For those who liked (or missed) my attempt at a beach read, you can download QQ#4 on significant figures in PDF format. Not everyone enjoys nor needs to get into the nitty gritty of calculations, but some appreciated being walked through the details.
If nothing else, I am satisfied that the last Quality Quarterly catalyzed a reunion with someone I used to work with who has also become a consultant. Although we focus on different aspects of quality, we both feel fortunate to have landed as foot soldiers who help bring new therapies to patients. The diversity in the functions that must be performed to achieve success in drug development creates an ever-evolving multitude of roles. As such, every success in drug development certainly deserves the spotlight, but it should also feel like a shared triumph reliant on a vast array of contributions.
A colleague recently forwarded this announcement regarding the first approved adenovirus-based gene therapy product: First Bladder Cancer Patient Dosed with Commercially Available Intravesical Gene Therapy ADSTILADRIN® (nadofaragene firadenovec-vncg) | BioSpace. I can only imagine how many people it took to bring this product to fruition; congratulations to all of you! But this success is also a testament to those whose work indirectly helped overcome the early setbacks in the field of gene therapy so kudos to you as well.
In Focus this Month: Reference Standard Management Programs in Drug Development
The subject of standards, and adenovirus in particular, has been on my mind for several reasons:
- The tragic death of Jesse Gelsinger in U Penn clinical trial in 1999 due to dose related toxicity of the adenoviral vector he received impacted the field of gene therapy in many ways. Responses to the federal investigation included development of the Adenovirus Type 5 Reference Material | ATCC produced in 2001 to facilitate control of future patient dosing.It took an incredible village of professionals to manufacture, characterize and make this highly stable material accessible. Unfortunately, the supply recently became depleted.The International Society for BioProcess Technology (ISBio) continues to play a critical role in development of its replacement and that of other new standards. Updates can be found online as well as details on the original Ad5 Reference.October 2023 marks the 20th anniversary of “Defining a Detailed Approach to Using the Adenovirus Reference Material (ARM),” an article I co-authored with Janice Callahan. Our involvement with the Ad5 reference material working group and aiding clients in how to use the standard revealed challenges that were not adequately addressed during its development and implementation. The need for clarity on the appropriate design and use of standards in general continues.
- In June, I attended and served as the official rapporteur for the IABS Meeting on maintaining the quality of vaccines through the use of references standards in Ottawa, Canada. The final meeting report will be published later this year, but a short summary and recommendations will be posted on the IABS website soon.There was consensus that standards continue to play a critical role in the development of safe and effective vaccines. There was also agreement that standardization is not an exact science.Effective use of standards requires identification of fundamental principles and evolution of best practices relies on strong science and valid statistical approaches. Additional conferences, establishment of working groups and generation of publications were all activities suggested to achieve greater harmonization in regulatory expectations.
- In July, the US FDA released a new guidance: Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products | FDA. This provides recommendations for managing manufacturing changes and assessing comparability for both investigational and licensed human CGT products while considering the unique challenges that apply to these products.The importance of a stable homogeneous material to measure assay variability is invoked with this excerpt.Small changes in an attribute can sometimes have a profound impact on the quality of CGT products. However, measuring such small changes can be challenging when the analytical methods are not precise. Therefore, it is especially important that the analytical methods used to assess the effect of manufacturing changes on product quality and process control are sufficiently precise.
- I recently attended the Joint USP-EDQM Symposium on Pharmaceutical Reference Standards held September 27-28, 2023 at USP Headquarters in Rockville, Maryland. The conference covered the use and establishment of reference standards, with an emphasis on reference standards for biologicals and small molecules.The event included discussion of regulatory expectations and harmonization across different regions. For biologics, a central theme was that “shift happens” over time and it is critical to distinguish between changes in reference material or drift due to assay changes. Challenges with the continuity of international standards related to differences in source material and the assignment of units based on collaborative studies were discussed. Problems tied to the introduction of new test methodology, propagation of error and the issue of using correction factors were additional hot topics.
- On October 5 at DC’s Watergate Hotel, Steven Walfish and I co-chaired a session as part of CHI’s Summit on Optimizing Bioassays for Biologics- Demonstrating Successful Bioassay Development in an Era of Emerging Modalities.The development of assays and standards to measure product potency can be particularly challenging. Presentations covered the concept of bridging as part of the analytical method lifecycle, similarity measures for sample suitability in bioassay and lot release acceptance models which are integral to understanding how references can be used as both calibrators and controls to verify assay performance over time.
Standards and Controls Are Critical Tools
Properly designed standards and controls are critical tools for monitoring the consistency of drug products and the performance of the assays used to measure their quality attributes. Ultimately, they serve to protect patients by assuring manufacturers and regulators that processes are operating in a state of control.
Procuring or preparing a reference material begins with taking into consideration how it is intended to be used and defining an appropriate target profile. The availability and applicability of international standards for calibration of in-house references is non-existent for most cutting-edge biologics. This means that organizations sponsoring clinical trials are responsible for creating and characterizing the standards necessary throughout the product lifecycle.
Design, manufacture, characterization, stability monitoring and inventory management are essential elements in the process of generating a standard that is available and suitable for its intended use(s). Ensuring that sufficient archived material is available for investigations into unexpected results requires a commitment to allocating resources to appropriate long-term storage and control. It also means planning far enough in advance for making replacement batches and performing the necessary bridging exercises to implement them.
As the conference conversations revealed, developers and end-users of standards are looking to regulatory authorities and standard setting organizations for clearer guidance and greater harmonization when it comes to expectations surrounding these programs. In the absence of detailed directives or prescriptive protocols, one or more cross functional teams in an organization can be tasked with developing an internal program in a phase appropriate manner and addressing the practical constraints that inevitably arise.
Although compliance to regulatory requirements should be prioritized, the scientific benefit of having standards available for process development, assay development and quality control activities should provide the motivation to ensure the resources and responsibilities required from each area are shared collaboratively.
To the extent possible, all activities should leverage existing quality systems to facilitate documentation and support regulatory filings as needed. However, the focus of a standards management program must remain on the scientific and statistical validity underpinning the uses of the references. This should manifest in thorough evaluation of the risks and tradeoffs accepted in making decisions about ensuring fitness for purpose.