BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 341

high specificity, selectivity, and volume reduction based on a highly specific
biological interaction such as that between antigen and antibody, enzyme and
substrate, or receptor and ligand). Additional details can be found in the PDA
Technical Report No.14, Validation of Column-Based Chromatography Processes
for the Purification of Proteins [22].
12.3.5.2 Quality Risk Management for Scale-Up Process The major risks asso-
ciated with the scale-up process are discussed in the following section.
Inappropriate Purification Techniques/Process Design For purification, scale-up
considerations are important from the earliest steps of product/process develop-
ment because the risk of using purification techniques that have limited scale-
up potential can be rate limiting for large-scale manufacturing. For example,
designing an elaborate peak collection scheme for column chromatography may
be unfeasible for implementation during large-scale manufacturing. In order to
minimize this risk to large-scale manufacturing, the relationship between con-
trolled purification parameters (e.g., temperature, pH, conductivity) and process
performance parameters (purification factors, yield) should be defined early in
development using laboratory systems to model the manufacturing equipment
and scale. This strategy helps define the edges of failure through experimen-
tal analysis of the input parameters or output variables, and also helps identify
the parameters necessary for reliable process performance. In addition, it is also
important to verify that a scaled-down process is an accurate representation of
the production process so that validation studies for issues such as viral clearance
and column lifetimes are justified and can be performed at the laboratory scale.
Viral Contamination One of the major risks during scale-up is viral contami-
nation. Viruses can be introduced into the process through the following routes:
source cell lines from infected animals, viral establishment of the cell line, use
of contaminated reagents or equipment, and improper handling of the cell line.
It is critical that the small-scale viral studies are accurately representative of
the production process. In addition, it is recommended that viral studies include
the use of typical critical operating parameters for each step of the process, as
well as conditions that represent a worst case for viral removal. For example,
for process validation of chromatography, the criticality of the viral inactivation
step usually demands that the validation be done at the extremes: for example,
at 90% of minimum time, at the highest pH (or lowest temperature), protein
concentration, reduced height, or contact time, and total protein capacity. Finally,
testing for absence of infectious agents should also be conducted at appropriate
stages/steps during the entire process (e.g., routine testing should include the
end-of-culture samples). Refer to Section 12.3.4 for additional information on
viral contamination.
Inadequate Process Controls Owing to the difficulties involved in maintain-
ing homogeneity during large-scale production, adequate monitoring/control of