Name: Proper Calculation of the Uncertainty Factors and its Application...
Start: 2024-07-11T04:30:00Z
End: 2024-07-11T04:32:02.000Z
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: Evaluating Analytical Strategies to Quantify Capsid Titre: Towards a Platform-Method Approach to Accelerate AAV Drug Product Development

Traditional capsid titre methods rely on ELISA which commonly suffers from long turnaround times, low throughput, and large volume sample requirements. This limits the application of ELISA-based methods to routine analysis, thus requiring development of alternative high-throughput (HTP) capsid titre methods. We have performed a comprehensive assessment on currently available orthogonal capsid titre methods using multiple serotypes at concentration range relevant in IND-enabling preclinical and first-in-human (FIH) clinical studies.

Evaluating Analytical Strategies to Quantify Capsid Titre...

The advancement in technologies and innovative thinking are profoundly changing biopharmaceutical drug production industry holistically, giving rise to “the factory of the future.” What will the factory of the future with respect to its structure, technologies, processes, and drug product delivery to the patient be? What enablers will manufacturers need in terms of strategy, leadership, employee skills, IT/OT infrastructure, regulatory oversight, and suppliers to make this a reality?

The factory of the future is an innovation vision on how manufacturers should enhance production by transforming manufacturing in three dimensions: plant structure, plant digitization, and plant processes.

Having a holistic vision of the process

Designing and implementing a flexible framework

Evaluating and implementing proper technology and skill

Emphasizing safety, quality, purity, efficacy and regulatory mandates

The bottom line – delivering ROI

The Factory of the Future

Defining limits for analytical method outputs is a central element of a control strategy. Traditional approaches usually focus on ensuring process consistency, while in more advanced approaches the understanding of structural-function relationships are utilized. This enables definition of patient centric limits that focus on controlling the impact of CQAs on product efficacy and patient safety. In certain cases, those limits and can be defined independent from a specific analytical method and where indicated can extend beyond a therapy specific clinical history. Process consistency control and change management are an integral part of the patient-centric specification and risk-based control strategy approach. The presentation will provide some practical examples for the definition of patient-centric specifications and process consistency control.

Defining Patient-Centric Specification in a Risk-Based Control System

Full title: Downstream Platform Process Development for AAV viral vectors; Challenges and Opportunities

This talk is designed for professionals and researchers from the scientific community, particularly those engaged in industry applications. In this session, I will delve into the concept of platformability in the context of AAV downstream processes. I will examine the opportunities this approach offers for enhancing efficiency, scalability, and reproducibility in viral vector production.

Key topics will include: -

Defining Platformability: Understanding its significance in streamlining AAV production.

Technological Opportunities: Innovative methods and tools available for optimizing downstream processes.

Challenges and Solutions: Identifying common obstacles and discussing potential strategies to overcome them.

Attendees will gain valuable insights into the latest advancements and practical solutions for developing robust downstream processes, positioning them at the forefront of AAV vector production technology.

Downstream Platform Process Development for AAV viral vectors...

Minute virus of mice (MMV) has contaminated biotechnological processes in the past and specific MMV testing is therefore recommended, if the production cell line is known to be permissive for this virus. Testing is widely done using cell-culture based adventitious virus assays, yet MMV strains may differ in their in vitro cell tropism. Here, I present growth characteristics of different MMV strains on A9 and 324K cells and identified significant differences in susceptibility of these widely used indicator cell lines to infection by different strains of MMV, which has implications for MMV detectability during routine testing of biotechnology process harvests [1]. An MMV specific PCR was evaluated as a more encompassing method and was shown as suitable replacement for cell culture-based detection of the different MMV strains, with the additional benefit that detection is more rapid and does also cover other rodent parvoviruses that might contaminate biotechnological processes. Although no MMV contamination event of human-derived cell lines has been reported in the past, biotechnological processes that are based on these also need to consider MMV-specific testing, as we showed e.g. HEK293, a human-derived cell line commonly used in biopharmaceutical manufacturing as susceptible to productive MMV infection.

[1] Farcet et al., Biotechnology & Bioengineering 2024; 121:131-138; DOI: 10.1002/bit.28573

Adventitious Agent Testing For MMV: How Much Do We Really Know?

Medical device chemical toxicological risk assessment is challenging because the risk assessor often needs to consider the many types of device intended uses, many types of materials used in design and manufacturing, and many types of intentional and unintentional chemicals that are or could be present in the final finished device. Medical device intended uses include the type of tissue contact, the contact frequency and duration, and the susceptibility of the device user to chemical exposure. Material factors include the material type (e.g., alloy, polymeric, ceramic, or natural), material properties (e.g., alloy surface characteristics, polymer plasticity, or polymer manufacturing process), and material chemical composition (e.g., chemical formulation, potent toxicants (if present), and the rate and duration of release). How to apply these considerations is described in the U.S. Food and Drug Administration (FDA) 2023 guidance Use of International Standard ISO 10993-1, “Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management process,” International Standard Organization (ISO) 10993 series, and ISO 14971. This presentation will describe how chemical toxicological risk assessment fits into the overall medical device biological risk management process (i.e., risk analysis, risk evaluation, or risk control). Additionally, what medical device use and chemical toxicological information to consider from the U.S. FDA 2023 guidance and ISO documents when estimating chemical toxicological risk will be covered, such as: approaches for characterizing the applicable chemical specific harm(s), estimating an exposure dose, deriving a tolerable intake (TI), and other critical factors to consider that could be useful in the determination of whether exposure to a medical device chemical presents a tolerable risk or could present a possible toxicological risk.

Medical Device Chemical Toxicological Risk Assessments...

Full title: Established Conditions in Analytical Procedure: Overview, Regulatory Examples and an FDA Laboratory Study

Established conditions (ECs) are manufacturing and control elements considered necessary to assure product quality (e.g., ECs in manufacturing process) and to help assure method performance (e.g., ECs in analytical procedures). ECs in analytical procedures help to maintain reliable results that can ensure the efficient product control strategy during the product life cycle. Changing ECs in analytical procedures may necessitate a certain level of regulatory activity and the level of regulatory activity can be different depending on the strategy defining ECs and the extent of changes. The presentation will first provide a high-level overview of harmonized scientific risk-based approaches for identifying ECs and determining the corresponding reporting categories based on scientific principles described in ICH Q12 and Q14 guidelines. Then, two regulatory examples involving ECs in analytical procedures will be discussed. It is noteworthy mentioning that both parameter and performance-based ECs in an analytical procedure are defined in these two examples. The last part of the presentation will be an FDA laboratory study on a mass spectrometry method for a recently identified NDSRI (Nitrosamine drug substance-related impurity). In this case study, analytical variables and method robustness were investigated according to recommendations from the ICH Q2R2 (draft) Guideline. Based on the impact of each variable on method performance, categorical and numerical ECs were proposed.

Established Conditions in Analytical Procedure: Overview, Regulatory Examples

The concept of a Microbiological Quality Level (MQL) has been proposed as a method for determining the acceptable level of microbial contamination permitted during the manufacturing of or on a finished pharmaceutical, biopharmaceutical or combination product. The Kilmer RMM and PAT collaboration teams, along with ASTM Committee E55, have been exploring the use of Microbiology Quality Level (MQL) as means to enabling this future and this webinar will introduce and eexplore this concept as a means of determining probability/quantification of microbial risk for each step and its contribution to the final product as a mechanism to differentiate the microbiological quality of finished product.

A Future of MQL and Managing Risk Release

Full title: Fully Continuous Purification Platform Using Nanoparticles With Ligands and Ultrafiltration

We present on a truly continuous purification technique with potential to reduce costs-of-goods for mAbs, over conventional chromatography-based separations.

We demonstrate the development and proof-of-concept application of a self-assembling affinity nanoparticle to enable affinity ultrafiltration of mAb from an impure mixture.

This technique leverages counter current flow ultrafiltration, concentration gradients between feed and product, in a series of filters representing the phases of the process. Impurity clearance can remain high while minimizing overall buffer consumption and consequently PMI for water.

Overall, these data represent an early advancement toward the development of a truly continuous, counter-current, and column-free method to capture and purify mAb without expensive conjugated resins. We envision further expansion of commercially available nanoparticles towards modality and application specific designs to enable PMI savings across therapeutic areas, delivering lower cost medicines to patients.

Fully Continuous Purification Platform Using Nanoparticles...

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

Biological drug products (biologicals; such as therapeutic proteins, vaccine-, gene-, and cell therapy-based) are produced via multi-step processes involving multiple materials contacting intermediates and sourcing numerous leachables into final drug products (DP). Such steps involve (i) purification of intermediates using chromatography, centrifuging, dialysis, filtering, and filling in final container closure system, etc., (ii) shelf-life storage and (iii) in-use hold of DP. The respective contact materials involve chromatography resins, filtering/dialysis membranes, tubing, collecting bags/tanks, gaskets, valves, final container closure systems, etc. By these, the assessment of leachables risk in biologics is the most challenging compared to other types of DPs. However, current guidances are generally focused on assessment of the leachables only from single manufacturing components, scored to be high-risk for leachables, and by this, underestimate other components scored to have the lower risk. Following these directions, manufacturers typically perform the assessments only for the high-risk components and by this, underestimate the contribution of other materials to the overall (cumulative) leachables profile in final DP. Other typical issues involve (i) non-validation of analytical methods, resulting in ambiguity in Analytical Uncertainty Factor (AUF) used for calculation of the Analytical Evaluation Threshold (AET; reporting limit in an assay), (ii) missing the assessment of elemental (ionic) leachables, or (iii) incorrect leachables study design; altogether also resulting in potential underestimation of the leachables risk. These issues usually cause multiple back-and-forth communications between the FDA and Sponsor during the applications’ (BLAs and supplements) review, typically ending up with post-marketing requirements.

Analytical Assessment of Leachables in Biological Drug Products: ...

Development and Implementation of a Fully Automated and Integrated System to Enable Continuous Biomanufacturing for Clinical Scale

There are many excellent and well-considered reasons for implementing next generation manufacturing (NGM). We have found that, for the most part, organizations will not fund NGM unless the implementation benefits the funding organization by providing a return of cash, time or needed capability. We will provide examples from the AstraZeneca development of NGM where the platform process proposed was based on a common framework for integrated and continuous biomanufacturing. This framework presents a new system that fully integrates and automates several unit operations, providing flexibility and easy implementation. Here we present the optimized process fit, sterility and bioburden control strategy, and automation features that allow this equipment to be tested for 14 days of continuous end-to-end process operation at the clinical manufacturing scale. We include implementation strategy for adoption in GMP manufacturing

Implementation of a Fully Automated & Integrated Continuous Biomanufacturing

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

Presented by Johannes Scheiblauer, Associate Scientific Fellow for Digital CMC at Takeda and Sean Bermingham, Head of Formulated Products at Siemens

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.


Link that was mentioned by Sean Bermingham: 
https://www.siemens.com/global/en/products/automation/industry-software/gproms-digital-process-design-and-operations/training-and-knowledge-transfer.html

Link that was mentioned by Johannes Scheiblauer: 
https://www.fda.gov/media/165743/download

Deploying Modeling & Simulation to Enable Advanced Process Monitoring & Control

Presented by Charlotte Masy, Senior Manager in Manufacturing Science and Technology GSK Vaccines and Ciaran O’Keeffe, Director, Business Development & Channel Sales, Asia Pacific

Digitalization has been used in a lot of biopharma processes. A lot of data are collected through sensor and process measurement and already used in Machine Learning model. However, regarding Incoming material that may have a huge impact on final drug products not much has been done. Historically this was due to the fact that exchange of data with interfaces was quite difficult. This is changing. Through this Webex we want to show advantages of collecting such critical material data from supplier. We will discuss standard and tips on  how to collect data and interact with supplier regarding incoming material. Concrete examples on how GSK use such tools will be shown. Future trends on how digitalization could be applied to more specific  Incoming material such as Single Use will be developed. Example in the field of extractable and leachable, design or investigation will be explained with expected benefits. This will show you that a new world is opening to all of us with digitalization tools.

How Digitization Can Improve Bioprocessing and Make Manufacturing More Robust

The webinar will provide an insight into a global deployment program for an automated solution for Endotoxin testing. A range of implementation aspects will be covered in the webinar including the change management approach for a global platform technology, technical implementation challenges and how they were overcome and harmonization of business processes and best practices within a global company.

LESSONS & BENEFITS GAINED FROM THE IMPLEMENTATION OF AN AUTOMATED BET SOLUTION

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

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...

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...

Full title: Proper Calculation of the Uncertainty Factors and its Application to the Analytical Evaluation Threshold and for Quantitation. Presented by Dennis Jenke, Chief Executive Scientist at Triad Scientific Solutions.

Followed by: The Impact of Physico-chemical Properties of Extractable Compounds on Their Analytical Responses: an Evaluation of GC/MS Response Data. Presented by Dr. Jan Baeten, Scientific Advisor R&D, at Nelson Labs Europe.

Proper Calculation of the Uncertainty Factors and its Application...

Analytical Evaluation Threshold

Extractables and Leachables

Medical Devices

Chemical charactersation

Regulatory compliance

Exhaustive Extractions

solvents

Toxicology

Extractable Compounds

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Proper Calculation of the Uncertainty Factors and its Application...

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