-scale operations may have oxygen trans-
fer limitations, and a different aeration strategy may need to be employed than the
one used during laboratory or pilot-scale production. Optimization experiments
can significantly help in reducing this risk.
Inappropriate Facility Design The use of inappropriate facilities or equipment
poses a considerable risk for biopharmaceutical production because biotechnology
products are inherently more complex and susceptible to harm (e.g., degradation,
aggregation, denaturation, or contamination). Scale-up primarily depends upon
a product's specific characteristics and the market demand for the product. As
it is not always feasible to design a new facility or to implement a new design
of large-scale equipment, and retrofitting a facility can be cost prohibitive, the
design of a process sometimes has to consider constraints imposed by existing
production facilities. As such, it is critical to review scale-up calculations for
the different process steps in an existing environment with minimal changes in
equipment, for example, buffer preparation, bioreactor operations, etc. [20].
12.3.6 Excipients
12.3.6.1 Process Overview Excipient control also influences product quality
and patient safety. Its impact is seen in microbial, pyrogen, and chemical con-
tamination. Basic information about excipient quality can be obtained from the
USP-NF if a monograph exists for that particular item, USP/NF 2009 and C.
Moreton [23,24]. Compendia standards can provide some assurance of mate-
rial quality; however, they may not always require tests for all relevant quality
attributes and should not be a substitute for rigorous material qualification.
The primary interest for excipients is the components in them. Excipients are
generally not pure compounds but rather mixtures of compounds, portions of
which may be critical to performance. Thus, the critical concern for excipients
is functionality, and purity may not be the major concern. Data from mate-
rial Certificates of Analyses may not coincide with performance in a specific
formulation.
Data from the manufacturer and previous lots can be analyzed to assess vari-
ability. Lot-to-lot variation in incoming lots can influence product variability.
Thus, manufacturers need to understand excipient variability to establish robust
formulations. The information needed for excipients varies with formulation and