Friday, March 7, 2014

How does one ensure comparability across the discovery/development manufacturing continuum?

This week, we've been hearing from Biopharmaceutical Development and Production Week speaker Dr. Janet Wolfe. We've heard about scaling up at an early stage to avoid manufacturing problems, key quality attributes of an ADC, and their characterization  among other things.  Today, we wrap up our interview with Wolfe and look at how to ensure comparability across the discovery and development manufacturing.

The aim of comparability studies is to evaluate the impact of manufacturing changes that typically occur throughout the life cycle of process and product development. So, comparability studies need to be based upon the body of knowledge that has been gained over the course of drug development.

At a very early stage, there is not going to be a huge body of knowledge. But by the time you are approaching commercialization, you will have gained an enormous knowledge of your product and the processes. So, what one wants to be able to do is use the results of comparability studies to verify that the products that are made at each stage have highly similar quality attributes and that they are also functionally equivalent to each other. And you want this all backed up by experimental data. In fact, regulatory agencies will require this.

With the number of variables that are in an antibody drug conjugate – the antibody, the linker, the payload, the variant’s reaction chemistry, the formulation, the process – it means that you could put yourself at risk of not having the same product when you are in the discovery, early development, mid-development or commercialization stage. So, that’s really the entire purpose of the comparability study.

Comparability studies, for them to be well-designed, they require an array of tests. These tests can be typical QC tests, but also bio-physical tests to characterize the molecule. We want to understand what the degradation pathways are, we need to understand the biological assays and the results that you get in those biological assays. You even want to understand the pharmacokinetic behavior of your molecule.

The degree of rigor of these tests is obviously going to change as a function of the development stage.

So, at the discovery and pre-clinical stage the tests are going to be more rudimentary and they are going to be based on the body of knowledge that you required at this point. As you move into early and mid-development the tests are going to be improved. By late stage and commercial stage, the methods are going to be optimized and you may not actually use every method. You are only going to be using the key method that inform where you determine that problems have arisen over the lifecycle of the development pathway. So, at the late stage and commercial stage, typically only the tests that are the most meaningful tests are going to be performed in addition, of course, to all the QC tests. Now, if there are batch failures, then the whole array of tests may be pulled out to identify what the problem was and to fix the problem and keep it from occurring again.

So, I think the whole point of the comparability design is not only to meet regulatory requirements, but it is also a very proactive and worthwhile step for organizations to take. Strategic comparability design ensures that the development lifecycle is conducted in a way to maximize the likelihood of success and minimize extra expenses and risk exposure that is unnecessary.

Janet will be presenting Key Attributes and Considerations for Developing Antibody Drug Conjugate Formulations on Thursday, March 27 in San Diego.  For more information on her session and the rest or the program, download the agenda.  If you'd like to join us for Biopharmaceutical Development and Production Week, as a reader of this blog, when you register to join us and mention code BDP14BLOG, you can save 20% off the standard rate.

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