Product Reference Material (RM) for determining potency of biopharmaceutical products is a critical manufacturing reagent. In a commercial environment, if a company allows their product RM to run out, newly manufactured product cannot be released. If an instability in the RM is discovered, not only can newly manufactured not be released, but all recently released batches using the unstable RM must be recalled. In this last case, the recently released batches are adulterated. Why? If we assigned potency utilizing an unstable RM, we have no idea what the true potency of the released batch is, thus it has been released without meeting the formal specification. Understanding the criticality of RM, most companies have an entire department whose reason for being is the care and feeding of their RM for commercial products.

Reference material management and monitoring is equally important during clinical development. However, the consequences of not understanding the needs may not be realized until years after the fact, when one is filing for a BLA. The development and management of clinical RM is typically assigned to a development team with little or no experience in handling this critical reagent. A common request from the regulators at the time of a BLA submission is to see the analytical link between the proposed commercial RM and all the references used to release clinical batches. Often these studies were done as single head-to-head comparisons or were not performed at all. Compounding the problem, the information as to which clinical RM was used to release which clinical batch is sometimes not easily accessible and needs to be dug out of development notebooks.

Part of the problem is the small batch sizes manufactured during early clinical development. This means that numerous batches of product may be designated as a RM. We consider these to be interim reference material (IRM). The IRM will be representative of the current clinical product. Although it is expected that during product development the characteristics of the clinical product will change, (impurity profiles will improve, formulations will change, etc.) it is standard practice to utilize an interim potency standard for as long as possible. This minimizes the number of analytical linkages needed to transition from one IRM to another. However, the ability to continue using the IRM across multiple clinical batches is determined by both the quantity of IRM available, its stability and whether it remains representative of the biological activity of the clinical product being released.

There is little regulatory guidance available detailing how to handle IRM during clinical development. BEBPA has therefore decided to put together a Virtual Reference Material Conference bringing together regulators and industry experts to discuss best practices of how to handle IRM.

The main conference will discuss the following topics:

• Challenges With the First Relative Potency IRM
• Potency IRM Bridging and Stability Challenge
• Relative Potency IRM Challenges New Modalities

BEBPA’s Virtual Reference Material Conference currently includes five invited FDA speakers, an invited speaker from NIBSC and six industry representatives. All have agreed about the criticality of the topic and are in various stages of getting formal legal approval to talk. The agenda is updated weekly as formal approval is received from speakers.

Topics presented will cover multiple product types such as Vaccines, Biosimilars, Protein Products, Cell and Gene Therapies. Case studies will focus on how to handle your IRMs to release clinical material and support commercial approval in the future.

This is a virtual conference, so no travel is needed. Everyone is welcome to attend. Don’t miss out on experience based valuable hints and being part of the conversation on what are the emerging best practices. Follow the link below and sign up for the conference today!