Cambridge Healthtech Instituteの第8回年次会議

Host Cell Proteins
(宿主細胞由来タンパク質(HCP))

検出・分析・制御戦略と技術

2023年8月14 - 15日、EDT(米国東部標準時)

宿主細胞由来タンパク質(HCP)などのプロセス関連の不純物における特性評価と制御は、バイオプロセシングにおける重要な要素です。企業は現在、規制当局により、新たなモダリティにおけるHCPの役割について多くのデータを求められるようになっています。CHIによる「宿主細胞由来タンパク質(HCP)」年次会議では、業界のリーダーが一堂に会し、このアナリティクス手法の進化、規制の影響、標準、制御戦略について議論します。

8月14日(月)

Registration and Morning Coffee8:00 am

9:55 am

Chairperson’s Opening Remarks

Nisha Palackal, PhD, Director, Protein Biochemistry, Regeneron Pharmaceuticals, Inc.

10:00 am

FEATURED PRESENTATION: A Journey through the Evolution of HCP Detection Methods: From Early Commercial ELISA Kits to Specific Assays

Nisha Palackal, PhD, Director, Protein Biochemistry, Regeneron Pharmaceuticals, Inc.

This presentation will cover the evolution of host cell protein (HCP) assays from generic to process-specific to platform, highlighting the importance of 2D gels and 2D westerns in establishing coverage. The advent of mass spectrometry (MS) technologies has significantly changed HCP detection, and problematic host cell proteins have led to the implementation of individual host cell protein assays for process control. Additionally, new technologies are being utilized for detecting and quantifying HCPs, leading to more efficient and effective bioprocess development and manufacturing.

NEW LC-MS APPLICATIONS AND TECHNOLOGIES
新しいLC-MSの応用と技術

10:30 am

Host Cell Protein Analysis of AAV-Based Gene Therapy Products by LC-MS

Yue (Emma) Zhang, PhD, Scientist, Analytical Development, Biogen

LC-MS has become an increasingly valuable analytical approach in the analysis of host cell protein (HCP) for biotherapeutic products. There are unique challenges in the application of LC-MS for HCP analysis of new modalities, including adeno-associated virus (AAV) products. The presentation discusses how to leverage our existing knowledge and expertise from biologics using LC-MS to overcome these challenges and generate comprehensive HCP profiles for AAV-based gene therapy products.

11:00 am

HCP Assays and GMP Release Testing with LC-MS for Vaccines and Advanced Cell & Gene Therapies

Ejvind Mortz, PhD, Co-Founder & COO, Alphalyse AS, Denmark

Regulatory authorities are increasingly requesting orthogonal LC-MS data for residual protein characterization and documentation. Often, available ELISAs do not have sufficient HCP coverage for the new manufacturing process and complex product. The presentation will present and discuss experiences from using quantitative LC-MS analysis on more than 300 projects, with case examples from vaccines, viral vector therapies, method validation, and GMP release testing.

Sponsored Presentation (Opportunity Available)11:30 am

Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:00 pm

Session Break12:30 pm

PRODUCT QUALITY AND IN-PROCESS CONTROLS
製品の品質とプロセス内制御

12:50 pm

Chairperson’s Remarks

Eric Bishop, Vice President, R&D, Cygnus Technologies

12:55 pm

Formation of Transient Highly-Charged mAb Clusters Resulted in Poor Clearance of Host Cell Proteins during Downstream Processing

Haibin Luo, PhD, Associate Director, AstraZeneca

Protein A chromatography with a high salt wash usually leads to robust clearance of host cell proteins (HCPs) in most recombinant monoclonal antibodies (mAbs), but a small subset of recalcitrant mAbs still show significant HCP copurification. Based on our investigation of 30-ish mAb molecules, we proposed a novel mechanism for HCP copurification; i.e., mAb-clustering strengthens interactions between mAb with HCPs. Breaking mAb-clusters effectively prevents HCP copurification.

  • Only small subset (10%) of mAbs exhibited significant HCP copurification issue
  • High-HCP mAbs share many common HCPs and similar copurification mechanism
  • HCP copurification correlates with mAb's self-association propensity
  • mAb-clustering strengthens interactions between mAb with HCPs
  • Breaking mAb-clusters effectively prevents HCP copurification
1:25 pm

Managing HCP Impurities during Development and Lifecycle

Erika M. Friedl, PhD, Quality Expert, Haematology & Transfusion Medicine, Paul Ehrlich Institute, Germany

For production of high-quality medicines, efficient removal and control of impurities during product development and lifecycle is mandatory. As critical quality attributes, HCP impurities are covered by specific guidelines. It is often challenging meeting the regulatory expectations regarding HCP removal, characterization, and control throughout the product lifecycle. Therefore, HCP case studies will be presented to highlight and mitigate the hurdles affecting the quality, efficacy, and safety of medicinal products.

Sponsored Presentation (Opportunity Available)1:55 pm

Networking Refreshment Break2:25 pm

2:40 pm

Identification and Mitigation of a Host Cell Protease That Cleaved a Therapeutic Protein

Gang Xiao, MSc, Senior Scientist, Process Development, Amgen, Inc.

Host cell proteases are enzymatically active and often impact therapeutic protein stability. The proteases such as cathepsins and asparaginyl endopeptidase are present in pro-enzyme forms and their activation often leads to fragmentation of therapeutic proteins. In this study, we demonstrated how monitoring the change of both proenzyme and mature forms of the host proteases would allow us to identify where and which protease cleaved one therapeutic protein in the bioprocess.

3:10 pm

Characterization of Polysorbate Degrading Enzymes in Biopharmaceuticals by a Novel, High-Throughput Assay

Sanjay Gupta, PhD, Scientist, Analytical Development, Roche, Germany

Problematic HCPs in extremely low quantities in biological drug products poses a major challenge towards their identification and characterization. We developed a highly sensitive, fast and high-throughput method to monitor the presence of hydrolytic activities in samples generated during bioprocessing. By utilizing a custom-designed surrogate substrate combined with a well-established and robust detection platform, the method provides a rapid electrochemiluminescence-based readout of the hydrolytic impurity status in a given sample.

Session Break and Transition to Plenary Keynote Session3:40 pm

PLENARY KEYNOTE: SOLVING TODAY'S CHALLENGES
基調講演:今日の課題を解決する

4:20 pm

Chairperson's Remarks

Susan D'Costa, PhD, CTO, Alcyone Therapeutics, Inc.

4:30 pm

Overcoming the Challenges of Bioprocesses: The Future of Biomanufacturing

Glen R Bolton, PhD, Executive Director, Late Stage Bioprocess Development, Amgen Inc

Novel therapies and technologies are emerging to meet the needs of patients; however, the manufacturing of biopharmaceuticals remains a complex and challenging process. As demand for biopharmaceuticals grows, the industry faces new challenges in terms of scalability, cost, and process robustness. The implementation of innovative technologies to improve process efficiency and the importance of process control and data analytics in ensuring process robustness are key levers to meet these challenges.

5:00 pm

Commercializing Gene Therapies - The Combined Power of Patient Advocacy and Cost-Effective Manufacturing

Rachel Salzman, DVM, Founder, The Stop ALD Foundation & Global Head, Corporate Strategy, Armatus Bio

There is only a very small handful of FDA-approved gene therapies. This presentation will examine the development of an FDA-approved gene therapy where patient advocacy played a critical role resulting in the first-ever clinical use of a lentiviral vector. Although manufacturing continues to represent a significant challenge throughout the entire R&D journey, there are opportunities for advocacy and manufacturing communities to seek alignment and combine their collective powers to achieve the common goal of increasing patient access to transformative medicines.

Welcome Reception in the Exhibit Hall with Poster Viewing5:30 pm

Close of Day6:30 pm

8月15日(火)

Registration and Morning Coffee7:30 am

EMERGING METHODS AND TECHNOLOGIES
新興の手法と技術

7:55 am

Chairperson’s Remarks

Georgeen Gaza-Bulseco, Principal Research Scientist, AbbVie

8:00 am

KEYNOTE PRESENTATION: Standard-Free Absolute Quantitation of Antibody Deamidation Degradation and Host Cell Proteins by Coulometric Mass Spectrometry

Hao Chen, PhD, Professor, Chemistry and Environmental Science, New Jersey Institute of Technology

Recently we developed a coulometric mass spectrometry (CMS) approach for absolute quantitation of proteins without the use of standards, based on the electrochemical peptide oxidation followed by MS measurement of the oxidation yield. CMS can be used for absolute quantitation of a low-level target protein in a mixture; for instance, 500 ppm of PLBL2, a problematic host cell protein (HCP), in the presence of mAb was successfully quantified by CMS. Taking one step further, our study demonstrated the unprecedented quantitative analysis of deamidatedpeptide products arising from the mAb heavy chain deamidation reaction.

8:30 am

Population Balance Modelling Captures Host Cell Protein Dynamics in CHO Cell Cultures

Sakhr Alhuthali, PhD, Honorary Research Fellow, Chemical Engineering, Imperial College London, United Kingdom

Increases in mAb titre has been achieved mainly by cell culture feed improvement and cell line engineering to increase cell density and specific mAb productivity. This has caused a higher accumulation of host cell proteins (HCPs) in the supernatant. Herein, a population balance model (PBM) has been built to capture Chinese hamster ovary (CHO) cell behaviour in bioreactors to predict HCP dynamics. The PBM then served as a platform for generating operating strategies that optimise antibody titre and increase cost-efficiency while minimising impurity levels. 

9:00 am

USP Standards to Support HCP Analysis by Mass Spectrometry

Anthony Blaszczyk, PhD, Senior Scientist, Global Biologics, US Pharmacopeia

Residual HCPs in biopharmaceuticals can impact product quality and safety. Mass spectrometry has become an increasingly common approach for identification and quantitation of HCPs to support risk assessment and process development, as well as characterization and quality control. In response to stakeholder needs, USP is developing standards and tools to support the quality and consistency of HCP measurements. The presentation will provide an overview of the proposed general chapter <1132.1> Residual Host Cell Protein Measurement in Biopharmaceuticals by Mass Spectrometry and an update on development of physical reference materials to support identification and quantitation of HCPs of particular concern.


9:30 am Talk Title to be Announced

Eric Bishop, Vice President of Research and Development, R&D, Cygnus Technologies

Coffee Break in the Exhibit Hall with Poster Viewing10:00 am

10:45 amBreakout Discussion Groups

Breakout discussions provide an opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges. Please visit the breakout discussions page on the conference website for a complete listing of topics and descriptions.

IN-PERSON ONLY BREAKOUT:

Use of LC-MS as a Release Method for HCP

Ejvind Mortz, PhD, Co-Founder & COO, Alphalyse AS, Denmark

  • Why is there a need for LC-MS as a release method?
  • What types of products/biologics would it be particularly relevant for?
  • What are the major challenges using LC-MS as release test? And how could these be overcome?
  • What will the new USP chapter and USP standards for HCP Analysis by Mass Spectrometry lead to?
  • What are relevant product release specifications CoA - total HCP amount? Individual amount of problematic HCP? Amount of Top20 HCPs?
  • Should animal ethics be a concern? Would you choose LCMS instead of ELISA that requires immunization and use of experimental animals?
11:30 am

Analysis of Biologically-Relevant Concentrations of Therapeutic Host Cell Proteins through an Ultrasensitive Quantification Method Coupling Limited Digestion to ProteoMiner Technology

Hui Xiao, PhD, Senior Principal Scientist, Regeneron Pharmaceuticals, Inc.

A new method is developed to quantify HCPs at sub-ppm levels with ProteoMiner enrichment, coupled with limited digestion, followed by targeted analysis with nano liquid chromatography-parallel reaction monitoring. The method can achieve LLOQ values as low as 0.06 ppm, with an accuracy of 85%-111% of the theoretical value, and inter-run and intra-run precision within 12% and 25%, respectively.

12:00 pm

Development of a Custom Automated Method for HCP Detection in Gene Therapy Products

Matthew J. Lotti, Senior Research Associate II, Ultragenyx Pharmaceutical, Inc.

During drug manufacture, large volumes of samples are submitted for host cell protein (HCP) quantitation to assess purification efficiency and ensure patient safety. Therefore, it’s beneficial to have methods with enhanced throughput. Here, we describe development of a custom HCP method that incorporates automated sample preparation with automated immunoassay and data analysis, resulting in a higher throughput assay that produces high-quality data needed to support gene therapy product development.

Sponsored Presentation (Opportunity Available)12:30 pm

Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:00 pm

Refreshment Break in the Exhibit Hall with Poster Viewing1:30 pm

PROBLEMS & SOLUTIONS
問題点と解決策

2:10 pm

Chairperson’s Remarks

Rachel Chen, PhD, Associate Director, Analytical Development, Biogen

2:15 pm

Case Studies of HCP Analytical Method Bridging and Phase-Appropriate Validation

Rosalind Ang, PhD, Associate Principal Scientist, Merck

Host cell proteins (HCP) are co-produced into cell culture harvest and must be removed to acceptable low levels by downstream process due to their potential impact on product quality, safety, and efficacy. The suitability of the analytical method (i.e., stringency) used to detect and quantitate these impurities is typically related to the development cycle at which the biologics is. This presentation will discuss the bridging and validation strategy used to support HCP analytical method change in a late phase drug development, to meet an accelerated timeline for regulatory filing.


2:45 pm

Choosing the Right Method: LC-MS/MS Based HCP Workflows and Case Studies for Process-Specific Method Development

Jia Guo, PhD, Principal Scientist, Analytical Development & Quality Control, Genentech, Inc.

The presentation shows our strategy for LC-MS/MS based HCP characterization workflows to enable fast support of process specific development. Three case studies will be discussed, including 1) supporting downstream process development using a robust high-load LC-MS/MS method, 2) identification of low-level polysorbate degradation enzymes in the final purification pools, and 3) using quantitative MS methods to support process-specific method development for PRDX1 clearance, when the specific ELISA is not available.

3:15 pm

Increase the Depth and Breadth of Host Cell Protein Analysis through Analytical Method Innovation and Digital Tools

Rachel Chen, PhD, Associate Director, Analytical Development, Biogen

Host cell proteins (HCPs) are one of the process-related impurities that may cause issues with the safety and stability of biotherapeutics. This presentation will cover recent analytical method innovations in sample preparation and mass spectrometry detection, to achieve in-depth characterization for low abundant HCPs. In addition, comprehensive HCP profiling by LC-MS coupled with proteomics analysis could help understand the HCP abundance change and its impact on various biomanufacturing processes.

Refreshment Break in the Exhibit Hall with Poster Viewing3:45 pm

4:30 pm

Methods Used to Identify, Quantitate, and Monitor High-Risk Host Cell Proteins

Georgeen Gaza-Bulseco, Principal Research Scientist, AbbVie

Host cell proteins (HCPs) are process-related impurities that have the potential to impact patient safety and product efficacy. Even with state-of-the-art downstream processing to remove HCPs, some make their way through the process and copurify with the biopharmaceutical product. High-risk HCPs that make it through the process should be evaluated. Methods used to detect, quantitate, and monitor high risk HCPs will be presented along with several case studies.

5:00 pm

Small Company Perspectives on CRO/CMO Support for HCP Control

Seth Levy, PhD, Director, Bioprocess Development, Modalis Therapeutics

Modalis delivers its CRISPR Guide Nucleotide Directed Modulation (CRISPR-GNDM) therapy via a single AAV vector. Cells used in the production of recombinant AAV contain host cell proteins (HCPs) that can contaminate drug products. Regulatory bodies expect these impurities be reduced to the lowest levels possible. Modalis utilizes an automated workflow evaluating HCP reduction across clarification, concentration, and purification steps, and ensures HCP levels at CDMOs align with internally developed processes.

Close of Host Cell Proteins Conference5:30 pm


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