Bench-Scale Characterization of Cleaning Process Design Space for Biopharmaceuticals - A method to evaluate the relative cleanability of new products. - BioPharm International


Bench-Scale Characterization of Cleaning Process Design Space for Biopharmaceuticals
A method to evaluate the relative cleanability of new products.

BioPharm International
Volume 22, Issue 3

Figure 2. SDS-PAGE gel to study degradation of protein products A and H during cleaning at 70 C in (a) 1% v/v CIP-100 and (b) 5% CIP-100. The first lane represents molecular weight markers. The numbers on the tops represents the reaction time divided by contact time (in min) with CIP-100 solution corresponding to that sample.
Figure 2 compares the formation of such smaller peptide fragments over time for products A and H when subjected to two different CIP-100 concentrations at 70C. As the figure shows, product degradation is much faster for 5% v/v CIP-100 than for 1% v/v solution. The hot alkaline wash achieves its cleaning action through a combination of protein degradation and enhanced dissolution. It is therefore expected that the cleaning time would decrease as the CIP-100 concentration is increased. Figure 1b shows that cleaning times, in general, are lower at higher CIP-100 concentrations.

However, the trend for the change in cleaning time is also product specific. Product H, for instance, exhibited a minimal cleaning time at an intermediate concentration of 1% CIP-100 (Figure 1b). Other products, such as B and E, also show an improved performance at 1% CIP-100 compared to 2% CIP-100. Such an increase in cleaning time at higher caustic concentration can potentially be attributed to factors such as a change in fluid properties and a change in surface morphology of the deposited product affecting the fluid diffusion into the deposit. This variability highlights the product-specific nature of the cleaning performance and the importance of characterization work in determining optimum cleaning conditions. However, this trend, established in Figure 1, is specific to a cleaning temperature of 70C. As we report later, temperature and cleaning agent concentration are strongly coupled parameters and it is necessary to understand their cross interaction to understand the complete behavior of the performance of the cleaning process.

Dirty Hold Time. Another factor governing the cleanability of equipment under manufacturing conditions is dirty hold time—the duration of time the soiled equipment and equipment parts are held before subjecting them to the cleaning cycle. Cleaning validation is often performed using the worst-case scenario of maximum expected dirty hold time. We studied the effect of air-drying at ambient temperature for different hold times on the observed cleaning time for the four products. Figure 1c shows that there is a significant effect on cleanability during the early hours of hold time (<16 h) because the protein soil is not completely dried. We observed a small increment in cleaning time once the coupons have been dried for 24 h at room temperature. This also justifies the choice of 24 h as a baseline drying time for the remaining evaluations in this study.

Agitation. One of the key operating parameters that contributes to the removal of the product soils from the equipment surface is the mechanical action generated by the cleaning fluid. The impingement action of the cleaning fluid spray ball is often used to generate this effect in automated clean-out-of-place (COP) baths. Because of the specificity of the cleaning action generated by a spray ball and its dependence on the location in the COP bath, this remains one of the most challenging operating parameters to scale down. In fact, in the scaled-down model we only aspire to mimic the worst-case scenario of lowest shear expected to be observed in the equipment holes, cavities, or corners in the COP bath with minimal fluid flow. Figure 1d shows how the cleaning times changed over four different agitation speeds of the shaking water bath.

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