PPQ（プロセス製造適格性評価）の複雑さを乗り越える

Validation is important because the US Food and Drug Administration (FDA) and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) requires it. During PPQ runs, you are varying certain parameters in the process, as well as trying to verify and validate a process can handle those variations. You’re already varying process parameters and therefore, you don’t want to vary other aspects of your experiment—i.e., your methods.

If your methods are validated, you’ll have confidence that the results are produced with a high level of accuracy and precision—you’ll know your optimal method operation range. It confirms what the center point is—where a method performs with the most precision and accuracy—because you will want to operate around that center point all the time. This ensures every single result you’re getting out of your process validation is sound—PPQ runs will be comparable to each other and they are analyzed by the same exact method.

Think about your critical product quality methods—i.e., purity, impurity, and potency methods. For example, when it comes to the FDA, most feedback we [Thermo Fisher] receive pertains to purity and potency methods which includes the aggregates, fragments, and the state of your molecule like oxidation, deamidation, and glycosylation. Cell-based assays must also be developed, preferably by the Phase III clinical study GMP batch releases, to ensure the potency of the biological molecule is monitored in an invivo setting.

Additionally, impurity always comes up for the regulatory agency because of the safety of the residual host cell proteins (HCPs) and the methods by which they are measured is important. For example, there is a set of high-risk HCPs that can have an adverse reaction with the human body. You’ll want to make sure you’re eliminating these throughout the purification process and the right method can identify them in the drug substance if they are still present. Finally, it’s important to remember that before Phase III, it is strongly recommended to have a residual HCP method that is process specific. While expanding methods to be process specific can be an incremental investment, it is critical to ensuring the success of your biology.

Think about your critical product quality methods—i.e., purity, impurity, and potency methods. For example, when it comes to the FDA, most feedback we [Thermo Fisher] receive pertains to purity and potency methods which includes the aggregates, fragments, and the state of your molecule like oxidation, deamidation, and glycosylation. Cell-based assays must also be developed, preferably by the Phase III clinical study GMP batch releases, to ensure the potency of the biological molecule is monitored in an invivo setting.

Additionally, impurity always comes up for the regulatory agency because of the safety of the residual host cell proteins (HCPs) and the methods by which they are measured is important. For example, there is a set of high-risk HCPs that can have an adverse reaction with the human body. You’ll want to make sure you’re eliminating these throughout the purification process and the right method can identify them in the drug substance if they are still present. Finally, it’s important to remember that before Phase III, it is strongly recommended to have a residual HCP method that is process specific. While expanding methods to be process specific can be an incremental investment, it is critical to ensuring the success of your biology.

The cell line and type of molecule in production are higher impact factors than size of project when considering an analytical method and its requirements. In general, biologics are extremely complicated, however, some are more complicated than others. For example, bispecific antibodies are relatively complex compared to conventional, monoclonal antibodies. This creates different methods and steps you must consider, especially when it comes to product quality. In short, if a more sophisticated and customized method is needed to assure the product quality, the closer it will need to be monitored.

First, ask a CDMO about their experience. How many method transfers have they done? What is the size, scale, and complexity of those transfers? You’ll want to validate their experience of transferring methods to ensure proper knowledge transfer is recorded in the method’s standard operating procedure. That’s what leads to successful method transfers—for the most part.

Also, be sure to inquire if they have their own platforms for method development. If a CDMO has developed their own methods and platforms, their analysts will more effectively be able to assess why a method is not performing. One of the major reasons a CDMO can be a strong partner is their ability to is to seamlessly and successfully conduct a method transfer and communicate why certain methods work better than others.