GMP Production of Liposomes—A New Industrial Approach

Abstract

A new scalable liposome production system is presented, which is based on the ethanol injection technique. The system permits liposome manufacture regardless of production scale, as scale is determined only by free disposable vessel volumes. Once the parameters are defined, an easy scale up can be performed by just changing the process vessels. These vessels are fully sterilizeable and all raw materials are transferred into the sanitized and sterilized system via 0.2 microm filters to guarantee an aseptic production. Liposome size can be controlled by the local lipid concentration at the injection point depending on process parameters like injection pressure, lipid concentration and injection rate. These defined process parameters are furthermore responsible for highly reproducible results with respect to vesicle diameters and encapsulation rates Compared to other technologies like the film method which is normally followed by size reduction through high pressure homogenization, ultrasonication or extrusion, no mechanical forces are needed to generate homogeneous and narrow distributed liposomes. Another important advantage of this method is the suitability for the entrapment of many different drug substances such as large hydrophilic proteins by passive encapsulation, small amphiphilic drugs by a one step remote loading technique or membrane association of antigens for vaccination approaches.

Conventional and Dense Gas Techniques for the Production of Liposomes: A Review

“…Wagner et al (56) presented a new scalable liposome production scheme for the ethanol injection technique that allowed production on a several litres scale. In this process a cross-flow injection module was used that allowed liposomes to be manufactured regardless of production scale and no mechanical forces were required to generate homogenous liposomes.…”

Preparation of liposomes: a novel application of microengineered membranes - investigation of the process parameters and application to the encapsulation of vitamin E

“…In particular, the size of liposomes affects drug loading, biodistribution, targeting, acoustic response, therapeutic efficacy and rate of clearance from the body. In addition, the method used for liposome preparation must be reproducible and process conditions must allow production at reasonable costs and economic scale-up [4]. Since the pioneering discovery of Bangham several decades ago [1], the development of liposomes preparation methods has been astonishing.…”

Characterization and stability studies of a novel liposomal cyclosporin A prepared using the supercritical fluid method: comparison with the modified conventional Bangham method

“…The freeze/thaw method has been proposed as the only method to allow for organic solvent-free preparation of liposomes with a large inner aqueous phase; 17 however, this method requires repeated freezing and thawing, thus consuming significant energy and time. Wagner et al 18 presented a new scalable liposome production scheme for the ethanol injection method that enables a several-liter production, but there is still the issue of residual ethanol in the final product. 19 An improved detergent depletion method (crossflow filtration) is also reported by Peschka et al for large-scale liposome production, but only preliminary studies have been carried out.…”