Monographs & Advanced Meds: USP's Morris Explains

Pharmalot: Tell us a little about what your department does and any new efforts being undertaken as a result of these new types of therapies. Morris: My department works with expert committees that set standards for all kinds of biologic medications. All of the standards are set by volunteer experts and USP staff serves as secretariat to the experts. There are three such committees right now – two create monograph standards that are product specific and one committee deals with general chapters, which are broad standards that apply to a large group of medicines…Biologics and biotech – covers everything that came from a living cell…also peptides that are synthetic, such as protein, heparin, gene and cell and tissue therapies, vaccines, blood products.

There are a couple of initiatives that are new. We’re working on monographs that are for very advanced therapies, which is very challenging. This would include cell therapy products – a patient autologous therapy. Each dose for each patient is different because the starting material came from the patient. What’s challenging is that when you make a traditional medicine, you make thousands of doses and they all look the same. The monograph we define for such a product includes quality attributes and the specs the medicine would comply with and FDA would check standards. For personalized medicines, the starting material comes from each patient and gets manipulated and injected back to patient. For us, the challenge then becomes how do you define quality attributes? And are the working principles and key quality attributes always the same?

Pharmalot: Sounds like you’re talking about Provenge, right? The prostate cancer vaccine. Morris: Well, there are others in the area of tissues and unique therapies that we’re working on. But in cell therapy, yes, Provenge is the most advanced one. Why is it so challenging? You have to accept, to a certain extent, that every dose is different. And this has an extremely short shelf life compared with even other biologics – insulin or Lovenox has a shelf life of years. The testing is accordingly straightforward; you have known stability parameters. But with a shelf life of 24 to 48 hours, how do you assure you can do rapid testing to ensure there are no viruses or other agents that shouldn’t be there? And to make sure it’s not contaminated? Another challenge is that the therapy is a living cell, so you can’t do many of the processing steps that other biologics go through. A highly processed recombinant protein has gone through different steps, different treatments, and you’ve established that the material has everything removed that shouldn’t be there. If a cell is living…ancillary materials present a risk.

Pharmalot: Step back for a moment and remind us why this is necessary. Morris: One of our new initiatives is to create standards for these types of process ingredients or ancillary materials. Patients are looking for advanced medicines at all times. Our standards assure that you are able to test advanced medicines and they are of a high quality and safe for the patient. Having public standards that are in our book (compendium) and reference materials available for testing broadly give access to those standards. If you don’t have a public standard, the only people who have expertise to test the medicine is the regulator, innovator or person making the med. But if there is ever a problem with the medicine and need to respond quickly, it’s good to have public tests to know what’s going on. At the same time, having a portfolio of materials helps manufacturers gain access to high quality ingredients. … In many of these advanced cell therapies, you have ancillary materials that go into the manufacturing process and don’t get removed. So if you have tests and standards you support quality of the end product. So we are looking at the product and how can you test the product so assure it’s of good quality.

Pharmalot: So what are you doing exactly to cope with this sort of challenge with individualized medicine? Morris: You can make a traditional reference standard for something with normal biologics. We have standards that a user could look at and compare, but you can’t do that in an individualized medicine situation. You have to come up with specs that don’t require traditional reference material and many times have unique ingredients. There can be very sophisticated process materials. So it has a lot of implications also for our more general guidances… The expert committees write chapters on gene, cell and tissue manufacturing, and this requires a constant evolution in thinking. It’s a quickly evolving field, so this also means that we have to constantly keep general chapters current.

Pharmalot: How does this behind-the-scenes work affect patients, though? Morris: It affects patients directly. If anybody became ill and had to go to a doctor and receive an advanced medicine, they would feel a lot more assured if they knew the quality was assured, beyond the fact that the manufacturer obtained its license and the FDA put it in the marketplace. There are quality safeguards. Our expert committees set standards for many different biologics and have a broader view. What we’re trying to look at is to see biologics overall, in a sense of product classes. When you think of the marketplace, you have diff types of medicines – cell and gene therapy, a whole bag of recombinant proteins and within that, there are monoclonal antibodies – which is the biggest class in terms of blockbuster drugs. So you need to ask - Do I look at every single product as a separate product or apply certain tests or critical quality attributes to the group as a whole? Is it beneficial to define what those tests should be? This sort of levels the quality playing field…

Pharmalot: How do drug makers and biotechs view this? Morris: We can frame it this way - Is there an opportunity to standardize the testing? Does that help the manufacturers? If so, then perhaps there’s a consistent level of expectations for the industry. We‘re taking that approach as well to see if we can bucket, if you will, certain types of biologic classes to define quality and testing expectations. And to take that step further – can we write procedural chapters with validated test measures and take that to industry?

Not every situation is like Provenge, where we’re fortunate to get information early in the product life cycle. We’re just now coming to the point where manufacturers are coming to us with proposals for monoclonal antibodies. We’re in the process of writing a chapter for monoclonal antibodies right now… We expect it to be published later this year…

We’ve had an increasing interest and cooperation from industry, especially on the broader initiative for general chapters, but also monographs. More manufacturers are coming to the table to work with us. Many areas in biologics manufacturing are maturing and there are new threats to product quality in supply chain management in the international marketplace. Manufacturers realize that having public standards helps the good players. Because you can test a product to a certain standards and prove its quality and that’s become important in an age when contamination is a concern…

Pharmalot: And what about biosimilars? Morris: If something were to be approved as a biosimilar in the US, it would have to be approved via this new pathway that was just put into the legislation, the BPCI Act (the Biologics Price Competition and Innovation Act), which was just enacted, although there’s no guidance yet… This is always a difficult question to answer. We are really not viewing it from the point of view of whether it’s a generic or biosimilar. If a product is on the market under particular name, and is called insulin, we’re dealing with a product at a level of quality and attributes, whether it’s made by a single manufacturer or multiple manufactuers.

Whether it’s a biosimilar or interchangeable or generic is for the FDA to decide. USP deals with product in the marketplace and how they enter the marketplace is an FDA decision. We can deal with tests , procedures and performance criteria for procedures for evaluating products..