Q&A: Advancing Standards in Cell and Gene Therapies

In this Q&A with Diane McCarthy, Ph.D., Vice President of Global Biologics at USP, she highlights the organization’s longstanding work with stakeholders in the cell and gene therapy space to address evolving challenges in biologics development. USP has convened experts to identify areas where public standards can support quality, safety, and efficiency, leading to the creation of several new chapters in the USP Compendium. These efforts focus on critical areas such as raw material quality for cell and gene therapies and specific modalities like adeno-associated virus (AAV).

McCarthy said USP has recently released a portfolio of reference standards, analytical reference materials, and resources designed to address stakeholder needs. Looking ahead, USP plans to expand its standards portfolio beyond AAV-based therapies to include lentiviral therapies and cell therapies such as CAR-Ts, which are central to personalized cancer treatment. She emphasized that USP will continue monitoring new modalities and engaging with stakeholders to ensure that emerging standards and solutions can help advance innovative therapies.

Pharmacy Times: What are biologic medicines, and how are they different from traditional (small molecule) drugs?

Diane McCarthy, Ph.D, Vice President of Global Biologics, USP: So, biological medicines are much larger, more complex molecules that can be used to treat a number of chronic and previously untreatable conditions, including cancer as well as genetic disorders. They are quite different from small molecules in the sense that small molecules are usually synthesized synthetically, whereas biologics are either made in living sources, like cells, or derived from living sources such as proteins, viruses, and nucleic acids.

Some examples would be insulin, which is a relatively simple biological molecule, but moving to more complex biological molecules, like monoclonal antibodies, vaccines, or cell and gene therapies, as I mentioned, they are made from or by living sources. They are also much more complex in terms of their molecular structure. For instance, a small molecule would typically have a molecular weight of a couple hundred, whereas a monoclonal antibody has a molecular weight of around 150,000, and an AAV-based gene therapy might have a molecular weight of up to 5 million. So, they’re much larger, and this creates a lot more complexity.

Also, because they’re much larger, they must be in a particular three-dimensional structure to be effective. This makes both the analytics and the manufacturing much more complex. Another important distinction is that, while most small molecules are delivered in an oral format, biologics are typically administered by either infusion or injection.

Pharmacy Times: Why are biologics becoming more important in healthcare?

McCarthy: Biologics really enable the treatment and management of a number of chronic diseases or genetic conditions that have been previously difficult—or in some cases not even possible—to treat. These include conditions such as autoimmune diseases, cancer, and genetic disorders. Cell and gene therapies in particular can offer true cures for diseases that were previously untreatable.

One of the reasons they are so effective is that they allow us to be more targeted and personalized in terms of treatment. For example, a monoclonal antibody can specifically target cancer cells without affecting healthy cells, or it can help reduce the number of proteins that cause inflammation in autoimmune disease. Gene therapies can completely modify gene expression, correcting genetic disorders, while cell therapies are used today to reprogram a patient’s own cells to fight their cancer and enable their immune system to do the same.

These more targeted approaches now allow us to enhance therapeutic efficacy and make some of these previously life-threatening conditions treatable.

Pharmacy Times: Why is quality testing for biologics more complicated than for other medicines?

McCarthy: So, biologics—because they are produced in or from living cells—have some inherent variability that can cause minor deviations within the molecular structure, which can then impact some of the quality attributes related to efficacy. The cells used to produce them add modifications that are important for function, but these can also vary slightly depending on the type of cell or the growth conditions.

What you really have in a biological medicine is a population of molecules with slight variations in certain attributes, rather than what you see in a small molecule, where you essentially have identical copies of a single molecule. This complexity requires much tighter control over manufacturing, along with a detailed understanding of the quality attributes that affect efficacy and safety. It also demands a rigorous quality control and testing framework to ensure that these variations remain within an acceptable range.

Pharmacy Times: How can improving standards help make quality biologics more widely available, and what effect do these standards have on the quality, safety, and regulatory acceptance of biologic therapies?

McCarthy: Standards can really help improve the efficiency of drug development for biologics by establishing a quality framework and clear expectations from the very beginning in terms of what quality attributes should look like. One of the things that USP does is develop physical standards and validated methods. These enable manufacturers to have confidence in their analytical results and reduce the need for each individual company to create their own methods and reference standards. This, in turn, builds efficiency.

Today, we see a big move toward platforms—both in manufacturing and analytical methods. This allows companies to apply the same manufacturing process and analytical methods across a family of products, such as multiple antibodies or AAV-based gene therapies, thereby shortening the development timeline. For example, in 2018 it typically took about 18 months to bring a new monoclonal antibody from the discovery stage to first-in-human trials. By 2022, that timeline had been cut almost in half, to around 9 to 12 months.

When it comes to addressing quality, safety, and regulatory acceptance, public standards organizations like USP work closely with manufacturers and regulatory agencies to develop standards that help tackle some of the challenging quality aspects of biologic development and manufacturing. These standards ensure that test methods are validated, reproducible, and suitable for their intended purpose. Physical standards can also serve as a bridge to newer, more efficient analytical methodologies as technology advances.

Overall, standards help manufacturers demonstrate consistency and safety to regulators. This can ultimately lead to faster review, broader acceptance, and increased confidence in these advanced therapies.

Pharmacy Times: Why is global collaboration important for the quality of biologic medicines?

McCarthy: Global collaboration is especially important for biologics, because most biologics manufacturers are developing therapies with the intention of seeking approval in multiple geographies. Having regulatory convergence and building consensus on what the key quality attributes are, as well as which test methods are most important, is critical. Global collaboration can help support regulatory efficiency and regulatory acceptance while also fostering innovation as we continue to develop scalable manufacturing platforms and advanced analytical methods.

Pharmacy Times: How is USP preparing for the next generation of biologic therapies, like cell and gene therapies?

McCarthy: USP has actually been working with stakeholders in the cell and gene therapy space for many years. We’ve been convening experts to discuss the challenges they’re facing and to identify some of the specific needs that public standards can help address. Over the last few years, this has led to the development of several new chapters in the USP Compendium that support, for example, the quality of raw materials used in cell and gene therapies, as well as certain specific modalities like AAV.

Recently, we’ve released a number of resources—a portfolio of reference standards, analytical reference materials, chapters, and other tools—designed to address the challenges we’ve heard directly from our stakeholders. Looking ahead, over the next few years, we’ll continue to expand our standards portfolio to support these areas, not only for AAV-based gene therapies but also for lentiviral-based therapies and cell therapies, such as CAR-Ts that are often used as personalized cancer medicines.

Beyond that, we will keep monitoring new modalities. There’s a lot of activity in this space, and we will continue to engage with stakeholders to identify where new standards and solutions are needed to help advance these innovative therapies.