Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes (Part 2) - Understanding the relationship between the process and CQAs. - BioPharm
Besides the obvious usefulness of PAT in ensuring that the process operates within the approved design space, PAT can also
be useful in broadening the design space based on enhanced knowledge and understanding. The case study involved an ion exchange
(IEX) chromatography step that removes an impurity (Impurity 1) from the product to levels below the drug substance specifications.8 A typical chromatographic profile is illustrated in Figure 3 with the earliest fractions (A) showing pure product, middle
fractions (F) a mix of product and impurity and latter fractions (Y) primarily impurities. In the traditional approach, pooling
of such a column is performed by UV absorbance at 280 nm. The key advantage of such pooling is the simplicity of implementing
UV-based pooling criteria in a manufacturing environment. This approach works well for bind-and-elute applications in which
the entire peak is collected from baseline to baseline and the protein concentration is linearly correlated to the absorbance
signal for the range under consideration. However, in the case of a high-resolution separation where a part of the peak is
being collected to pool the product and reduce one or multiple impurities, this approach is not optimal because absorbance-based
methods are not able to differentiate between product and other proteins or other species that have a similar absorbance profile.
Thus, if the impurity levels in the feed material vary from lot to lot, pool purity will also vary. This could result in lot
rejection if the load material had a higher level of Impurity 1 than the IEX column is capable of clearing. To prevent such
an event, the process parameters for the process column would need to be maintained within tight ranges, resulting in a narrow
design space for the IEX column. On the other hand, in a PAT based approach, an online high performance liquid chromatography
(HPLC) system could be used to design a dynamic control scheme that would allow testing of the IEX column eluate as it elutes
in real time. Thus, irrespective of the concentration of Impurity 1 in the feed material, the IEX column pooling procedure
can be adjusted such that the pool quality is consistent and meets the drug substance specifications.8
Case Study 4: Monitoring the Dryer Bowl
Figure 4
A second case study involving use of PAT sensor technology to monitor a drying end point is shown in Figure 4. Traditional
approaches to drying might minimally utilize time and temperature to control the drying process. At the end of a defined drying
period, the operator is generally required to sample the powder bed to obtain the loss-on-drying values and compare the results
against approved specifications. If the results are satisfactory, drying is complete and material is transferred to the next
manufacturing step. Alternatively, if results are above the in-process specification limit, the material can be re-dried.
Anurag S. Rathore, PhD, is a consultant, Biotech CMC Issues, and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.
Articles by Anurag S. Rathore, PhD
