Biomedical Engineering Reference
In-Depth Information
An assessment was made on the ranges to be tested on the basis of knowledge of
process capability and knowledge gained from earlier studies as to the function and
impact of the individual excipients on the biologic. Instead of individual salts, the buffer
was considered as a single composition variable based on buffer strength, since once it is
formulated, it is controlled by conductivity and pH limits. With buffer conductivity
acceptance limits of 0.8-1.2mS/cm, it was determined that a 15mM or a 25mM buffer
would fall outside the limits and therefore represents an appropriate range for buffer
strength. The range for pH was set between 5.2 and 5.8 based on earlier pH-stability
studies. The ranges for excipients 1 and 2 were set at 0.6-1.7 and 0.6-3.4 molar ratio of
excipient to protein, respectively, based upon previous experience and preformulation
studies. A range for excipient A was not evaluated since the specification range for
osmolality would identify any anomalies in the level of the tonicity adjuster, and the
amount was considered robust for the function as stabilizer due to its large molar excess
compared to the active.
A simple half factorial experimental design with four factors and center point was
conducted as shown below in Fig. 10.5. Formulations were prepared and placed on
Figure 10.5. Experimental design for robustness of product composition. The center point
represents the optimal or target composition. (See the insert for color representation of this
figure.)
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