Understanding the Sterile Filtration of Nanosuspensions

Pall: Aude Iwaniec, John Welsh, PhD., Kalliopi Zourna, PhD., Stephen Turner, Nigel Jackson

LIPOSOMES & EMULSIONS FOR DRUG DELIVERY – INTRODUCTION

Pharmaceutical liposomes

• Small, spherical, and enclosed compartments that separates 2 aqueous parts by a phospholipid bilayer; which allows the delivery of either hydrophilic or hydrophobic substances

Pharmaceutical emulsion

• Heterogenous system of one liquid dispersed throughout another in the form of droplets, stabilised by surfactants.

Advantages

• Increased drug solubility, absorption and bioavailability
• Reduces dosages and toxicity
• Various routes for administration, including topical oral and injectable drug delivery

Manufacturing challenges

• Time consuming processes/intensive labor
• Process reproducibility and scale-up
• Control of size/size distribution
• Stability issues
• Appropriate characterization of liposomes and emulsions throughout manufacturing is critical/ important

Requirements for sterile filtration

(PDA Technical Report No 26);

“A filter that reproducibly removes test microorganisms from the process stream, producing a sterile filtrate.”

Liposome and emulsion sterilization challenges due to:

• Propensity to chemical/physical degradation (stability issues)
• Filtration/flux issues
• Likehood of bacteria, failures during validation
• Adsorptive impact of sterilizing grade filters on liposomes
• A greater understanding of liposome and emulsion formulation properties and sterile filtration of liposomes and emulsions is required to ensure the best selection of sterile filter technology and highest degree of process safety

CHARACTERIZATION OF LIPOSOMES AND EMULSIONS

Sizing characterization

Other important properties are: surface tension, pH, solubility, viscosity and filterability

OD600 results obtained after a 45-fold dilution in PBS

Zeta potential buffer system:10-fold dilution in 0.1x PBS

OPTIMIZATION OF LIPOSOMES AND EMULSIONS MANUFACTURING PROCESS

Manufacturing process

The premixes are processed on the M-110EH Microfluidizeru processor through the F12Y (75 µm) interaction chamber (IXC), APM H30Z (200 µm) through sequential passes (from 20.000- 30.000 psi). High shear fluid processor using continuous operating pressures up to 30,000 psi (2068 bar). By maximizing energyper-unit fluid volume uniform submicron particle and droplet sizes are produced. 

A higher number of passes results in: droplet size, size distribution and polydispersity decrease and capacity of filtration increase

EFFECT OF FILTRATION CONDITIONS/ PARAMETERS ON STERILE FILTRATION

Higher throughput and similar to lower average diameter are obtained in the 2nd filtration compared to the 1st filtration.

The controlling factor in the pressure effect on liposomes filtration is differential pressure rather than upstream pressure.

CONCLUSIONS AND RECOMMENDATIONS

Sterile filtration optimization can be achieved by:

• Targeting optimum size/size distribution range. Using microfluidization optimization is possible to control size and size distribution.
• Using serial filtration to (a) improve storage/stability/sterility and (b) obtain higher throughputs (not significant).
• Using higher pressures/differential pressures for (a) higher throughput/best utilisation of filtration surface area and (b) avoid adsorption.

We acknowledge Microfluidics for their generous contribution.