4月 22, 2021 By Elena Gontarz (5 minute read)
Method qualification is monumentally important before process performance qualification (PPQ). This early assessment of your method’s performance characteristics is critical as it pertains to method validation and its parameters such as precision, accuracy, and linearity. Most importantly, these analytical considerations demonstrate not only the quality and safety of drug products, but further demonstrates that your product meets the quality expectations of regulatory bodies—which is key for getting your drug to commercialization.
Consider the following situation: As a company is preparing for commercialization in Phase III, they are notified of a process failure. Upon further investigation and as the validation of the analytical method begins, it is revealed that they don’t have a firm historical understanding of their methods. Furthermore, the strategy and logistics of validation execution are so complex that a validation run no longer represents a typical assay run. The linearity assessment using an intermediate precision run—a single assay which takes up to 12 hours to execute—reveals several variables that weren’t present in the quality-controlled (QC) lab. The root cause analysis identified that the original studies may have been too detailed, time consuming, and inconsistently run, resulting in failed validation criteria because the linearity/precision run is not representative of the QC lab run.
This type of scenario is common and can cause biologics innovators to play catch-up in the final stages of their development journey—a risk that can be easily mitigated with robust method validation.
Elena Gontarz, PhD, Manager, Scientific and Technical Affairs
Elena is an analytical development subject matter expert who partners with pharmaceutical clients to support their analytical method development, transfer, qualification, and validation. She earned her PhD in Biochemistry from the University of Missouri—St. Louis. After receiving her doctorate, Dr. Gontarz joined the Analytical Development and Formulation Sciences Group at Patheon by Thermo Fisher Scientific where she expanded her knowledge and expertise of analytical method development from Phase I to commercial manufacturing.
Dr. Gontarz’s expertise also includes product comparability and Phase III forced degradation studies. As a Senior Analytical Development Scientist, Elena performed responsibilities of liaising between technical teams and clients. Now, as a Manager of Scientific and Technical Affairs, Elena is providing technical support for clients and Thermo Fisher Scientifics’s Business Development Group, as well as leading various technical development projects within Thermo Fisher Scientific.
See how Elena supports process commercialization analytical support and method transfers in her role at Thermo Fisher, and what kind of communication to expect from a contract manufacturing and development organization (CDMO) below.
Why is it critical to validate analytical methods prior to process performance qualification, i.e. PPQ?
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.
Which methods are the most critical to meet the expectations for regulatory agencies?
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.
What challenges may a biopharma company anticipate if they are not prepared for regulatory agency expectations?
Prepare to interact with agencies early because if you wait until Phase III, the requirements may become exponentially complicated.
Every detail must be considered. Not only on the process side but also from an analytical standpoint and product quality perspective. Critical planning across all regulatory check points is essential to prepare for the commercialization stage. For example, if you don’t think about the specific processes to validate your residual HCP method, or the robustness of the analytical methods ahead of time, you’ll be trying to squeeze the timeline and may take unnecessary shortcuts in the method lifecycle. This increases the potential risk of method validation failure, delaying approval with the FDA.
Would these analytical methods change depending on the size of the project? If so, why?
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.
What questions would you suggest asking a potential CDMO when considering a method transfer?
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.
To learn more about how you can ensure the quality and safety of pharmaceutical drug products with better method validation strategies, please download this whitepaper.