Manufacturing affects protein performance

/Home/Excipients - Protein Formulation

Manufacturing affects protein performance
09/08/2006
By Gregory Roumeliotis
In-PharmaTechnologist.com
The excipients used in a protein formulation and the method of production can impact not just the physical and chemical stability of biologics but also their in vitro and in vivo performance, cautions Durect?s executive director of biopharmaceutical R&D.
In a speech at the Controlled Release Society's annual meeting in Vienna, Franklin Okumu presented data that showed how sensitive protein stability is to manufacturing and how different processing technologies have both advantages and disadvantages.
Most process methods for proteins now focus on solid formulations because of their increased stability which makes storage and distribution easier. Such formulations are increasingly tested in advanced drug delivery systems such as pulmonary and transdermal.
The most common of these methods is freeze drying (lypophilisation), which involves freezing a protein solution, drying it to remove the majority of bulk water by sublimation and then drying it again by desorption to produce a dry cake.
Thus, freeze drying does not lead to well-defined microparticles and can be an expensive and time-consuming process. Nevertheless, freeze drying remains popular as it allows the large-scale preparation of proteins, it involves no powder filling and there are plenty of contract manufacturing organisations (CMOs) that can perform it under good manufacturing practice (GMP).
Spray drying, on the other hand, does generate a powder and is carried out in a one-step process that involves atomisation of the liquid feed, which is injected into a drying chamber containing hot air or nitrogen, forcing the protein to instantly dry into solid particles.
Unlike lypophilisation, spray drying leads to small particles and takes less time, but it requires aseptic handling and therefore an aseptic GMP facility must be available.
Moreover, spray drying typically requires high drying temperatures that may degrade or inactivate the protein.
One of course can combine elements of freeze drying and spray drying. In spray freeze drying the protein solution is nebulised into a cryogenic medium, such as liquid nitrogen, to quench the droplets which are then dried by lyophilisation.
As this process involves no heat for drying, the denaturation associated with the spray drying process can be avoided. Still, aceptic powder handling is needed and the production yields are low.
A variation of is this process is spray freezing into liquid, where the impingement of the feed solution onto the cryogenic liquid results in intense atomisation into micro-droplets which freeze instantly. The microparticles can then be separated by sieving or evaporation of the cryogen and the sublimation of the solvent.
Spray freezing into liquid allows particularly good size control and fast freeze but it still involves aseptic powder handling.
No single method is suitable for all proteins of course as the protein formulation and processing method affect each other.
?Variables such as protein concentration, metal ion complexation, the stabilizing agent and the surfactants used all have to be considered when a process is selected,? Okumu said.
?Choosing the right formulation and process variables is crucial in delivering a protein in the desired way.?
Freeze drying is recommended for relatively large particle size, 10 to 30 microns and irregular, spray freeze drying for 2 to 12 microns, while spray drying for a regular size of 2 to 4 microns.
To illustrate the effect of formulation and process variables on a protein's in vitro release, Okumu presented clinical data of human growth hormone (hGH) and human monoclonal antibody (huMAb) developed with Durect's controlled-release technology which uses a biodegradable gel that can be formulated for parenteral, oral, dermal or other route of administration of active agent.
By trying different solvents, excipients and processes, Durect achieved effective monthly subcutaneous injections for hGH as opposed to daily and subcutaneous injections for huMAb HER2 as opposed to intravenous.
Although 98 per cent of available proteins are still delivered by injection, the drive towards non-invasive drug delivery is turning more and more manufacturers to new formulations and processing technologies, where success awaits only those who best understand the impact production has on a protein's therapeutic effect.