Name: Validation of Microbiological Methods - Expectations for Regulatory Compliance
Start: 2015-05-22T15:10:00Z
End: 2015-05-22T15:11:09.000Z
Location: BrightTALK
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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...

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

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: ...

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 Digital Transformation Journey in Process Development – Building Automated Data Flows, from Equipment to eLN to Advanced Analytics
Sanofi CMC/Process Development is implementing a comprehensive Digital Transformation program to improve our productivity and reduce our development timelines. We are deploying a standardized digital workflow across our development sites globally (target: 2,000 users) and building automated data access to ensure scientists can document, visualize, and analyze their experimental work. We will discuss the progress, successes, and pain-points encountered by the development teams as we progress towards our digital ambition.

A Digital Transformation Journey in Process Development...

Pharmaceutical forensics is a unique industry field, where samples of unknown identity, composition, quality, or origin are analysed. Every case differs in nature, ranging from detection of counterfeit drug products, evaluation of patient complaints, and analysis of foreign/extraneous matter from manufacturing investigations. Portable spectrometers have many applications in this industry due to the compact, fast, and in-field capabilities of the instrumentation. The objective of this presentation is to highlight real-world applications of portable technologies in the pharmaceutical forensics field such as screening/testing of counterfeit drug products, moisture analysis of disintegrated tablets, and more.

Application of Portable Spectrometers in Pharmaceutical Forensics

Full title: Building an Innovative Integrated Continuous Downstream Manufacturing Platform for the Production of Biologics

-Next generation manufacturing (NGM) for biologics is focusing on cost reduction and smaller facilities for an increased productivity. Integrated continuous bioprocess (ICB) is a powerful way to achieve that.

-A streamlined control strategy for AstraZeneca’s development of ICB to test this implementation for 14 days of continuous end-to-end process operation at the clinical manufacturing scale will be presented.

-It involves dealing with variable perfusion flow rate, normalization of dynamic perfusion titer profile, sizing between intermittent (bind-elute chromatography) and continuous (viral inactivation) unit operations, and integrating PAT when and where possible.

-Some scenarios of in-process divergences and their impact on an optimized downstream process sizing will also be included.

Building an Innovative Integrated Continuous Downstream Manufacturing...

Presented by Dr. Parthasarathy Sampathkumar, Head, Group Center for Operational Excellence at Biocon Biologics and Sara Jane Bresee, Managing Director of APAC at MasterControl

This presentation will cover The Opportunity Landscape & Methodology utilized at Biocon to drive OE, The Group Level Structure & glimpses of The OE Framework.

Opportunities Landscape & Methodology

At Biocon, we believe that the most fundamental way of identifying Opportunities is by virtue of “The 3Ms.” These being Mura, Muri & Muda. These are Japanese terms that stand for as Un-evenness or variability, Overburden or Under-capacity and Wastes, respectively.

The Group COE (Center of Excellence) Structure

The purpose of The COE Structure is to identify, exploit and translate the opportunity landscape into viable improvements under the umbrella of Business Excellence Framework providing Centralized Governance and driving Institutionalization of OE Leveraging Digital Transformation.

Operational Excellence Framework – An Introduction

The OE Framework is an Agile, Scalable, Holistic yet Flexible Model with a capability to Balance, Integrate and Assimilate all existing and any future initiatives under One Umbrella including Digital Interventions. This encompasses the Strengths of tried and tested International Excellence Frameworks with high internalization & contextualization to The Biocon Group in totality. The individual elements of The Framework will enable seamless delivery of Business Objectives with a strong linkage to robust Business Processes.

Leveraging Digital Transformation To Deliver Operational Excellence

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...

Presented by Sethu Madhavan, Global Head of Insulin Operations at Biocon Biologics and Yvan Ruland, Head application APAC - Sartorius Chromatography Equipment

-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

Full title: Advanced Technologies for Media and Process Optimization for Biologics Manufacturing

Cell culture media composition and upstream bioprocess conditions are crucial factors affecting protein yield in the production of biologics and biosimilars. Recently, advanced new techniques were developed that use IT approaches, including computer simulation of bioprocesses, AI tools and ‘multi-omics’ methods for analysis of cellular metabolic pathways. These techniques allow optimization of both process and media composition for maximizing culture performance and protein production. In my talk, I will discuss the importance of cell culture media optimization and feeding conditions for achieving the most out of biologics pipelines. I will also discuss about other supplements that can help achieve faster cell growth and higher productivity.

Main topics of my talk:

DoE approaches for media formulation and feeding optimization

‘Digital Twins’ bio-simulations for reducing wet data requirements and allowing rapid optimization of feeding manner

Multi-omics and metabolic flux analysis for identification of metabolic bottlenecks and critical media components, for development of enhanced basal and feed media

Supplements for productivity enhancement

Advanced Technologies for Media and Process Optimization for Biologics Manu...

Full title: Navigating The Complexities of AAV Scale Up to Keep Pace with the Increasing Demand For these Viral Vector Delivery Systems

Presented by Seth Levy, Director of Bioprocess Development at Modalis Therapeutics and Gael Nicolas, Senior Technical Sales Specialist at Refeyn

Modalis’ epigenetic editors are designed to efficiently target genes and control chromatin conformation by coupling an engineered Cas9 variant with epigenetic effector domains; referred to as GNDM (Guide Nucleotide Directed Modulation), which is delivered via a single AAV vector.

Most AAV capsids used for systemic treatments require high doses,

leading to safety concerns. To overcome such obstacles, Modalis has evaluated numerous novel AAV capsids allowing for reduced dosing, increased safety margins, and higher

therapeutic efficacy. These novel capsids do not always play nicely with standard manufacturing techniques and available reagents, so creative process development and analytics are needed to bring these promising therapeutic molecules to patients.

Navigating The Complexities of AAV Scale Up to Keep Pace with the Increasing...

Full Title: Building the House of Rapid Sterility - A Successful Platform Approach to introducing Rapid Methods

This webinar will focus on the implementation of rapid sterility using a strategic platform approach to reduce the post-approval change burden, introduce the use of rapid methods earlier in the pipeline, and reduce validation time. It will also cover overcoming business challenges with alternative methods, perceptions of risk, regulatory challenges, and finance. It will discuss examples of these challenges regarding several products. This technology has been used both in development and commercial spaces, as these areas are very different and require different approaches to implementation. Although this presentation will focus on ATP bioluminescence, this approach may be used for all new alternative or rapid methods.

Building the House of Rapid Sterility - A Successful Platform Approach...

Full title: Validation of Test Result Equivalence for Alternative BET assays, Including Recombinant Methods

Presented by Karen Zink McCullough, Owner, Principal Consultant at MMI Associates, John Duguid, Executive Director, Research & Development at Vericel Corporation, Steven Walfish, Principal Consultant at Statistical Outsourcing Services and Allen L. Burgenson, Global Subject Matter Expert, Testing Solutions at Lonza

Both FDA’s 2012 Guidance for Industry and USP <1223> specifically use the term, “equivalence” as a requirement for validating an alternative test. Traditional methods, such as the Limulus amebocyte lysate (LAL) assay, are widely accepted and have a proven record of assuring parenteral drug and device safety, but they have limitations, including reagent variability and sustainability concerns. As a result, new methods using a number of innovative platforms, including recombinant technology (rFC and rCR), have emerged. The concept of test result equivalence bridges the gap between old and new technologies, offering cost-effective, environmentally friendly, and reproducible means of endotoxins detection, advancing the industry's ability to ensure continued product quality and patient safety.  This webinar will explore the concepts of equivalence, comparability, and statistical methods used to evaluate them.

Validation of Test Result Equivalence for Alternative BET assays...

It is a regulatory requirement (ICH Q5A Revision 2) to demonstrate viral safety of biotechnology product derived from in vitro cell culture, including viral-vector derived products like recombinant Adeno-Associated virus used as a delivery medium for gene therapy products. Viral clearance in gene therapy product poses different challenges from the other non-viral biotechnology product in the viral removal strategies. In this webinar, we will present a case study with a clinically relevant AAV8 downstream process:
1 The rationale of the study design: the choices of virus panel, surrogate and the unit operation for demonstrating viral clearance.
2 Present the clearance achieved in a scaled down model of the process

The Importance of Viral Clearance and Characterization in Gene Therapy Products

Full title: Leachable Risk Assessment Approaches: A Comparison of USP <665>,Biophorum, and Other Methods For Assessing Leachable Risk In Biopharmaceutical Manufacturing Systems

There is currently no agreement on a format for a leachable risk assessment approach when applied to a biopharmaceutical manufacturing system. USP and Biophorum have published some guidelines, however both guidelines have (in the opinion of this speaker) some gaps and flaws. This webinar will provide review of the USP and Biophorum guidance and suggest an alternative approach, which seeks to address these gaps. The approach providing both a consideration of leachable risk in terms of both severity of harm and probability of harm, and its associated uncertainty as a result of a biopharmaceutical manufacturing process and its effect on patient safety.

The approach outlined borrows heavily from principles outlined in ICH Q9 and has been presented in part through ELSIE’s whitepapers published to their website. Its key recommendations are to establish a process whereby the leachable risk is clearly identified, followed by a scoring of the risk through a risk analysis then a risk evaluation against a pre-agreed risk matrix that will output a clear decision on whether further risk control is required and the risk is either accepted or needs reduction. Subsequent study design and requirement is thus based on these principles, rather than a pre-stipulated design.

Leachable Risk Assessment Approaches: A Comparison of USP <665>...

Full title: Current State of PAT Applications for a Reliable and Effective PCM Equipment Operation

PAT is an integral part of every Pharmaceutical Continuous Manufacturing (PCM) control strategy. On the other hand, PAT sensors can cause equipment and process inefficiencies due to the complex nature of those instruments. Sensor technology, data volume, sensor maintenance or the interface to the process contribute to operational complexity.

Nonetheless, PAT is required to measure Critical to Quality product Attributes (CQA), on-line or at-line and is enabling Real Time Release strategies. Furthermore, PAT sensors are also used during process and predictive model development, CQA monitoring, diverting Out of Specification (OOS) material and thus are essential for Real time Release testing applications.

Consequently, the selection of PAT applications is a critical step in every PCM business case assessment and during the entire engineering phase of a PCM system. This presentation will provide an overview of commonly used PAT sensor technologies and their selection criteria. Furthermore, it will revisit process design criteria for the optimal positioning of those sensors within the given process flow.

The overall control strategy defines what level of PAT implementation is necessary to run a successful continuous operation. All examples will be supported by real world PAT applications in operating PCM installations. 

Finally, this presentation should provide confidence in available PAT technologies. Innovation will aim for new even more sophisticated sensor technologies and new analytical software tools, but today PCM drug substances and drug product applications are covered and allow lead users to achieve the expected Overall Equipment Effectiveness (OEE) and required Net Present Value (NPV).

Current State of PAT Applications for a Reliable and Effective PCM...

Microbiological methods play a critical role in ensuring safety and efficacy of drugs and biologics. Most microbiological methods are described in compendia and do not need method validation. However, rapid microbiological methods and other alternate methods require full validation. Due to large inherent variability and complexity of microbiological methods, there are challenges in validation of such methods. This webinar will discuss, ways of performing validation of microbiological methods, with a view to achieving regulatory compliance.

Validation of Microbiological Methods - Expectations for Regulatory Compliance

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Validation of Microbiological Methods - Expectations for Regulatory Compliance

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