Thin film freezing is overcoming many of the challenges that plague freeze drying and other drying techniques for biologics and small molecules. This new method, presented at the American Association of Pharmaceuticals Scientists (AAPS) PharmSci 360 Meeting, is compatible with continuous manufacturing. It enables biologics to be delivered directly deep into the lungs using a dry power inhaler and also allows liposomal adjuvants to maintain their integrity throughout the freeze-thaw cycle and is compatible with continuous manufacturing.

GEN spoke with the technology’s developer, Robert O. Williams III, PhD, University of Texas at Austin, and special advisor to TFF Pharmaceuticals, during the AAPS meeting.

“We demonstrated that stable powders containing anti-PD1 mAb, anti-TNF-α mAb and AUG3387 mAb could be made by thin-film freezing, delivered directly to the lungs while maintaining their binding/neutralization activity,” he said. “Their excellent aerosol properties enable thin film freezing to work with different types of commercially available dry powder inhalers, which is a key benefit.”

Method disperses active protein and liposomal adjuvant

The thin film freezing process disperses the active protein and liposomal adjuvant in an aqueous liquid with a buffer and other inactive ingredients.

“We then take that liquid and apply it as droplets, using a stainless-steel rotating drum onto a cooled substrate (between -40° and -180°C). It then forms very frozen thin films. The ice sublimates, leaving a brittle matrix powder that can be delivered to the lungs, nose, or other target,” Williams says.

Notably, thin film freezing has an intermediate freezing rate that is neither too fast nor too slow and, therefore, does not denature the proteins or affect the liposome integrity. Additionally, he points out, “No or minimal shear forces are applied to the liquid,” further reducing the risks of protein degradation.

This method enables excipients to be eliminated for some small-molecule formulations, he continues. “For others, we can have up to 80 or 90 percent drug loading,” as long as there is enough mass to deliver it through a dry powder inhaler. This freezing method has been tested using some 30 different types of drugs, which suggests broad applicability.

The chief limitation is that any drug frozen using this method must be soluble in a solvent that works with this process, such as water and certain organic solvents. “We’ve had good results with most biologics, but some proteins may be inherently too fragile to be processed by any powder forming technique,” he tells GEN.

TFF has a commercial-scale manufacturing process and is supplying Phase I and II materials for two clinical trials and is working with several CDMOs.

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