재조합 단백질 백신, 바이러스 유사체 백신

재조합 단백질 백신 공정

재조합 단백질 백신이 백신 업계에서 실적을 쌓은 것은 지난 1980년대 중반, 지금은 필수예방접종 대상 백신이 된 B형 간염 백신을 개발하면서부터 였습니다. 재조합 단백질 백신은 전통적인 백신 제조법 이외의 방법으로 제조된 최초의 백신으로, 재조합 단백질 백신을 통해 전통적인 백신개발 및 생산방식의 한계를 뛰어넘을 수 있게 되었습니다. 불활화 병원체로부터 항원을 정제하는 방식이 아닌, 항원을 재조합 생산하는 방식으로 백신을 제조하므로 발현율을 높이고 백신의 안전성도 증대할 수 있습니다.

백신 전문가 상담

재조합 단백질 백신이란?

재조합 서브유닛, 또는 재조합 단백질 백신은 이종발현체계에서 생산 가능한 외래 단백질, 즉 항원을 주성분으로 하는 물질입니다. 생산하는 항원이 무엇이냐에 따라 박테리아, 효모, 곤충세포, 포유류 세포, 식물 등 다양한 발현 시스템의 사용을 모색할 수 있습니다. 오늘날 백신 업계에서는 재조합 단백질 백신을 통해 다양한 발현 시스템을 스케일업하여, 각 질환에 대응하는 항원에 정확히 부합하는 다운스트림 공정을 개발해 내는 것을 목표로 하고 있습니다.

재조합 단백질 백신이 팬데믹 대응 등에 있어 앞으로의 백신업계의 희망이 될 수 있는 이유

수년 전, 재조합 단백질 백신은 백신 업계의 일대 혁명을 불러일으켰고, 이로 인해 미충족 수요에 부합하는 백신을 만들어 낼 수 있게 되었습니다. 오늘날, 재조합 단백질 백신을 제외하고 백신 개발 파이프라인을 논할 수는 없을 것입니다. 재조합 단백질은 RSV 백신, HIV 백신의 유력한 후보물질임은 물론, 차세데 인플루엔자 바이러스 백신의 개발에도 재조합 단백질이 널리 활용됩니다. 이번에 창궐한 신종 코로나바이러스감염증의 경우에도, 백신 후보물질 중 30% 이상이 재조합 단백질 백신으로, 이들 대부분은 바이러스의 스파이크 단백질을 방어하는 기전을 계획하고 있습니다. 특히, 전염병이 창궐하는 상황에서는 재조합 단백질 기반의 백신을 개발하는 전략을 취함으로써 기존 시설을 활용하면서도 안전한 백신을 높은 수율로 생산할 수 있다는 장점을 취할 수 있습니다.

바이러스 유사입자 기반 백신의 효과성.

다중 단백질 구조의 바이러스 유사입자(VLP)는 조직 및 형태적 측면에서 원바이러스와 유사하면서 유전정보는 빠져있다는 장점이 있어, 단백질 단독투여 시 대비 적은 투여량으로도 더 높은 수준의 면역반응을 유도할 수 있습니다. VLP는 바이러스 구조 단백질을 개별 발현시킴으로써 생산됩니다. 개별 발현된 바이러스 구조 단백질은 바이러스 유사 구조로 자기조립되는 원리입니다. 피막 VLP는 세포로부터 발아, 방출되어 나오는 방식으로 조립되며, 비피막 VLP는 다운스트림 공정 과정 중에 조립됩니다. 구조에 따라 다르지만, VLP에 사용되는 발현 시스템은 박테리아, 효모, 곤충세포, 식물 / 포유류 세포주 등으로 다양합니다. 효모에서 인유두종바이러스를 발현한 것을 VLP 백신의 성공사례로 꼽을 수 있습니다.

이처럼 재조합 단백질 백신의 개발은 높은 수준의 변동성을 동반하기 때문에, 모든 개발단계에 대응하는 통일된 기성 플랫폼을 마련하는 것은 불가능합니다. 이에, 안전한 재조합 단백질 백신을 고수율 생산하기 위해서는 혁신 솔루션을 제공할 수 있는 전략적 파트너와의 협업이 무엇보다도 중요합니다.

재조합 단백질 백신

세포주 개발

Needs	Solutions
Developing cell lines that produce commercially acceptable yields can be difficult and labor-intensive, so the selection of a high-producer cell line is critical. Vaccine manufacturers rely on proper high-throughput development tools to confidently select a stable and safe cell line that meets regulatory requirements. Selection of the appropriate raw materials is essential to ensure process safety during cell-line generation, and many in industry are moving toward chemically defined (CD) media to support process safety and robustness. Adequate and compliant cell banking and testing is an industry imperative to ensure sufficient quality supply for as long as the product is needed.	The flexibility and functionality of Ambr^® 15 & Ambr^® 250 can accelerate cell line development and process optimization. Ambr^® is the only high-throughput cell culture system with scalable, multi parallel mini-bioreactors and automated functionality. Proven technology with all suspension cell lines and for fermentation applications Capable in all operation modes: batch, fed-batch, perfusion Integrated with a wide range of connectivity of inline analytics, including BioPAT^® Spectro Available with MODDE^® software to facilitate DoE Additional solutions to consider: With more than 70 experienced scientists in the US and Europe to conduct a full package of cell line and product testing compliant with current regulations, Sartorius is well-positioned to support customers, from cell line development and cell banking to commercial manufacturing. Sartorius’ cell line development services ensure the best clone selection for high-productivity stable cell lines and protein expression in CHO DG44 when CHO cell lines are used. Sartorius offers a new generation of chemically defined (CD) and animal component-free (ACF) cell culture media for mammalian and insect cell lines developed and tested with Sartorius bioreactors.

Needs

Solutions

Developing cell lines that produce commercially acceptable yields can be difficult and labor-intensive, so the selection of a high-producer cell line is critical.

Vaccine manufacturers rely on proper high-throughput development tools to confidently select a stable and safe cell line that meets regulatory requirements.

Selection of the appropriate raw materials is essential to ensure process safety during cell-line generation, and many in industry are moving toward chemically defined (CD) media to support process safety and robustness.

Adequate and compliant cell banking and testing is an industry imperative to ensure sufficient quality supply for as long as the product is needed.

The flexibility and functionality of Ambr^® 15 & Ambr^® 250 can accelerate cell line development and process optimization. Ambr^® is the only high-throughput cell culture system with scalable, multi parallel mini-bioreactors and automated functionality.

Proven technology with all suspension cell lines and for fermentation applications
Capable in all operation modes: batch, fed-batch, perfusion
Integrated with a wide range of connectivity of inline analytics, including BioPAT^® Spectro
Available with MODDE^® software to facilitate DoE

Additional solutions to consider:

With more than 70 experienced scientists in the US and Europe to conduct a full package of cell line and product testing compliant with current regulations, Sartorius is well-positioned to support customers, from cell line development and cell banking to commercial manufacturing.
Sartorius’ cell line development services ensure the best clone selection for high-productivity stable cell lines and protein expression in CHO DG44 when CHO cell lines are used.
Sartorius offers a new generation of chemically defined (CD) and animal component-free (ACF) cell culture media for mammalian and insect cell lines developed and tested with Sartorius bioreactors.

Upstream Processing (USP)

Needs	Solutions
Seed expansion from cell bank to production bioreactor is critical to effectively seed the production bioreactor. The latest innovations use process intensification to reduce the seed train and ensure the highest possible process consistency while Process Analytical Technologies enable full process control. Meanwhile, robust & high yield protein production relies on scalability from process development to production scale manufacturing. The use of Process Analytical Technologies enables process controls and monitoring, while implementation of process intensification leads to a higher protein concentration. In both cases, manufacturers need to: Ensure high productivity to allow production out of smaller bioreactors and decrease overall costs Ensure full scalability from process to development to manufacturing scale and demonstrate process robustness Demonstrate overall process safety and quality, in compliance to the requirements of the industry Ensure flexibility to adapt the production to the demand, especially when facing an outbreak	Biostat STR^® is a single-use bioreactor offering the widest range of PAT in a Biosafety Level 2 environment, making it the perfect match for viral production: A unique and robust film across the process ensures excellent cell growth Demonstrated for mammalian cell lines, insect cell lines, as well as fermentation applications with low demand in oxygen Capable in all operation modes: batch, fed-batch and perfusion, allowing process intensification Integration of a wide range of PAT, including BioPAT^® Viamass, BioPAT^® Trace and BioPAT^® Spectro Built on Biosafety principles to reduce risk of contamination and loss of product Direct scalability from Ambr^® to STR for rapid process development Additional USP solutions to consider: Biostat^® RM, a fully GMP-compliant, wave-mixed bioreactor, is an easy-to-use system for seed expansion offering the widest range of PAT in a Biosafety Level 2 environment Biostat^® D-DCU is a compact bioprocess system available in microbial or cell culture versions with vessel choices from 10 to 200L working volume A new generation of chemically defined (CD) and animal component-free (ACF) cell culture media for mammalian and insect cells developed and tested with Sartorius bioreactors

Needs

Solutions

Seed expansion from cell bank to production bioreactor is critical to effectively seed the production bioreactor. The latest innovations use process intensification to reduce the seed train and ensure the highest possible process consistency while Process Analytical Technologies enable full process control.

Meanwhile, robust & high yield protein production relies on scalability from process development to production scale manufacturing. The use of Process Analytical Technologies enables process controls and monitoring, while implementation of process intensification leads to a higher protein concentration.

In both cases, manufacturers need to:

Ensure high productivity to allow production out of smaller bioreactors and decrease overall costs
Ensure full scalability from process to development to manufacturing scale and demonstrate process robustness
Demonstrate overall process safety and quality, in compliance to the requirements of the industry
Ensure flexibility to adapt the production to the demand, especially when facing an outbreak

Biostat STR^® is a single-use bioreactor offering the widest range of PAT in a Biosafety Level 2 environment, making it the perfect match for viral production:

A unique and robust film across the process ensures excellent cell growth
Demonstrated for mammalian cell lines, insect cell lines, as well as fermentation applications with low demand in oxygen
Capable in all operation modes: batch, fed-batch and perfusion, allowing process intensification
Integration of a wide range of PAT, including BioPAT^® Viamass, BioPAT^® Trace and BioPAT^® Spectro
Built on Biosafety principles to reduce risk of contamination and loss of product
Direct scalability from Ambr^® to STR for rapid process development

Additional USP solutions to consider:

Biostat^® RM, a fully GMP-compliant, wave-mixed bioreactor, is an easy-to-use system for seed expansion offering the widest range of PAT in a Biosafety Level 2 environment
Biostat^® D-DCU is a compact bioprocess system available in microbial or cell culture versions with vessel choices from 10 to 200L working volume
A new generation of chemically defined (CD) and animal component-free (ACF) cell culture media for mammalian and insect cells developed and tested with Sartorius bioreactors

Downstream Processing (DSP)

Needs	Solutions
Vaccine developers must develop a downstream process tailored to their antigen, whether it is a protein or a virus-like particle. The choice of expression system will influence the choice of technologies. In either case, the steps will be the following: Harvest and clarification to efficiently remove cell debris, large aggregates, and insoluble contaminants Capture and polishing achieve the highest purity and recovery of the antigen Crossflow filtration to concentrate the product and exchange buffers before/during chromatography steps or for final formulation Sterile filtration to prevent microbial contamination and ensure patient safety Which leads to the following needs: In the absence of an affinity ligand, a wide range of chromatography resins and ligand is needed to find the best purification strategy and ensure a rapid and efficient purification of the antigen A solution to address the variety of contaminants that will have to be removed, depending on the expression system: DNA, host cell proteins, viruses, baculoviruses, endotoxins, etc. High-capacity, high-recovery technologies are needed to optimize overall yield and manage costs, which becomes increasingly challenging as the process is intensified Ensure flexibility to adapt the production to the demand, especially when facing potential outbreaks	Hydrosart^®, a state-of-the-art crossflow membrane designed for low adsorption of proteins, has the benefit of resistance to chemicals, steam, heat and gamma-irradiation, allowing a wide range of operating conditions for protein-based vaccines: Available with molecular weight cut-off membrane ranging from 2kD up to 300kD Provides low adsorption, high flow rate and high product recovery Compatible with a wide range of chemicals for a broader spectrum of operating conditions and cleaning protocols Can be delivered gamma sterile, allowing closed, ready-to-use and sterile processing compliant to Biosafety Level 2 Available in standard and single-pass format for continuous ultrafiltration and diafiltration Additional DSP solutions to consider: A wide range of chromatography resins for protein capture and the widest range of membranes for VLP capture and polishing A unique orthogonal platform for state-of-the-art virus clearance when antigens are produced in mammalian and insect cells Virus Counter^® to monitor baculovirus titer for proteins and VLP produced in insect cells Sartopore^® Platinum for final filling applications. The unique surface modification of the PES membrane provides the lowest adsorption for high product yield and secure wetting for reliable integrity testing

Needs

Solutions

Vaccine developers must develop a downstream process tailored to their antigen, whether it is a protein or a virus-like particle. The choice of expression system will influence the choice of technologies.

In either case, the steps will be the following:

Harvest and clarification to efficiently remove cell debris, large aggregates, and insoluble contaminants
Capture and polishing achieve the highest purity and recovery of the antigen
Crossflow filtration to concentrate the product and exchange buffers before/during chromatography steps or for final formulation
Sterile filtration to prevent microbial contamination and ensure patient safety

Which leads to the following needs:

In the absence of an affinity ligand, a wide range of chromatography resins and ligand is needed to find the best purification strategy and ensure a rapid and efficient purification of the antigen
A solution to address the variety of contaminants that will have to be removed, depending on the expression system: DNA, host cell proteins, viruses, baculoviruses, endotoxins, etc.
High-capacity, high-recovery technologies are needed to optimize overall yield and manage costs, which becomes increasingly challenging as the process is intensified
Ensure flexibility to adapt the production to the demand, especially when facing potential outbreaks

Hydrosart^®, a state-of-the-art crossflow membrane designed for low adsorption of proteins, has the benefit of resistance to chemicals, steam, heat and gamma-irradiation, allowing a wide range of operating conditions for protein-based vaccines:

Available with molecular weight cut-off membrane ranging from 2kD up to 300kD
Provides low adsorption, high flow rate and high product recovery
Compatible with a wide range of chemicals for a broader spectrum of operating conditions and cleaning protocols
Can be delivered gamma sterile, allowing closed, ready-to-use and sterile processing compliant to Biosafety Level 2
Available in standard and single-pass format for continuous ultrafiltration and diafiltration

Additional DSP solutions to consider:

A wide range of chromatography resins for protein capture and the widest range of membranes for VLP capture and polishing
A unique orthogonal platform for state-of-the-art virus clearance when antigens are produced in mammalian and insect cells
Virus Counter^® to monitor baculovirus titer for proteins and VLP produced in insect cells
Sartopore^® Platinum for final filling applications. The unique surface modification of the PES membrane provides the lowest adsorption for high product yield and secure wetting for reliable integrity testing

Other Technologies

데이터 분석

Advanced chemometric methods, such as Design of Experiments (DOE) and Multivariate Data Analysis (MVDA), give broad visibility into data, ultimately leading to greater process reliability and robustness in addition to cost savings.

Needs	Solutions
Quality by Design (QbD) relies on DoE to understand critical process parameters, which is dependent on implementing many experiments – a tool that can help design and plan experiments alleviates the burden. Process Analytical Technologies generate a lot of data that is difficult to analyze, resulting in significant demand for a tool to evaluate historical data in order to identify correlations, conduct troubleshooting and gain process understanding. Most vaccine developers and manufacturers are not statisticians and rely on user-friendly interfaces and software.	The Umetrics^® suite includes three user-friendly and intuitive software solutions designed for process developers and manufacturers to support data analytics through unique data visualization, extensive wizard functionality and customizable plots to maximize usability and versatility: MODDE^® is an advanced, high-quality DOE solution designed for ease of use. The benefit of DOE is to gain knowledge and estimate the best-operating conditions of a process or product, and with MODDE^® the graphical interface and analytics support make it easy to interpret results with complete confidence SIMCA^® Multivariate Data Analysis (MVDA) software is used for scale and batch-to-batch comparison investigations. SIMCA^® transforms data into visual information for easy interpretation, enabling decisions and actions to be taken rapidly and with confidence. SIMCA^® helps to analyze process variations, identify critical parameters and predict final product quality. An overview of the process status can be obtained in a few clicks SIMCA^®-online is a highly efficient software for real-time multivariate statistical process monitoring and control. SIMCA^® online provides a complete set of interactive and visual monitoring tools to production teams to ensure that batch and continuous operations run smoothly These software solutions are fully integrated in most Sartorius systems and are available as stand-alone programs.

Needs

Solutions

Quality by Design (QbD) relies on DoE to understand critical process parameters, which is dependent on implementing many experiments – a tool that can help design and plan experiments alleviates the burden.

Process Analytical Technologies generate a lot of data that is difficult to analyze, resulting in significant demand for a tool to evaluate historical data in order to identify correlations, conduct troubleshooting and gain process understanding.

Most vaccine developers and manufacturers are not statisticians and rely on user-friendly interfaces and software.

The Umetrics^® suite includes three user-friendly and intuitive software solutions designed for process developers and manufacturers to support data analytics through unique data visualization, extensive wizard functionality and customizable plots to maximize usability and versatility:

MODDE^® is an advanced, high-quality DOE solution designed for ease of use. The benefit of DOE is to gain knowledge and estimate the best-operating conditions of a process or product, and with MODDE^® the graphical interface and analytics support make it easy to interpret results with complete confidence
SIMCA^® Multivariate Data Analysis (MVDA) software is used for scale and batch-to-batch comparison investigations. SIMCA^® transforms data into visual information for easy interpretation, enabling decisions and actions to be taken rapidly and with confidence. SIMCA^® helps to analyze process variations, identify critical parameters and predict final product quality. An overview of the process status can be obtained in a few clicks
SIMCA^®-online is a highly efficient software for real-time multivariate statistical process monitoring and control. SIMCA^® online provides a complete set of interactive and visual monitoring tools to production teams to ensure that batch and continuous operations run smoothly

These software solutions are fully integrated in most Sartorius systems and are available as stand-alone programs.

공정분석기술

The increasing development of single-use technologies with integrated single-use sensors has not only enabled real-time data gathering and analysis, it has resulted in process efficiencies, reduced risk of contamination, improved operator safety and overall titer improvements.

Needs	Solutions
Vaccine manufacturers want to better understand and control their processes, which are very complex and highly regulated, but to do so requires real-time measurement of critical process parameters to allow process monitoring, set-point control (feed control and bleed control), event time point predictions (harvest and infection) and timely identification of process deviations. A range of PAT sensors would be required to effectively apply QbD principles and ensure consistency in product quality and quantity, quickly identifying and correcting process deviations to reduce the risk of lost batches. The ability to integrate PAT into single-use systems would mitigate risk of spillages and contamination during sampling.	BioPAT^® toolbox, an expending range of fully qualified single-use sensors, are integrated across the Sartorius portfolio making Sartorius the market leader for PAT Available in process development and manufacturing technologies for full process understanding, monitoring and control Data analysis is straightforward thanks to the full integration in the Sartorius products and technologies 활성 세포 밀도의 인라인 모니터링 및 Cell Bleeding 자동 제어 기능의 BioPAT^® Viamass 포도당과 젖산염의 온라인 모니터링 및 피딩 자동 제어 기능의 BioPAT^® Trace for inline monitoring of CO2 and O2 BioPAT^® Spectro platform for Raman spectroscopy integration in Ambr^® and STR bioreactor systems for non-invasive, inline measurement of multiple analytes BioPAT^® Single-Use Sensors for accurate monitoring of critical process parameters, including pH, conductivity, dissolved oxygen, flow rate and pressure. These sensors are integrated throughout the Sartorius portfolio of Bioprocessing Systems, according to each unit operation’s specific needs

Needs

Solutions

Vaccine manufacturers want to better understand and control their processes, which are very complex and highly regulated, but to do so requires real-time measurement of critical process parameters to allow process monitoring, set-point control (feed control and bleed control), event time point predictions (harvest and infection) and timely identification of process deviations.

A range of PAT sensors would be required to effectively apply QbD principles and ensure consistency in product quality and quantity, quickly identifying and correcting process deviations to reduce the risk of lost batches.

The ability to integrate PAT into single-use systems would mitigate risk of spillages and contamination during sampling.

BioPAT^® toolbox, an expending range of fully qualified single-use sensors, are integrated across the Sartorius portfolio making Sartorius the market leader for PAT

Available in process development and manufacturing technologies for full process understanding, monitoring and control
Data analysis is straightforward thanks to the full integration in the Sartorius products and technologies
활성 세포 밀도의 인라인 모니터링 및 Cell Bleeding 자동 제어 기능의 BioPAT^® Viamass
포도당과 젖산염의 온라인 모니터링 및 피딩 자동 제어 기능의 BioPAT^® Trace
for inline monitoring of CO2 and O2
BioPAT^® Spectro platform for Raman spectroscopy integration in Ambr^® and STR bioreactor systems for non-invasive, inline measurement of multiple analytes
BioPAT^® Single-Use Sensors for accurate monitoring of critical process parameters, including pH, conductivity, dissolved oxygen, flow rate and pressure. These sensors are integrated throughout the Sartorius portfolio of Bioprocessing Systems, according to each unit operation’s specific needs

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백신 전문가 상담

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