Name: USP General Chapter <665>: Separating Fact from Fiction
Start: 2026-05-20T13:30:00Z
End: 2026-05-20T13:32:30.000Z
Location: BrightTALK

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Full title: Analytical Assessment of Leachables in Biological Drug Products: FDA Approach in Reviewing Information and Representative Review Cases

Presented by Andrey Sarafanov; PhD., Principal Investigator at U.S. FDA, Center for Biologics Evaluation and Research

Analytical Assessment of Leachables in Biological Drug Products

The Monocyte Activation Test (MAT) is globally recognized as a scientifically and ethically superior in vitro alternative to the in vivo Rabbit Pyrogen Test (RPT), capable of detecting both endotoxins and non-endotoxin pyrogens. While the European Pharmacopoeia (Ph. Eur.) actively mandates the MAT as the default method, the United States Pharmacopeia (USP) still requires a full method validation for MAT acceptance.

This shared presentation will provide a robust, two-tiered strategy for validating and implementing the MAT to meet both European and U.S. regulatory expectations. It will provide practical insights into the generic, product-independent validation and comprehensive robustness testing required for successful regulatory submissions. Crucially, the presentation will feature data demonstrating the non-inferiority of the MAT compared to the RPT, a data package that successfully led to FDA acceptance of the MAT as an alternative pyrogen test for a parenteral product.

Additionally, the session will delve into the regulatory framework, including current FDA expectations for alternative methods, and explore advanced method development and optimization techniques necessary for challenging pharmaceutical matrices. This discussion offers a practical roadmap for laboratories seeking to transition to a modern, animal-free pyrogen testing system.

Validation and Implementation of the Monocyte Activation Test as an Alternative Method to the Rabbit Pyrogen Test

This presentation will explore the integration of recombinant Cascade Reagents (rCR) with centripetal microfluidic technology. We will detail our multi-matrix approach for comparing LAL and rCR on different sample types and how we assessed performance metrics such as sensitivity, specificity, and reproducibility across diverse sample types. We also address key technical challenges and practical considerations encountered during this research. Finally, the results of the study will be presented.

Validating rCR on a Microfluidic Platform: A Multi-Matrix Approach

Full title: Regulatory Challenges of Recent Low Endotoxin Recovery Regulatory Queries: Pfizer’s Strategy to Evaluate and Implement Global Changes to Meet Evolving Expectations

The frequency and scope of inquiries related to Low Endotoxin Recovery (LER) from health authorities for biotherapeutic product submissions have dramatically increased over the past year. LER studies are required by the Center of Drug Evaluation and Research (CDER) – Food and Drug Administration (FDA). The Parenteral Drug association (PDA) Technical Report (TR) No. 82, Low Endotoxin Recovery, is used as a guidance for performing LER studies for Biologics License Application (BLA) submissions to CDER, although some recent queries diverge from PDA TR 82. In September 2023, the European Medicines Agency (EMA) published Questions and Answers on biological medicinal products, containing the question, “When should Low Endotoxin Recovery (LER, also known as “endotoxin masking) be investigated?”. 
The provided answer to this question does not specifically define LER or offer detailed
instructions on study methodologies. Due to the increase in queries, an assessment of the queries in a trackable database was completed. This presentation will highlight the major themes observed in these queries, particularly those that had tangible impacts on our LER strategy.

Regulatory Challenges of Recent Low Endotoxin Recovery Regulatory Queries

• Overview of matrix approach for potency assay development 
• Review of available regulatory guidance and expectations for phased-based approach to potency assay development 
• Tools and considerations when measuring biological cascade of RNA & LNP delivery in-vitro 
• Challenges associated with potency assay development for gene editing products

Second talk: Advancing the Analytical Characterization of mRNA-LNPs using Capillary Electrophoresis

Overview of analytical characterization methods for mRNA-LNPs 
Utilizing icIEF technology to assess identity and stability using charge separation analysis 
Improving the separation of LNP samples by optimizing solubilizing conditions 
Assessing multiple attributes including stability, lipid composition variations, surface charge heterogeneity, packaging efficiency

Considerations for mRNA-LNP Potency Assay Development for Gene Editing Products

The Pfizer Continuous Manufacturing Module (PCMM) is capable of manufacturing tablets via either direct compression (DC) or wet granulation (WG).  The initial commercialization of DaurismoTM (Glasdegib) and CibinqoTM (Abrocitinib) was achieved in 2018 and 2021 respectively using a PCMM- DC continuous direct compression approach. In this presentation we will discuss the development and application of PCMM-WG technology to Pfizer’s third NCE small molecule compound.  We will discuss our rational for drug product design, components of the emerging control strategy, and an overview of multi variate experimental and modeling efforts supporting this effort.

Expanding Continuous Manufacturing at Pfizer, Enabling High Drug Load Formulations via Wet Granulation Technology

Full title: Addressing Subvisible Silicone Oil Droplets-Industry Challenges, Analytical Strategies, and USP's Rationale for a New General Informational Chapter

Subvisible silicone oil droplets (SiOPs) originating from siliconized prefilled syringes have become a significant contributor to subvisible particulate matter (SbVP) in biopharmaceutical products. While silicone oil is essential for device functionality, dispersed droplets complicate compendial particle measurements, challenge method specificity, and may interact with therapeutic proteins. This presentation synthesizes insights from a recent Pharmacopeial Forum Stimuli article titled and “Addressing Subvisible Silicone Oil Droplets—Industry Challenges, Analytical Strategies, and USP's Rationale for a New General Informational Chapter”.

We will examine the industry context of subvisible silicone oil droplets (SiOPs) across evolving delivery systems, including prefilled syringes and autoinjectors, and various administration routes except intravitreal use. This overview will compare analytical strategies such as light obscuration, flow imaging with morphology filters, orthogonal methods like NMR/ICP-MS and Raman/FTIR, and emerging tools such as holographic microscopy and AI-enabled image analysis, focusing on their limitations, variability, and fit-for-purpose application. Clinical and safety data will be discussed, emphasizing the low intrinsic toxicity of silicone oil and the context-dependent nature of immunogenicity risks. We will also outline development and lifecycle control strategies—covering siliconization processes, container selection, formulation factors, and manufacturing controls—and present a risk-based framework for product-specific specifications and regulatory engagement when SiOPs impact apparent SbVP levels.

Addressing Subvisible Silicone Oil Droplets-Industry Challenges, Analytical Strategies, and USP's Rationale...

This presentation explores the use of solid phase cytometry for in process bioburden, short shelf-life product and water testing. Solid phase cytometry is being looked at as the new frontier for pharmaceutical microbiology especially for cell and gene therapy. The presentation looks at the practicality, use and limit of detection of these methods in a GMP QC environment and determines what further work might be required. It focuses mainly on low bioburden and in process testing for small molecules. Other new technologies are discussed such as solid phase real time imaging and real time imaging for pharmaceutical development.

Sophie Drinkwater, Associate Director in Microbiology at AstraZeneca

Recent revisions to EU GMP Annex 1 have significantly reshaped expectations for contamination control strategy (CCS), requiring manufacturers to adopt a holistic, risk-based approach. This poster presents a real-world case study from a global pharmaceutical company that has implemented a novel, structured framework for CCS development and deployment. The approach includes standardized global risk questions, tools for consistent assessment, and guidance for lifecycle management. The result is local CCS programs that align with the global CCS strategy with execution through scalable templates and practical implementation tools, enhancing compliance and supporting long-term contamination control

Developing a Site-Wide Contamination Control Strategy: From Risk Mapping to Implementation

The development of mRNA-based medicines requires robust potency assays to assess both translatability and biological activity. These assays can be either cell-free or cell-based assays; each provide a different assessment but are complementary to each other. As such, we will discuss various strategies for assessing mRNA DS and DP potency evaluation and the advantages and disadvantages between cell-free and cell-based assays.

mRNA Products: An Overview on Strategy for Potency for DS vs DP

Medium-chain fatty acids are used extensively as additives to plastics and elastomers. Plastics and elastomers are in turn used in the fabrication of components which then are used in the fabrication of drug product container closure-delivery systems and medical devices. As a result, these medium-chain fatty acids routinely appear in extractables profiles from these components as well as in leachables profiles of drug products. The most commonly used medium-chain fatty acid additive is “Technical Grade Stearic Acid” either as the free base or salt (e.g., Mg, Ca, Zn). Technical Grade Stearic Acid contains a mixture of fatty acids, with Palmitic (C16) and Stearic (C18) acids being the most abundant. These fatty acid mixtures are of biological origin, either plant or animal derived (bovine). It is well established in the scientific literature that the ratios of C16/C18 in fatty acid mixtures vary with origin. 
This presentation focuses on the use of extractables and leachables profiles to indicate the origins of fatty acid additives in packaging and medical device components. Data will be presented from both GC/MS and LC/MS analyses of various extractables/leachables profiles and compared with the chromatographic profiles of fatty acid mixtures of known origin. It will be shown that plant and animal derived C16/C18 ratios can be distinguished by either analytical technique, alerting the analytical chemist to the possibility of a bovine sourced additive with the potential of carrying Bovine Spongiform Encephalopathy (BSE).

Fatty Acid Extractables/Leachables Profiles as an Indicator of Technical Grade Stearate Acid Additive Origin

Over the past few years, the mass spectrometry-based Multi-Attribute Method (MAM) has gained traction due to its potential to streamline lab work and decrease development time. However, several barriers to adoption remain, one of which is evaluating performance of MAM vs. conventional methods.  

To evaluate the performance of MAM vs conventional methods, adalimumab and etanercept were procured from multiple sources, and subjected to forced degradation to generate a range of modifications. Samples were analyzed using both conventional and MAM approaches to evaluate size variants, charge variants, glycosylation, sialic acid content, and other molecular variants like oxidation, deamidation, and glycation.

The ability of each technique to detect differences between nominally similar products and forced degradation-induced changes was evaluated. Physiochemical differences were compared to functional and structural changes detected using cell-based assays, binding assays, and circular dichroism. The knowledge base from this study can help lower the barrier to adoption of MAM, enabling greater efficiency and reducing costs.

Enabling Broader Adoption of MAM: Comparison of MAM vs. Conventional Methods

Since the initial Valsartan contamination incident in 2018, the issue of N-Nitrosamines has continued to present major challenges for the pharmaceutical industry.  This webinar will seek to chart the evolution of the issue, from the initial concerns relating to formation of Nitrosamines during the synthesis of the drug substance, to the wider challenges of the risk of formation of Nitrosamine Drug Substance related impurities (NDSRIs). It will discuss the evolution of the regulatory framework and associated risk assessment tools and how knowledge has shaped this. it will look to highlight the remaining challenges, including in particular the analytical challenges of this ultra trace analysis paradigm we are in.

N-Nitrosamines - Past, Present and Future Through the Eyes of an Analytical Chemist

The absence of adventitious agents is critical for the quality of pharmaceuticals, where contamination event can arise from starting materials or during production (e.g., cell line, cell substrates, equipment, facilities and/or operators). 
 
Rapid microbial methods offer alternatives to traditional compendial methods: reduced time for testing, reduced sample volume requirement, possible automation, increased sensitivity and accuracy. These technologies are most suitable for products with a short life, limited supply, and urgent needs and which may be infused into patients before the completion of the test.
 
The presentation will provide a general overview of the official USP RMM chapters and those under drafting or commenting. In addition, the frequently asked questions, general principles and future developments of the USP <72> and <73> chapters will be explained in detail.

Overview and Future Plans of the USP Rapid Microbiological Methods Subcommittee

Advances in extreme ultraviolet lithography have unlocked the computational power needed to produce chips and GPUs capable of training and deploying GenAI models that are reshaping the way we work and interact with technology. These breakthroughs have been both frightening and inspiring for the manufacturing industry. The ability of these models to process massive amounts of data and deliver insights in ways humans can easily interpret is truly remarkable.

Yet, because AI has not been part of foundational education curricula, widespread misunderstandings persist—even among technically skilled professionals outside the AI field. Market pressures to include “AI” in products and business strategies are also creating significant pressure on executive teams to invest in AI applications without a clear understanding of potential use cases, implementation requirements, or expected return on investment.

In this webinar, I will explore key considerations for integrating various forms of AI—not just GenAI—across the pharmaceutical value chain, with a particular focus on manufacturing and quality. My goal is to provide executives and managers with actionable insights to define realistic strategic objectives, achieve measurable ROI, and avoid common pitfalls in AI adoption.

Developing and Deploying Digital & AI Solutions in Pharma: The Reality vs. the Hype

The emergence of mRNA modality as a therapeutic alternative for treatment of viruses, infectious disease, and various therapies has highlighted the need for high quality mRNA. To meet the quality requirement, developers continue to examine raw material quality, process controls and appropriate analytical methods to ensure the manufacturability of high quality mRNA. As such, we will discuss various strategies to ensure the manufacturability and characterization of high-quality mRNA.

Strategies for Controlling the Quality of mRNA

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

This presentation summarizes USP General Chapter <665>, which provides guidelines for qualifying plastic components and systems in pharmaceutical and biopharmaceutical manufacturing. It introduces a risk-based framework, starting with an initial suitability assessment and a matrix that classifies components as low, moderate, or high risk. Testing requirements—such as extraction solvents, temperature (40 °C), and duration—are tailored to each risk level to ensure science-driven practices.

The scope covers all drug products and biopharmaceuticals, excluding APIs for traditional small molecules and certain auxiliary items. The chapter emphasizes dynamic extraction conditions and standardized surface-area-to-solution ratios for consistency. While <665> is currently informational, it may become enforceable if referenced in USP notices or monographs. Alternative, scientifically justified methods are acceptable for compliance. The goal is to clarify regulatory expectations and support a flexible, risk-based approach.

USP General Chapter <665>: Separating Fact from Fiction

USP General Chapter <665>

pharmaceutical manufacturing

biopharmaceutical manufacturing

risk-based framework

pharmaceutical drug products

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USP General Chapter <665>: Separating Fact from Fiction

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