Tackling Formulation and Delivery

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The final hurdle in getting a product to market is the formulation and fill–finish step in process development. By their nature, protein therapeutics are more fragile and require a great deal of work to achieve product stability in final formulations. A cell line can be highly productive and efficient in protein production, but if you can’t stabilize the resulting protein and deliver it to patients intact, that’s a costly and useless exercise. The Formulation and Drug Delivery track of the conference will focus on the problems that have been identified in the industry and help attendees who work in this area of the process development cycle to solve problems they may experience. The track will focus specifically on stability testing, high-concentration and novel formulations, protein aggregation, and new developments in delivery.

Mary Cromwell, senior scientist at Genentech, will speak about opalescence in formulation. Cromwell explained that this phenomenon is common in formulation science, and she will present a case-study from her company. The concern about opalescence involves its correlation with aggregation and thus the related concern about product immunogenicity. However, Cromwell explained that this connection between immunogenicity and opalescence isn’t that straightforward. Instead, the case-study she presents will show how opalescence is actually a demonstration of a more commonly observed phenomenon. This is a “critical phenomenon,” when the solution reaches a critical point (e.g., pressure, temperature, pH) and starts exhibiting different behavior. In this case, that behavior is opalescence, which is caused by reaching a critical temperature.

“In this system, when the critical temperature comes into play, you start getting liquid–liquid phase separation,” said Cromwell. She compared this phenomenon to what you would see in chemistry class when cooling a mixture of cyclohexane and isopropynol.

“So opalescence doesn’t necessarily cause a problem,” explained Cromwell. “On the other hand, it may indicate that you have a solution that when taken to the right temperature may show phase separation, and thus you may need to control your temperature a little bit differently.”

The product in her case study is a monoclonal antibody, but the problem of opalescence is a prevalent issue within the formulation discipline. “It’s not limited to MAbs,” said Cromwell. “All proteins can do this potentially. As long as we’ve been producing protein formulations, there have been observations of opalescence.”

Prickly Issues: Another area that will be covered at the meeting is the issue of high-concentration formulations. This is the result of needing to deliver large quantities of a protein therapeutic to patients in the least painful and most effective manner. Highly concentrated solutions have viscosity issues that cause normal delivery methods to be impractical. Using a large-diameter needle to deliver drugs isn’t the preferred option from a patient perspective, so formulations scientist need to develop other solutions. One idea that has been developed involves delivering large volumes subcutaneously using a synthetic version of hyaluronidase that degrades to hyaluronic acid, which is a major component of tissues throughout the body. The hyaluronidase enzyme breaks down gel-like hyaluronic acid in the tissues and facilitates the penetration or diffusion of the therapeutic component into the body.

“There are definitely some questions regarding this technology,” said Cromwell. “But I think it offers an alternative when you don’t have other formulation options due to viscosity.”

Delivering Content: Two presentations at the conference will cover new delivery technologies: prefilled syringes and transdermal delivery. Choosing which delivery method to use is an important consideration in product development. The decision is largely based on a drug’s indication, which determines whether local delivery or systemic delivery is needed.

“For local delivery, I think you’re going to see inhaled and transdermal delivery being used quite frequently,” said Cromwell. “There are, however, significant challenges in systemic delivery that have still not been overcome. The Holy Grail of this method is obviously the oral route.” Cromwell posited that this method would likely be limited to a small number of proteins due to problems with the relative size of protein therapeutics compared small-molecule drugs.

Other high-interest topics that will be covered include control of protein aggregation, forced degradation studies for validation of stability-indicating analytical methods, and the impact of freeze–thaw processing on stability and long-term storage.