Core-Shell Chromatography Particles for AAV Separation
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Solution Overview
Problem
Current chromatography methods face challenges in efficiently and scalably separating fully packaged and empty adeno-associated virus capsids, due to the diversity of capsids, small differences in purification parameters, and co-elution of partially packaged capsids.
Innovation Solution
A separation matrix comprising chromatography particles with a core and a surrounding layer, where the core has a first average pore diameter that excludes target molecule diffusion, and the layer has a second average pore diameter at least 1.5 times higher, allowing partial diffusion of the target molecule.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional chromatography particles with uniform pore structure are used, then the separation process is simple, but peak broadening occurs due to longitudinal diffusion and mass transfer resistance
Solution Approach 1:
The chromatography particle is divided into two distinct regions: a core region with small pores (first average pore diameter) that excludes target molecule diffusion, and an outer shell region with large pores (second average pore diameter at least 1.5 times higher than the core) that permits target molecule diffusion. This segmentation resolves the contradiction by creating a core-shell structure where each region serves a specific function: the core prevents longitudinal diffusion while the shell enables mass transfer.
Solution Approach 2:
Different regions of the particle are given different pore sizes tailored to specific functions. The core region has small pores optimized for preventing diffusion and maintaining peak sharpness, while the outer shell region has large pores optimized for allowing mass transfer. This local differentiation of pore properties resolves the contradiction between peak sharpness and mass transfer efficiency.
2Manufacturing precision
If the pore diameter is reduced to prevent longitudinal diffusion, then peak broadening is reduced, but mass transfer resistance increases
Solution Approach 1:
The particle is segmented into a core with small pores (preventing longitudinal diffusion) and an outer shell with large pores (enabling efficient mass transfer). This segmentation allows the system to simultaneously achieve peak sharpness through the core and maintain productivity through the shell, resolving the contradiction between these two opposing requirements.
Solution Approach 2:
The core region is given small pore diameter for peak sharpness, while the outer shell region is given large pore diameter for efficient mass transfer. This local quality differentiation allows each region to optimize for its specific function, resolving the contradiction between peak sharpness and mass transfer rate.
3Productivity
If the flow rate is increased to improve productivity, then separation speed increases, but peak broadening increases due to reduced diffusion time
Solution Approach 1:
The core-shell structure with its small-core and large-shell pore configuration allows the system to maintain peak sharpness even at high flow rates. The core prevents longitudinal diffusion while the shell facilitates mass transfer, enabling high productivity without sacrificing peak sharpness.
Solution Approach 2:
The particle structure parameters (pore diameter distribution) are changed from uniform to bimodal (core with small pores, shell with large pores). This parameter change enables the system to maintain both high separation speed and peak sharpness by optimizing diffusion characteristics for high-flow conditions.
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
This approach results in improved resolution and faster mass transfer of analytes, leading to sharper peaks and enhanced separation of target molecules, particularly in the context of adeno-associated virus capsids.
Implementation Method 1
the core has a first average pore diameter that excludes diffusion of a target molecule through the pores of the core, while the layer surrounding the core has a second average pore diameter that at least partly permits diffusion of the target molecule through the pores of the layer
Data Source
AI summary
The present disclosure is directed to a separation matrix comprising a plurality of chromatography particles, each chromatography particle comprising a core and a layer surrounding the core, wherein the core has a first average pore diameter and the layer surrounding the core has a second average pore diameter, wherein the second average pore diameter is at least 1.5 times higher than the first average pore diameter, wherein the first average pore diameter excludes diffusion of a target molecule through the pores of the core and wherein the second average pore diameter at least partly permits diffusion of the target molecule through the pores of the layer surrounding the core. Further disclosed are a method for preparing such a separation matrix, uses of such a separation matrix and methods for separating target molecules by use of such a separation matrix, in particular a method for separating adeno associated virus capsids fully packaged with genetic material from adeno associated virus capsids not fully packaged with genetic material, and compositions obtained by said method.