Continuous Liposomal API Manufacturing With In-Line Mixing and TFF

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Solution Overview

Problem

There is a lack of reliable manufacturing methods for liposomal active pharmaceutical ingredients (liposomal APIs) that can support commercial scale-up and continuous manufacturing processes.

Innovation Solution

A method for manufacturing liposomal APIs in a continuous manner by mixing lipid and aqueous API solutions in-line, followed by tangential flow filtration (TFF) units, including single pass TFF (SPTFF) units, to form and refine the liposomal encapsulated API.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If batch mode manufacturing is used for liposomal APIs, then process flexibility is maintained, but productivity and consistency are insufficient for commercial scale-up

Engineering Contradiction:

Improveproduction throughputVSAvoidprocess complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The manufacturing process is divided into distinct modular units: a mixing unit for liposome formation, a first TFF unit for buffer exchange, and a second TFF unit for concentration. Each unit operates independently in continuous flow, allowing the system to maintain complexity while achieving high productivity through standardized, repeatable modules

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent implements continuous manufacturing where lipid solution and aqueous API solution flow continuously through the mixing unit to form liposomes, which then continuously pass through the TFF units for buffer exchange and concentration. This eliminates batch cycles and maintains constant production throughput, directly addressing the productivity requirement for commercial scale-up

Inventive Principle:

Principle #20Continuity of useful action

2Reliability

If continuous manufacturing process is implemented, then productivity and consistency are improved, but device complexity increases

Engineering Contradiction:

Improveproduct consistencyVSAvoidsystem complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent incorporates feedback control through continuous monitoring of process parameters such as flow rates, pressures, and temperatures in the mixing and TFF units. This ensures consistent liposome formation and filtration conditions, maintaining product reliability while the modular design keeps system complexity manageable through standardized sensing and control points

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The process maintains product consistency by precisely controlling critical parameters: the flow rates of lipid and API solutions in the mixing unit, the transmembrane pressure in the TFF units, and the filtration conditions. These parameter controls are integrated into the continuous flow system, achieving reliability without requiring overly complex equipment

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If traditional TFF is used, then buffer exchange is achieved, but shear forces are high and process time is extended

Engineering Contradiction:

Improvebuffer exchange efficiencyVSAvoidshear force on liposomes

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The patent uses an intermediary approach by implementing a two-stage TFF system where the first TFF unit performs buffer exchange with controlled shear conditions, and the second TFF unit completes the concentration. This intermediary staging allows buffer exchange to occur gradually with reduced shear forces on the liposomes compared to single-stage traditional TFF

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The TFF units operate with dynamic control of flow rates and transmembrane pressure to optimize buffer exchange while minimizing shear forces. The system adjusts operational parameters in real-time based on liposome concentration and flow conditions, making the process adaptable to maintain low shear stress throughout the buffer exchange operation

Inventive Principle:

Principle #15Dynamics

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Enables efficient, continuous production of liposomal APIs with improved consistency and quality, reducing capital expenditures and overall costs while maintaining product quality.

Implementation Method 1

introducing the liposomal encapsulated API into a central vessel comprising a first inlet, a second inlet, a first outlet and a second outlet, through the first inlet. The first outlet of the central vessel is in fluid communication with an inlet of a first tangential flow filtration (TFF) unit

Methodology Applied

Scientific EffectTangential flow filtration: Filter (physical)

Implementation Method 2

mixing a lipid solution comprising a lipid dissolved in an organic solvent with an aqueous API solution, wherein the lipid solution and aqueous API solution are mixed from two separate streams in an in-line fashion, and wherein a liposomal encapsulated API is formed at the intersection of the two streams

Methodology Applied

Scientific EffectEmulsion formation: Emulsion

Data Source

PatentUS20250325481A1Methods for continuous manufacture of liposomal drug products

Publication Date: 2025.10.23 INSMED INC

AI summary

Provided herein are methods for making liposomal API formulations via continuous in-line diafiltration processes. Also provided herein are liposomal API formulations manufactured by the disclosed methods.