Name: Current Bacterial Endotoxins Test (BET) and its Intended Use
Start: 2020-09-24T14:00:00Z
End: 2020-09-24T15:49:20.000Z
Location: BrightTALK
Rating: 5

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.

Full title: Variability, Limits, and Other Considerations for the Next Generation of Pyrogen and Endotoxin Testing

The Limulus Amebocyte Lysate (LAL) test has been the “gold standard” test for endotoxins since the 1980s. In 2023, we find ourselves at an exciting crossroads. We are thinking “outside of the box” with respect to using recombinant and cellular based technologies that promise to make improvements to the existing lysate-based methods. But as technology evolves, should we also be evolving in our thinking regarding assay capability/variability? Given the clear benefits of the LAL test in process control and the statistically irrelevant final sample size for drug product testing, should we consider parametric release? How do we think about setting appropriate endotoxin limits for complex or combination drugs or drugs used in infusions? Is 20EU/device an appropriate limit for all medical devices? Given ongoing research into microorganism adaptation and microbiome, what is the appropriate role of the current purified E. coli calibration standard?

Can we be content with 2023 technologies that are mired in 1980s thinking? This webinar describes the events and thinking that got us here and poses some food for thought moving forward.

Variability, Limits, and Other Considerations for the Next Generation of Pyrogen

Endotoxins, otherwise known as lipopolysaccharides (LPS), are non‑infectious pyrogens associated with the cell membrane structure of Gram‑negative bacteria. The following article outlines endotoxin detection challenges encountered during the development of a novel virus-like particle (VLP). Furthermore, this article provides a review of current methodologies accepted within industry to measure both endotoxin (i.e., LPS) and non-endotoxin pyrogens (NEPs).

Endotoxin Detection Challenges Associated With The Development Of A Novel VLP

Full title: Application of Low Field Bench Top NMR for Upstream and Downstream Stages of Biomanufacturing Process

The development of applications using the low field bench NMR equipped with the flow cell will be discussed for selected process steps at upstream and downstream stages. In scope will be metabolite concentration measurement during fermentation, and concentration of residuals and excipients during antigen purification.

Application of Low Field Bench Top NMR for Upstream and Downstream Stages...

Full title: Evaluation of Optimal Extraction Conditions for Polypropylene, PBT Resins, and Chlorobutyl Rubber Elastomer - Using a Variety of Solvents and Extraction Conditions

Chemical safety assessment is one necessary step to demonstrate that the polymer used is free from harmful chemicals. The assessment should start with adequate material characterization using state-of-the-art analytical methods, including various chromatography techniques most often hyphenated with mass-spectrometric detection. Since polymers are usually incompatible with direct analysis using chromatography-based techniques, an extraction step is required prior to analytical testing. This paper provides information for practitioners who need to understand how to develop science-based extraction conditions that enable the determination of the polymer composition with respect to volatile compounds. Analytical data sets for three types of polymers (polypropylene, polycarbonate, polybutylene terephthalate, and a rubber elastomer) are presented using three different solvents and three different extraction techniques. The extracts were collected at different times during extraction and analyzed by GC-MS. The differences observed between extraction techniques, conditions, and solvents are discussed to better understand the impact of these parameters in extractable studies.

Evaluation of Optimal Extraction Conditions for Polypropylene, PBT Resins...

During biopharmaceutical development large data volumes are generated in many stand-alone devices. Furthermore, with increasing projects and requirements to compress development timelines, high throughput and automation systems are being increasingly implemented. The resulting high pace of data generation augments error rates thereby risking data integrity.

This presentation will provide insights into the strategies and tools for data collection, storage and visualization to transform data into knowledge ensuring leaner, more efficient and integral data generation.

An assessment for each process step and equipment connectivity was performed to map, categorize and highlight gaps during data generation. Based on this preliminary assessment, a data architecture composed of multiple tools was designed to close gaps associated to data traceability, integrity & amp; extractability. Moreover, to support decision-making, multiple modelling tools were developed to focus on specific needs during process development, including process optimisation.

Through increasing instrument and system automation & amp; interconnectivity, data traceability, extractability and searchability are improved, and lab efficiency is increased by >20%. Moreover, with the use of mechanistic models, prediction of culture performance becomes a reality uncovering optimized feeding strategies to significantly increase productivity. In summary, our combined data architecture and process modelling techniques provide better insights thus improving process understanding while accelerating process development.</p>

The road to digitalisation of a research Lab

Several enabling technologies change the way we do pharmaceutical development: automation & digitalization, advanced analytical methods, modeling & simulation. But especially the latter are not silver bullets, and it is important to have a closer look why and when one might use them.

In this presentation, we focus on the real-time applications of modeling & simulation in the context of process monitoring & control: how to leverage the underlying technologies to better visualize current process data, improve process control decisions and anticipate future process trajectories.

We discuss factors and prerequisites supporting a successful and sustainable implementation, from the “digital maturity” of the processes over the necessary technical building blocks (like robotics & high-throughput experimentation) to aspects of people mindset and change management: what it means for an organization to embrace these new ways of work.

Deploying Modeling & Simulation to Enable Advanced Process Monitoring & Control

The confirmation of microbial quality of drug products manufactured by contract manufacturing organisations (CMOs) is a key component of product release.  Whilst the responsibility for product release may lie with the CMOs quality organisation, the sponsor is required to ensure the appropriate quality of the article. 

 Compendial methods for microbial enumeration and sterility are provided in the harmonised pharmacopeia’s (USP, Ph Eur, JP1,2,3), however within the framework of the  compendial chapters, there are a variety of approaches which can be made to meet the requirements.

Whilst compendial methods provide a starting point to define a product specific method, the presence of the test article can lead to interference with the proliferation and detectability of microorganisms.  It is essential the product specific method is demonstrated to be suitable in the laboratory that is conducting the routine testing.

During this webinar you’ll hear an overview of the different approaches to meeting the compendial requirements for the tests for sterility and microbial enumeration.

Considerations For Sterility Test Methods When Working With CDMOs

Full Title: De-bottlenecking Challenges in Large Scale Viral Vector Manufacturing for Gene Therapy Applications

The rush to develop an affordable and accessible COVID-19 vaccine not only accelerated research and development of therapeutic modalities like viral vector, mRNA and pDNA based vaccines but also challenged the bioprocess community to solve for unique scale-up related challenges to manufacture these important life-saving medicines. 

Adenoviral vectors are attractive vectors for delivering genes for other gene therapy applications. These vectors can accommodate large transgenes, transduce quiescent and dividing cells, and do not integrate into the host’s genome. Adenoviral vector technology using HEK293 host cells has been around for a long time and the manufacturing process includes upstream processing (HEK293 cell culture and viral infection), followed by series of clarification, filtration, and chromatography steps to produce drug substance with high purity. Although, the process unit operations seem uncomplicated, manufacturing at large scale in single use systems has remained a major challenge due to poor and inconsistent cell growth in suspension culture during scale-up, low viral titers, product aggregation, inefficient separation of empty and filled viral capsids, as well as complexities related to handling large volume viral infection. Hence, there is a strong requirement to build robustness and scalability in early process development to minimize unnecessary late-stage process changes, as well as design cGMP facility and strong quality culture to handle operational complexities and reduce risks associated with viral vector manufacturing. The webinar will illustrate key questions and challenges in large -scale manufacturing of viral vectors from a process robustness, facility design and product quality standpoint as well as our experiences in debottlenecking these challenges to scale adenoviral vector technology at 2000L and beyond.

De-bottlenecking Challenges in Large Scale Viral Vector Manufacturing...

Downstream protein purification and product concentration is known to be the most challenging part of the process development. It is also known that the Downstream process development is critical to ensuring protein drug quality, safety & efficacy meet regulatory expectations. When initiating the development, the Chemistry, manufacturing and controls considerations for process development and manufacturing must include molecule complexity. Raw materials, process development. Equipment and manufacturing, Quality and Regulatory Affairs

The critical factors for development and manufacturing is performing a stage-wise assessment on Product development, analytical and process development and not least, the manufacturability assessment. The expected qualities of a superlative process shall include increased capacity, flexibility, cost-effectiveness, controllability, scalability, and efficiency

However, general challenges exist in downstream process development involving,

Balancing higher cost chromatography resins and solvents
Constrained purification space for molecules prone to degradation at a wide range of pH and temperature
Process fit to multi-product facility,
PAT availability to accelerated processing
Adaptation of new technologies is one of a smarter way to address the challenges:
Non-Protein A process
use of next-generation chromatography resins
Continuous processing for capture, intermediate purification, Viral clearance

Best Practices of Downstream Protein Purification and Product Concentration

Eli Lilly realized that the professionals (chemists, pharmacists, engineers, biologists, biotechnologists, etc) in charge of the Flow Teams and Process Teams (providing oversight to sterile manufacturing operations) required to strengthen the technical capabilities related to sterile manufacturing. After a thorough analysis, a Team of people developed a program consisting of approximately 40 computer-based courses to be delivered to professionals joining the flow teams and process teams from school or from different roles. The project was accomplished leveraging more than 30 subject matter experts in various disciplines, and an external contractors specialized in computer-based courses. These courses have been integrated with movies of production environment, animations, pictures, etc…

Topics covered include all Sterility Assurance topics (both for standard clean rooms + RABS +Isolators), Process (Formulation, Sterile Filtration, Filling, Inspection), Lab methods (Chemical, biological, physical), Validation (Process, Cleaning, Sterilization), Control strategy, Material Science, Forensic, etc… All courses are freely available to Lilly employees and are included in the Lilly Education and Training electronic system

Capabilities Development for Sterile Manufacturing

This webinar will outline elements to consider in the ruggedness and robustness of methods of analysis for nitrosamine from elastomers used in pharma. It will present a review of sources of nitrosamines in elastomers, together with how these have changed over time. It will give a chronology of the concerns and regulatory interest in nitrosamines over the last forty years. It will review choices that need to be made for methods of analysis during development of a method, and it will explore how those choices might influence the quality of the method produced. The webinar will present key factors to consider when creating a robust and reliable method and how analysis of pharmaceutical elastomers must consider the sample preparation considerations which may be specific to this application. The webinar will also illustrate the validation of a method for nitrosamines and show each element of the validation to consider together will hints and tips to ensure any method is both robust and rugged when challenged and operated in routine use.

Ruggedness and Robustness in Nitrosamine Analysis from Pharmaceutical Elastomers

Full title: Technologies and Platform Approach for Optimizing Downstream Purification of Viral Vectors

The promising success stories and advancement of viral vector-based gene therapy are emblematic of the future of Gene therapy. With the promising future, we still see multiple setbacks and technological challenges towards manufacturing and the higher cost of drug products, which makes it clear that technological challenges must still be overcome, working together with the Gene Therapy industry.

The viral vector production and purification processes are widely divided through the use of different technologies and tools available across industries. Therefore, a platform approach will be beneficial for harmonizing production processes for multiple viral vectors, which will help in optimized manufacturing efforts, thus reducing the cost of goods for manufacturing.

Adeno-associated virus (AAV) and Lentivirus (LV) are two major viral vectors being used for in-vivo and ex-vivo gene therapies respectively, which have unique manufacturing challenges of their own. Based on the multiple serotypes of AAV or multiple pseudo-typing strategies for Lentivirus, the process development is challenging. In this webinar, we will provide an overview of technologies available for the production and downstream purification of AAV & LV vectors and how utilizing the platform approach can help in optimization and reducing the cost of manufacturing.

Technologies and Platform Approach for Optimizing Downstream Purification...

In this webinar, Lawrence De Belder will give an overview of the history, present, and expected future of continuous manufacturing for drug product, drug substance, and biologics. This talk will cover the evolution of equipment design where simplification and modular design are increasingly important. To reap the benefits of continuous manufacturing, business strategies have evolved differently in various areas of the world, while support from worldwide health authorities has shifted over time. Initial thoughts about benefits have adjusted now that more data from industry is available and assumptions can be based on reality instead of estimations. Science has helped to build the rationale behind robust control strategies; valuable knowledge is being shared through clusters of consortia – to be combined in a central repository in the future. Will this evolution help to reduce the barriers of widespread adoption? What might trigger exponential growth of the amount of approved continuous processes? This webinar will describe the aspects that are critical in an integrated continuous manufacturing approach and discuss the logical consequences of market demand and quality control that will assure the future.

Followed by CM re-invented: A novel solution for Continuous Direct Compression (CDC)

Presented by Jan Vogeleer, Managing Director at Fette Compacting

Trends and Future of Pharmaceutical Continuous Manufacturing

-Migrating Bioprocessing into the Existing Infrastructure with Carefully Controlled Risk Management Systems

-Addressing The Opportunities and Challenges Associated with Continuous Bioprocessing and The Importance Data Integrity and Management

-Discussion On The Challenges Specific To Continuous Manufacturing Such as Process Optimization, Process Characterization, Automation, In-Line Process Analytics

-Emergence Of Continuous Manufacturing As The Preferred Manufacturing Platform

Challenges And Opportunities Of Continuous Bioprocessing And Risk Management

The counterfeit business is booming. Counterfeit goods account for a whopping 27 billion EUR revenue lost annually in the Pharma industry due to counterfeits. Moreover, it has an extensive negative impact, leading to product recalls lawsuits, consumer illness or death, and eventually, long-term reputational harm. Blockchain helps tackle counterfeiting by identifying the provenance (i.e., proof-of-origin) of a product because blockchain provides a secure and trusted tracking system from one end of the supply chain (the creation or mining of raw materials) all the way to the other end of the supply chain (where the end user enjoys the finished product). Because blockchain can identify provenance, legal enforcement agencies can more conclusively establish the counterfeit nature of suspect products, and pharma companies can protect their bottom line, ultimately stabilizing and creating a more resilient supply chain

Stabilising The Biologics Supply Chain with Blockchain

Full title: Burkholderia Cepacia Complex and Aqueous Non-Sterile Drug Manufacture: Updates from a CDER Microbiologist's Perspective

During this webinar, Dr. Metcalfe will:

Provide a short background regarding FDA concerns pertaining to Burkholderia cepacia Complex (BCC) and the manufacture of non-sterile drug products

Provide reference to pertinent areas of the 2021 FDA Draft Guidance for Industry-Microbiological Quality Considerations in Non-sterile Drug Product Manufacturing

Present recent events in the US pertaining to BCC

Explore recent FDA Warning Letters to address common industry questions regarding BCC and the manufacture of non-sterile drugs

Burkholderia Cepacia Complex and Aqueous Non-Sterile Drug Manufacture...

Continuous processing is being explored in various ways throughout the biopharmaceutical industry.  New process technologies and business considerations are driving process design towards more agile, modular, and highly productive paradigms.  Continuous manufacturing provides potential benefits such as reduced process scale and the implementation of single-use technologies.  However, these benefits may come at the cost of complexity.

This presentation will review a case study analyzing the conversion of a traditional GMP process into a continuous manufacturing paradigm. Discussion will include the development of integrated continuous operations, control strategy, and process design considerations.  The outcomes of the process conversion will also be discussed.

GMP Implementation of Continuous Manufacturing: A case study

The presentation aims to provide an overview of challenges that can be faced with the knowledge that a one size fits all approach cannot be taken. While individual challenges may not be unique to cell therapies. They way they can impact cell therapy facilities can be unique with additional considerations given the nature of cell therapy products and production methods. Each process and facility is unique with some processes far removed from a traditional biologics facility and others that may be closely aligned with traditional production methods. Challenges outlined in the presentation related to some aspects that are related to process and materials that can be presented during cell therapy manufacturing. These include:

Shelf life considerations for starting materials and finished product

Contamination Control Schemes for Facilities and it’s importance in facilities.

Control of personnel and the “human aspect” of cleanroom control.

Manual nature of cell therapy production.

Risk Reduction measures.

Criticality of right first time

Benefits and Drawbacks of isolator Technology.

Contamination Control Challenges Facing Cell Therapy Facilities

Presented by Karen Zink McCullough, Owner, Principal Consultant at MMI Associates and Veronika Wills, Manager, Technical Services

The Bacterial Endotoxins Test is not a test for pyrogens (fever causing agents). It is not a test for the presence of Gram negative bacteria. Based on extensive comparisons of endotoxins activity in the BET and fever rabbits executed in the 1970s and 1980s, we may say that the BET is a test for levels of Gram negative bacterial endotoxins activity that may be predictive of a fever in mammals.

The various methodologies that are described in the harmonized in the harmonized chapter use the primary Reference Endotoxin Standard (RSE) or secondary Control Standard Endotoxin (CSE) to prepare assay standards, perform suitability testing as instructed in the chapter and inoculate positive product controls. These standards are relatively pure preparations of lipopolysaccharide. However, the utility of the compendial assay for non-compendial applications is limited. Our discussion will focus on the compendial uses of these BET assays.

Current Bacterial Endotoxins Test (BET) and its Intended Use

Biopharma

Biologics

Bacterial Endotoxins Test

Endotoxins

Gram Negative Bacteria

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Current Bacterial Endotoxins Test (BET) and its Intended Use

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