Name: PDA Technical Report on Low Endotoxin Recovery: Implications to the Industry
Start: 2019-05-03T08:00:00Z
End: 2019-05-03T08:01:10.000Z
Location: BrightTALK
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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: 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...

Full title: A systematic approach to deliver data science solutions for bioprocess development leveraging digital infrastructure and data management solutions

A streamlined approach to analytics can play a crucial role in optimally using digital infrastructure and data management solutions to realize the full potential of advanced analytics for process development. We will discuss our systematic approach to develop scalable advanced analytics solutions including multivariate statistics, digital twins based on AI/ML, mechanistic or hybrid approaches, and more.  Emphasis will be laid on the strategy to democratize and decentralize development efforts and empower citizen data scientists to use these methods to bring new medicines to patients. A diversity of skill sets required to deliver these solutions, including collaboration with our IT partners will be presented. We will also share our experience in employing cloud-based analytics platforms to build an eco-system of data science products that are widely accessible for end-user consumption as well as to inspire other potential citizen data scientists.

A Systematic Approach to Deliver Data Science Solutions for Bioprocess...

Full title: A Systematic approach to define operating space and MRT for continuous manufacturing ER tablets: Opportunities and Challenges

Presented by Ahmed Zidan, Senior Staff Fellow (Pharmacologist) Center for Drug Evaluation and Research at FDA, Owen Rehrauer, President of Sentronic US Corp and Rodolfo J. Romañach, Ph.D. Center for Structured Organic Particulate Systems (C-SOPS) at the University of Puerto Rico

Twin-screw wet granulation is an emerging continuous manufacturing (CM) technology for solid oral dosage forms. Compared to batch operation, this technology offers several advantages including reduced processing time, uniform granule size distribution and shape, and real time process control. Continuous granulation process has been successfully employed for commercial manufacture of IR tablets. However, the high polymer content in the ER formulations has poised challenges by narrowing the design space of screw configuration and operating parameters. This design space defines the flow dynamics within the barrel and plays a crucial role in determining the granule properties. This work pursues a systematic approach for defining the optimum operating space and mean residence time (MRT) through understanding the interaction effects of the screw design and processing parameters on the critical characteristics of granules and tablets. The study identified further the opportunities and challenges of using CM granulation for manufacturing of ER formulations containing high load of swellable polymers.

This presentation will showcase a systematic approach for optimizing the operating parameters and process understanding of a twin-screw granulation to manufacture ER tablets. Examples of failure modes will be discussed, along with the implementation of quality-by-design coupled with PAT tools to monitor the critical quality attributes of granules.

A Systematic approach to define operating space and MRT...

Full title: Applications of Next Generation Sequencing for Viral Safety in Light of ICH Q5A R2

Applications of Next Generation Sequencing for Viral Safety...

Presented by Karen Zink McCullough, Owner, Principal Consultant at MMI Associates and Allen L. Burgenson, Global Subject Matter Expert, Testing Solutions at Lonza

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

Full title: A Digital Transformation Journey in Process Development – Building Automated Data Flows, from Equipment to eLN to Advanced Analytics

A Digital Transformation Journey in Process Development...

Full title: The use of AI and ML in pharmaceutical manufacturing - the evolving regulatory environment in the GMP and CMC Reg space in the US and Europe, illustrated with some application case studies.

The use of Artificial Intelligence (AI) and Machine Learning (ML) models in the GMP space has been discussed for a couple of years as one important element of an Industry 4.0 approach for Pharma. More recently, both the FDA - via a discussion paper on “Artificial Intelligence in Drug Manufacturing” - and EMA - as a topic for their Quality Innovation Group Listen & Learn Focus Group event -have shown interest in developing a regulatory framework or guidance for the use of these types of models.

This presentation will start with the larger evolving legislative framework on AI in Europe and the US, and then move on to describe the FDA discussion paper topics, as well as the EMA interest and potential next steps. The interplay between existing topics of regulatory interest, such as the use of modeling, and AI/ML-specific new aspects will be discussed. The presentation will also show some internal case studies and use cases that span the spectrum of potential applications (from knowledge management to process monitoring to more direct quality control), which many pharma companies are known to work on towards implementation in commercial manufacturing.

The Use of AI and ML in Pharmaceutical Manufacturing...

Presented by Dr Clemens Günther, Senior Expert Nonclinical Safety, Director at Bayer AG, R&D Pharmaceuticals

Toxicological Risk Assessment on Extractables and Leachables

Full title: Leveraging Development and Commercial Knowledge for Root Cause Analysis of Commercial Near-infrared Methods

Bristol Myers Squibb manufactures a high-volume drug product which is tested for release primarily by Near-infrared spectroscopy (NIR) assay and content uniformity analytical methods. Due to the large testing volume, the performance of these NIR methods has been challenged with respect to system suitability, reference method comparability, statistical control limits, and release specifications. These events trigger investigations or proactive initiatives, which require root cause analysis. The determination of root cause for these NIR based methods is very different compared to the deviations and investigations typically encountered with traditional HPLC release methods. For example, NIR method performance events are rarely associated with laboratory error. Also, the multivariate calibration models and associated diagnostic metrics are abstract mathematical concepts, which can be difficult to interpret or assign to specific risk factors. However, within the appropriate context, the additional details available from these multivariate models can be leveraged to determine root cause. Appropriate context can be adopted from historical knowledge available either from the quality by design strategy used for NIR method development or from method robustness trends during commercial operations. This talk will discuss actual examples of leveraging these knowledge sources for root cause analysis of atypical NIR method performance events.

Leveraging Development and Commercial Knowledge for Root Cause Analysis...

HCP Analysis in Biopharmaceuticals by Mass Spectrometry 
Best Practices for HCP Analysis in Biopharmaceuticals by Mass Spectrometry Presented by Annu Uppal PHD. Director-Scientific Affairs & Strategy at USP 
And
Mass Spectrometry based Qualitative and Quantitative Profiling of HCP. Presented by Anita Krishnan, Head of Analytical Sciences at Biocon Biologics 
Mass spectrometry has become an increasingly common approach for identification and quantitation of Host cell proteins (HCPs) to support risk assessment and process development, as well as characterization and quality control. This presentation will provide an overview of the proposed general chapter <1132.1> Residual Host Cell Protein Measurement in Biopharmaceuticals by Mass Spectrometry. The best practices for instrument selection, sample preparation, LC separation, MS data acquisition, MS data analysis and reporting, with particular attention to the orthogonality of MS and traditional methods will be discussed. Additionally, there will be an update on the development of physical reference materials to support identification and quantitation of HCPs of particular concern.

HCP Analysis in Biopharmaceuticals by Mass Spectrometry

Full title: Insights into Practical Issues Associated with Extractables Testing of Medical Devices

It is a well-known adage that “the devil is in the details.” As authoritative texts and regulatory guidelines that address the chemical characterization of medical devices usually present concepts and generalities and lack granularity, sponsors seeking to design and implement extraction studies for medical devices occasionally struggle to establish and justify critical experimental details that are scientifically sound, practical, achievable, and regulatorily compliant.

This presentation provides insights into several of these critical experimental details, addressing concepts that include:

The “It all comes out at Once” Paradox

Exhaustive Extractions as a Source of Kinetic Release Data

Predicting Exhaustive Extractions with a Minimum Number of Extraction Steps

A Rational (?) Approach to Quantitation and Managing the AET

Accurate versus Protective Quantitation

What exactly is a “Semi-polar” Solvent?

Insights into Practical Issues Associated with Extractables Testing...

This presentation will outline Quality and Compliance Requirements For Cell and Gene Therapy Products which incudes”:

- Facility compliance

- GMP quality Management system

- Consideration in IPQA checks and batch release procedure

- Consideration in “ Patient to product tracking system”

- Temperature-controlled clinical trial supply chain

Quality and Compliance Requirements For Cell and Gene Therapy Products

Presented by Clare Blue, Director of Biologics / Gene Therapy Development at Biogen, Ryan Smith, British Pharmacopoeia Specialist at Medicines and Healthcare products Regulatory Agency and Franz Schnetzinger, lead analytical development and QC at Gyroscope Therapeutics, A Novartis Company

The British Pharmacopoeia Commission is producing non-mandatory best practice guidance for analysing advanced therapy medicinal products (ATMPs). This guidance ensures regulatory compliance, patient safety, and industry innovation. Non-mandatory best practice guidance can enhance industry practices, especially in technical fields such as biotech. Vector copy number and empty capsid ratio analysis are crucial in gene therapy development, and accurate analysis is essential for safety and efficacy. Best practice guidance can provide a standardised approach for consistency and encourage innovation. Organisations can learn from each other and improve the quality of research and development. The webinar will cover two guidance documents: Vector Copy Number and Characterisation of the Vector Particle Population of AAV Products.

British Pharmacopoeia’s ATMP Guidance

Sterility Assurance is an essential component of a contamination control strategy for aseptic processes and manufacturers of sterile products. With the recent revisions to Annex 1 heavily emphasizing the importance of a contamination control strategy for manufacturers, Takeda sought to enhance sterility assurance for aseptic production sites, as well as aseptic practices for low bioburden manufacturing sites. The program was developed via design thinking methodology with quality and manufacturing subject matter experts from global sites coming together in a workshop approach to define current challenges and potential opportunities for the sterility assurance program. The program was designed to be a collaboration between global and local functions to support standardization, harmonization, and implementation of best practices across aseptic manufacturing sites. Ultimately, the program will offer training and capability building on sterility assurance and aseptic practices throughout the network.

Design of a Global Sterility Assurance Program

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

There is no specific endotoxin test for VLPs, but they can be problematic during downstream processing, so the focus of the seminar would be to discuss approaches to address endotoxins/pyrogens, including the testing. General benefits/limitations from a scientific/regulatory compliance for each endotoxin/pyrogen test will also be discussed.

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...

Presented by Lindsey Silva, Ph.D. Director, Microbiology in Analytical Sciences at Genentech, Evelyn Der, Senior QC Scientist at Genentech, Kevin L. Williams, Endotoxin Sr Scientist at bioMérieux and Allen L. Burgenson, Global Subject Matter Expert, Testing Solutions Lonza Walkersville, USA

The webinar will provide insight into the regulatory landscape for recombinant Factor C (rFC) implementation as a sustainable endotoxin test method. A range of considerations for method validation activities to ensure health authority acceptance will be covered in the webinar including rFC method validation requirements as an alternative non-pharmacopeial method, rFC method implementation considerations for pharmaceutical water and product testing, and rFC method transfer strategy for QC network adoption.

RFC Implementation Strategy For Endotoxin Testing

The newly revised Annex 1 emphasizes Quality Risk Management (QRM) and highlights how this can inform and direct a contamination control strategy (CCS). The CCS is not a new initiative. The intention of Annex 1 is to use this as a single point of reference that helps define critical control points through data-informed risk assessment, and ultimately to demonstrate a state of process control. But this is not a static state, and the CCS is expected to be a living document, with periodic reviews that drive continuous improvement to further reduce the risk of contamination. 

Sterile filtration plays a critical role in aseptic manufacturing. As innovation in new therapeutic modalities evolve, it is important that end-users understand how to implement a CCS throughout the product lifecycle. Here we outline regulatory expectations for sterile filtration at each stage of product development, and how those feed into the CCS. We also show how shared responsibilities between the end-user and supplier help ensure compliance to Annex 1. Finally, we provide a perspective from a Contract Development and Manufacturing Organization (CDMO) on best practices to ensure compliance with Annex 1.

Building an Effective Contamination Control Strategy for Sterile Filtration

Since first reported by Chen and Vinther in 2013, the phenomenon known as low endotoxin recovery (LER) has been broadly observed in certain matrices commonly used for biologic formulations and certain therapeutic proteins. LER is defined as the inability to recover >50% activity over time when endotoxin is added to an undiluted product. LER is a temperature-and time dependent process, which usually does not occur immediately but after several hours to several days. Compendial LAL method qualification (Bacterial Endotoxin Test = BET per USP /EP 2.6.14/JP 4.01) does not include defined hold time conditions, which may explain why LER has not been detected by following compendial BET guidance. Because of the potential impact to patient safety and complex nature of the LER issue, the Parenteral Drug Association (PDA) published a Technical Report (TR) on LER. This TR was authored by subject matter experts from academia, U.S. FDA, biopharmaceutical companies, and reagent suppliers/testing contractors. The PDA Technical Report on Low Endotoxin Recovery provides a science-based and data-driven strategy in dealing with the LER phenomenon. The author of this article, who acted as co-lead of the TR authoring team, provides first hand information that allows companies to develop product specific solutions to the LER problem.

PDA Technical Report on Low Endotoxin Recovery: Implications to the Industry

Bioprocessing

Low Endotoxin Recovery

Parental Drug Association

Endotoxin

Bacterial Endotoxin Test

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PDA Technical Report on Low Endotoxin Recovery: Implications to the Industry

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