Name: Beyond USP <86>: Supplemental Testing
Start: 2025-04-28T14:00:00Z
End: 2025-04-28T14:02:00.000Z
Location: BrightTALK
Rating: 0

BioPharma Webinars aims to keep its global audience abreast of all developments in the areas of Drug Development, Manufacturing, Quality Assurance, Outsourcing and Regulatory Affairs, with only the highest quality webinars, presented by the most respected people, working with companies in Pharmaceutical, Biopharmaceutical, Biologics and Biotech Industry.

Detection of bacterial endotoxins is a critical quality attribute of parenteral pharmaceuticals and medical devices.  Bacterial endotoxins are cell wall components of Gram-negative bacteria, ubiquitous in nature, difficult to destroy and can cause pyrogenic responses or worse.

We are at a generational change in bacterial endotoxins test method options.  Creating the infrastructure to enable broader use of recombinant reagents advances the science while maintaining the safety and quality of medicines.  Recombinant reagents are derived from established biotechnology principles which begin with the same mechanism of action as the natural protein derived from horseshoe crabs; the detection of bacterial endotoxins by the Factor C protein.  Recombinant reagents also afford improvements in quality, supply chain, and sustainability.

The USP Microbiology Endotoxin and Pyrogens Subcommittee developed a recombinant reagent bacterial endotoxins test chapter which is based on the underlying science, and data from the peer-reviewed literature, sponsor and supplier validations, and ring study trials.

The presentation will provide a general overview of the Subcommittee work, and detailed information regarding the recombinant bacterial endotoxins chapter, associated guidance, and the public health reference standard endotoxin.

An Overview of Recent USP Bacterial Endotoxins Standards Development

The topic will focus on the various aspects of study designs in order to perform for Medical device and Pharma product in a general view. The main focus will be on sample preparations, extraction techniques and quantifications approach in a systematic approach. This will enable to design the studies with scientific rationale. Also, I would like to discuss the aspects of dealing with Identification and classification of compounds observed in the E & L studies. The presentation is focused on approached to be followed while working with various categories of Identification level of compounds.

Effective Extractable & Leachable Study Design

The demand for Advanced Therapy Medicinal Products (ATMPs) to treat diseases continues to grow, and, for many patients, ATMPs represent the last treatment option. As a result, it is crucial for manufacturers to produce and deliver these therapies in a timely manner while ensuring they meet all required safety and efficacy standards.

With the introduction of new manufacturing and testing methods, such as automation, decentralized models, and rapid testing; adopting a risk-based approach for testing and releasing ATMPs is no longer optional—it is essential.

This webinar will examine the potential risks involved in enabling just-in-time or real-time release of ATMPs. We will assess each stage of an example traditional autologous manufacturing process and identify potential risks and the factors that could allow for more efficient, timely release of these therapies.

While the webinar will focus on autologous manufacturing as an example, the insights shared can also be applied to other manufacturing methods.
The views and opinions expressed during the webinar are those of the presenter and do not reflect those of Adaptimmune or its affiliates.

Just in Time Release of CAR T Cell Therapies

This presentation will cover the current sustainability challenges for biopharma industry and how biopharma industry should prepare to solve for this looming sustainability challenges. This talk will also indicate on some aspects of future of manufacturing processes through technological evolution.

Finally, the audience will also hear on a case study which stresses on how a technology evolution and process development can enhance the sustainability issues of Biomanufacturing. 

The second presentation will cover guidance of adopting Phase appropriate orthogonal high-end tools in early-stage product development and Selection of analytical tools for expedited biopharmaceutical development. This talk will provide overview on Significance of High throughput and sensitive analytical tools from Clone to Formulation ranking. This talk will also cover the contemporary challenges in HCP by ELISA and approach to defeat these challenges by alternate approach.

Enhancing Sustainability in Biopharmaceutical Drug Development and Manufacturing

Andrey Sarafanov; PhD., Principal Investigator at U.S. FDA, Center for Biologics Evaluation and Research
Presenting: Analytical Assessment of Leachables in Biological Drug Products: FDA Approach in Reviewing Information

Sandi Schaible, Executive Director, Analytical Chemistry and Regulatory Toxicology at WuXi AppTec

James Hathcock, Sr. Director, Regulatory and Validation Strategy at Cytiva

Analytical Assessment of Leachables in Biological Drug Products: FDA Approach in Reviewing Information

Cell and gene therapy (CGT) is particularly well-suited for the application of big data analytics.  Although our understanding of these complex therapies remains limited, CGT manufacturing processes and analytical methods generate substantial datasets that can be analyzed using artificial intelligence and machine learning algorithms. These advanced computational tools are instrumental in identifying critical characteristics of novel CGT products, optimizing manufacturing and analytical methods, and defining predictive biomarkers, among other applications. This presentation will discuss the role of big data in the development and manufacturing of CGT products and will explore opportunities for crowdsourcing data in the precompetitive space.

Big Data Strategies for Cell Therapy Manufacturing

Continuous capture chromatography is a chromatographic technique promising higher efficiency through higher resin utilization, higher productivity and lower buffer consumption compared to batch chromatography capture processes.

Designing cSMB processes is more challenging than designing standard batch processes because each chromatographic phase is influenced by the previous phase. An iterative approach can be used to identify optimal conditions.

Our traditional process design approach was based on single column breakthrough curves and feeding the breakthrough data into a model. However, this concept leads to a sub-optimal process as it is based on a single loading flow rate during all phases, while effectively, flow rates and volumes in interconnected and parallel load phases should be different for an optimal process. In this webinar, I will present an approach where different flow rates and different breakthrough curves are used as model inputs together with pressure-flow dependencies for the resin of interest. Using the improved process design, significantly higher productivities were achieved compared to the standard procedure. The effect was confirmed for a given in-house model process with approximately 50% higher productivities which has been confirmed at laboratory scale. Finally, implications of the new cSMB design approach for large-scale manufacturing are discussed.

Optimisation of Continuous Capture Chromatography Processes

Presented by Yana Chervona, Drug Safety Team Lead in Drug Safety Research and Development at Pfizer

Read Across Assessment for Potential Leachables Without Toxicological Data

Full title: Advancing Cell & Gene Quality Control with GMP Next Generation Sequencing (NGS): Regulatory Insights and Industry Case Study

This webinar focuses on the established role of GMP-compliant Next Generation Sequencing (NGS) in quality control for cell and gene therapies. With evolving regulatory guidelines addressing advanced therapeutic products, NGS offers a robust and highly sensitive approach to ensure compliance and product safety.

Key topics include an overview of the regulatory landscape, insights into GMP standards for cell and gene therapy products, and a real-world industry case study demonstrating the practical application of NGS. The session will address common challenges, implementation strategies, and best practices for integrating NGS into quality control workflows.

Designed for professionals in quality control, regulatory affairs, and biopharma manufacturing, this session provides valuable guidance on leveraging NGS for enhanced safety in cell and gene therapies.

Advancing Cell & Gene Quality Control with GMP Next Generation Sequencing (NGS)

Using risk management to design aseptic process simulations:

Annex 1 states that “QRM (Quality Risk Management) applies to this document in its entirety”. Does this mean we can use QRM to justify non-compliance with Annex 1 requirements? The answer here is obvious: No.

So when and where can we use QRM? And for what purposes?

During this webinar we will go through several real and practical examples for using QRM to design Aseptic Process Simulations (media fills): 1) When using QRM is not allowed, 2) When it is permitted; and 3) When it is mandatory.

Using Risk Management to Design Aseptic Process Simulations

Establishing a personnel monitoring (PM) program requires a risk-based approach per the current EU Annex I. Presently, there is no specific industry or regulatory guidance on how to establish sample locations and sampling frequencies using Quality Risk Management (QRM) for personnel monitoring and the methodology behind a risk-based approach can vary greatly from site to site. Implementing a global risk-based methodology is desirable for consistency.  Takeda has developed a global personnel monitoring risk assessment tool that can be used across a range of production facilities.  This tool applies to both gowning qualification sample site determination and routine personnel monitoring associated with batch production.  Utilizing QRM principles, contamination hazards and sources were identified and assessed to inform risk scoring criteria.  The personnel monitoring assessment takes into consideration the process understanding of both gowning and manufacturing operations. A case study for the application of the risk-based tool will be presented.

Design of a Global Risk-Based Personnel Monitoring Assessment for a Multi-Production Operation Company

The principles for developing traditional biologics are well established, but do not always translate well to cell and gene therapy products.  Creative yet practical adaptations are necessary to advance gene therapy programs toward licensure.  During this presentation we will explore three key areas where practical adaptations are required:

Building toward the commercial process: change control and managing product evolution for non-traditional development pathways, comparability challenges, and regulatory expectations

Maturation of analytics – the level of product understanding expected as programs advance, method advancement from early to late phase, ensuring repeatability and robustness in method performance

Finding the right partners – finding the right match in terms complementary capabilities, technical performance, phase-appropriate GMP compliance and client service infrastructure

CMC Progression from Early to Late Phase – Practical Considerations for Gene Therapy

The toxicological risk assessment of E&L compounds is typically conducted on a compound-by-compound basis; however, for compounds that lack toxicity data, it may be useful to group compounds together that have similar structural and physical-chemical properties, as
well as a similar toxicological mechanism of action, to derive a class-specific Tolerable Intake (TI) or Permitted Daily Exposure (PDE) that is applicable for all compounds in that group. This talk explores ways to group compounds based on their structural and toxicological
similarity and how to use computational models to identify a proposed toxicological mechanism of action for compounds in a group. The presentation will also review methods to conduct a cumulative risk assessment of the
compounds in the assembled group. This approach of first assembling a group of compounds with a common toxicological mechanism, then conducting a risk toxicological assessment of the compounds in the group, has the potential to streamline the toxicological risk assessment
process when large numbers of extractable or leachable compounds are released from a polymeric material and provides a science-based method for setting TI/PDE values that is presumably less conservative than the use of Threshold of Toxicological Concern (TTC) values as default TI/PDE values for the individual compounds

Grouping Extractable and Leachable (E&L) Compounds with a Common Mechanism of Action for Toxicological Risk Assessment

Biologic manufacturing processes are vulnerable to microbial growth, requiring strong contamination controls and in-process bioburden monitoring.

Bioburden in-process limit excursions should be rare but when they occur, the impact from microbial impurities can be unclear. Filtration alone does not remove them and unlike endotoxin, there is no reliable way to detect the full range of microbial by-products, e.g. exotoxins, PAMPs, and proteases. From a patient safety and product quality perspective, the potential impact of microbial contamination must be assessed as part of the investigation.

The biologics industry has not harmonized on a method for conducting microbial impact assessments. This leads to inconsistency in how firms respond to in-process bioburden excursions, particularly when deciding whether to release or to discard the resulting batch.

This presentation will highlight the specific challenges and best practices for assessing the potential product quality impact of an in-process bioburden contamination, including two distinct approaches: a quantitative method built on extensive studies of Roche/Genentech, and a qualitative approach focused on process vulnerability from PDA TR. 90.

Microbial Impact Assessment of In-Process Bioburden Limit Excursions

The approval and widespread adoption of mRNA vaccines have revolutionized the field of immunization, offering rapid and scalable solutions to combat infectious diseases. This success has spurred significant research into using mRNA for other therapies, including cell therapies, protein production, genome editing and protein replacement. Ensuring the quality and safety of mRNAs in these therapies is crucial, requiring detailed impurity profiling and advanced analytical techniques. Incorporating mRNA into drug products presents significant manufacturing and analytical challenges, particularly in maintaining the integrity of mRNA drug substances and drug products. Rigorous release and stability testing are essential to ensuring these therapeutic products remain effective and safe throughout their lifecycle.

Impurity profiling is an essential part of analytical characterization for mRNA-based products. During production, both process and product impurities can arise, such as truncated mRNA fragments, double-stranded RNA (dsRNA), and residual DNA from the plasmid template. These impurities can potentially impact the drug’s performance or trigger unintended immune responses. This presentation explores the types of impurities commonly found in mRNA-based products and the advanced analytical methods used to analyze them. We will also discuss the challenges faced, potential solutions, and the importance of analytical methods in supporting development programs and meeting expanding regulatory requirements. Continuous improvements in these analytical methods are crucial to address the evolving challenges in mRNA-based drug production and to maintain high standards of safety and effectiveness.

Navigating the Complexities of mRNA Therapies Analysis: Challenges, Techniques, and Quality Assessment Strategies

Transfer of equipment and materials is identified as “one of the greatest potential sources of contamination” in cleanrooms as per EU Annex 1 (Aug 2022); therefore, effective material transfer processes within classified and critical areas play a key role in the safety and quality of products.

This presentation will describe one firm’s risk-based approach to material transfer validation. Key aspects of the approach include identifying and evaluating critical factors associated with the process of material transfer (such as impact on product contamination, impact on environmental contamination, cleanability, and materials/equipment size) and a roadmap to validation execution. Through a structured risk management framework, the critical factors are analyzed to determine their impact on contamination control, and the validation execution and maintenance ensures robust planning, testing, and lifecycle management. The result is a material transfer process integrated into the site’s contamination control strategy, supported by evidence-based validation.

Case Study: A Risk-Based Approach to Material Transfer Validation

This webinar will provide an in-depth exploration of a QbD-based method development approach for quantifying host cell DNA in gene therapy products, a critical quality attribute to ensure product safety and regulatory compliance. The session will begin by examining the measurement principles of two widely used techniques: qPCR and dPCR, while highlighting their respective advantages and limitations. A central focus will be on establishing a robust conversion factor for dPCR implementation. This factor is critical for accurately converting results from copies/μL, the standard dPCR output format, to ng/dose, as required by regulatory guidelines. The discussion will emphasize the importance of selecting an appropriate target gene and utilizing reliable reference materials to ensure precise reporting. Additionally, the webinar will address other essential aspects of method development, including sample dilution requirements, the primary sources of residual host cell DNA, and a summary of the method qualification results.

The Critical Role of Conversion Factor in Quantitative Determination of Host Cell DNA with dPCR

USP <86>, “Bacterial Endotoxins Test Using Recombinant Reagents” states, “Regulatory authorities may require supplemental data prior to acceptance…An example of supplemental data may include a comparative study of the material tested by techniques described in this chapter and those in 〈85〉.”  The term, “supplemental data” may refer to the use of a statistically robust analysis of test results obtained from a single sample containing assayable levels of endotoxins activity, using both the predicate assay (<85>) and the candidate recombinant assay (<86>) .

This webinar discusses the difference between 50-200% acceptance testing and statistical equivalence.  In addition, using data in the public domain as examples, the speakers will stress the importance of using a split sample containing assayable levels of contaminating or potentially contaminating endotoxins activity as the test article for these studies.

Beyond USP <86>:  Supplemental Testing

BET Assays

Recombinant Methods

Limulus amebocyte lysate

Endotoxin testing

Microbiological testing

Bacterial Endotoxin Tesing

Recombinant Factor C

Recombinant Cascade Reagents

pharmaceutical industry

biotech

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Beyond USP <86>: Supplemental Testing

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