Biomedical Engineering Reference
In-Depth Information
should be evaluated in a holistic manner. One such approach may be to determine the
desired product quality from the final process step and towork backward in the process to
ensure that each step of the process delivers the required product quality needed for the
next step to meet the quality target of the final step. To provide an example of this
approach, we can revisit the above example of a desired level of 2% aggregate in the final
drug product. In this particular case, design space should be developed for all parameters
of the production process that can potentially impact the level of aggregate in the final
drug product. The maximum level of aggregate resulting from each of the steps in the
process does not need to be less than 2%, particularly steps that are upstream in the
process such as the protein A purification, the first columns used in the purification of an
antibody. The development of the design space including the design of experiments is
discussed in detail in Chapters 5-7.
1.4 RAW MATERIALS AND THEIR IMPACT ON QbD
In addition to the design space and CQAs, other factors also play an important role in
implementing QbD, and raw material is one such factor. Cell culture processes used to
make recombinant proteins use complex growth media such as hydrosylates and also
feeds such as vitamins for the cell. The understanding of how the various components of
these complex raw materials affect the productivity of the cells and the quality of the
product is not a trivial task. It requires a thorough analysis and quantitation of the
various components of the raw material. Raw material analysis and correlation between
rawmaterial components and the productivity of cells and product quality is an area that
has not been sufficiently explored by the biotechnology industry. However, the evolution
of instruments such as high-resolution nuclear magnetic resonance spectroscopy, near
infrared spectroscopy, and mass spectrometry has provided an opportunity to analyze
complex mixtures of raw materials. In addition, the availability of sophisticated
statistical tools for deconvolution and pattern matching of complex data sets has further
refined the approach to analyzing rawmaterials. Once the correlation between the critical
components of the growth or feed media and the performance of cells is understood, the
ultimate goal of rawmaterial analysis in the context of QbDwould be to fortify the media
as needed with the relevant component so as to ensure the desired productivity and
product quality. Further details of analysis of complex raw materials are provided in
Chapter 11.
1.5 PROCESS ANALYTICAL TECHNOLOGY
Since one of the goals of QbD is to maintain control of the process to achieve the desired
product attributes, process analytical technology (PAT) is an important tool for QbD. PAT
entails analysis of product quality attributes during the various stages of the manufactur-
ing process of a biomolecule. The analysis is often conducted online using either probes
inserted into the bioreactor to monitor critical components such as the cell density or
sterile sampling devices to divert the stream from a purification column to assess the
