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Full Title: Regulatory Strategies For Rapid Sterility Testing of Gene and Cell Therapy Products

The need to utilize rapid sterility testing is gaining momentum within our industry, especially for short-life drugs with an immediate patient need, such as advanced therapy medicinal products (ATMPs; cell and gene therapies). This webinar will explore the challenges of manufacturing and releasing ATMPs and the benefits of implementing rapid sterility test strategies. In particular, we will discuss valorous global regulatory initiatives and policy changes that support the use of rapid sterility tests for these types of products, as well as the introduction of compendial chapters providing guidance for validation and implementation. We will finish with case studies on how rapid sterility validation studies may be performed.

Regulatory Strategies For Rapid Sterility Testing...

Full Title: Overcoming Antibody-Drug Conjugate (ADC) Process Development & Manufacturing Challenges

Presented by Dr. Jincai Li, Vice President of WuXi Biologics

Overcoming Antibody-Drug Conjugate (ADC) Process Development...

Full Title: In-line monitoring of surfactant clearance in viral vaccine downstream processing

In-line monitoring of surfactant clearance...

Rapid methods have been available to the pharmaceutical industry for decades. And although global regulations have changed to encourage their use, especially for rapid sterility testing, and the compendia enhanced their chapters to promote the validation and implementation of these technologies, only a handful of firms have embraced rapid methods to their fullest potential. This presentation, which will include audience participation, will once and for all disprove the misconceptions and address any confusion surrounding rapid method applications and acceptance. We will also discuss the most current enablers, including guidance from USP, Ph. Eur., Annex 1, FDA and EMA, and share successful case studies where rapid methods have had the greatest impact.

We Are Going Back to the Future with Rapid Methods

Genotoxic compounds can be released from some medical devices during their clinical use.  The ISO 10993-17:2002 standard outlines steps to assess the risk posed by patient exposure to genotoxic compounds released from device materials.  It is important to note; however, that the ISO 10993-17 standard is currently undergoing revision and the procedures for conducting a toxicological risk assessment of genotoxic compounds are likely to change following revision of the standard.  This talk will outline the proposed changes to the ISO 10993-17 standard regarding methods to assess the risk posed by patient exposure to genotoxic compounds released from medical devices and will describe steps to mitigate the risk using risk management strategies.  The talk will also briefly address how Carcinogenic, Mutagenic, and Reproductive (CMR) compounds will be handled in Europe under the new Medical Devices Regulation 2017/745/EU.

Handling mutagenic extractable and leachable compounds released from devices

Full Title: CCAB: A universal tool to address the risk of microbial impurities in parenteral drug manufacturing including ATMPs

For parenteral drugs such as monoclonal antibodies, injectable oligonucleotides, and RNA- or DNA-based ATMPs, filtration using pore sizes ranging between 0.02 and 0.2 µm is the method of choice to reduce bioburden and ensure terminal sterilization of the drug product. While filtration efficiently removes intact microbial cells it does not remove subcellular microbial components like toxins, lipopeptide/lipoproteins, flagellin, bacterial and fungal DNA, cell wall polysaccharides, extracellular proteases or endoglycosidases. These microbial impurities can have a significant impact on product quality and patient safety when critical loads are exceeded during a contamination event. The CCAB approach described here enables a comprehensive assessment of these risks.

CCAB: A universal tool to address the risk of microbial impurities...

An overview of single use manufacturing for the production of AAV gene therapy products with comparisons to traditional monoclonal antibody production.  Specific challenges of scaling up AAV production and considerations to accommodate a range of demands of differing gene therapy products will be discussed.  I will review the reasons for starting and the challenges of being the inhouse manufacturing facility for a rapidly growing company.  The challenges of making non-COVID products in the era of Warp Speed along with future commercial production comparing fully single use with a hybrid facility will be explored.

Single Use Process for Production of AAV Gene Therapy Products

Full Title: Rapid methods- The Next Phase : A Framework For Multi-Product Adoption Of Rapid Sterility Testing

The adoption of rapid sterility testing has significant benefits to the pharmaceutical industry; providing early notification of control drifts, a non-subjective answer to the sterility test and a faster time to product release.  However the challenges of adoption can be daunting.  By enhancing the benefits of regulatory interactions in the development phases, a complex post-approval regulatory change can be mitigated, however with limited material available, the outlined strategy provides a robust way forward to adopt rapid sterility and capture the benefits.

AstraZeneca considered the global operations of a major pharmaceutical company in the adoption of rapid sterility.  Utilising risk assessment tools and a holistic overview of pharmaceutical clean room flora, a representative panel of global microorganisms was selected.  Variability between product, consumables, organisms origin & status and testing sites was factored in. 

Focused studies were performed and data will be shared to provide an outline of the operating range that has been verified for the ATP Bioluminescence based sterility test.

The presentation will outline a vast & powerful data set which supports the robustness of the rapid sterility test, to enhance our product understanding.  Additional data was leveraged in time to result studies for “challenging organisms” such as slow growers.

Rapid methods- The Next Phase : A Framework For Multi-Product Adoption...

At Merck, we aim to recruit, retain and promote the best talent around the world to support our drive for innovation and growth. This includes ensuring balanced representation of women across all levels in the organization. Our leaders are committed to fostering a culture where women can thrive, because we believe gender equity helps our business and our patients. 

Our global strategic diversity, equity and inclusion plan has a particular focus on gender. We aspire to increase representation of women in management and leadership positions across our healthcare, life science and electronics sectors. The leaders at Merck will track progress of women in leadership roles, along with other key metrics, including gender balance in our development courses, succession plans, and the sponsorship of women. In a world where women make up 50 percent of the population, we want to make Merck more reflective of the countries in which we do business and better reflect the customers we serve.
We believe that a diverse workforce paired with a respectful and inclusive company culture is fundamental to our ability to innovate and contribute significantly to our business success. Curious minds make Merck better.

The Importance of Women Leaders at Merck KgaA Darmstadt, Germany?

Presented by Irving Ford, Site QA Head multi-product CAR T facility at Bristol Myers Squibb

Just in Time Release of CAR T Cell Therapies During Covid-19

Full Title: Near-infrared spectroscopy for monitoring Maillard reaction and critical process parameters of a C. tetani bioprocess

Near-infrared spectroscopy for monitoring...

Full Title: Using PAT to accelerate and optimize the process development of solid dosage forms. 

Near-infrared spectroscopy (NIRS), as one of the major PAT tools, has attracted lot of attention from the pharmaceutical industry. NIRS can analyze samples without previous pretreatment, therefore reducing or eliminating wet chemistry analysis. During development of the drug product process, each unit operation brings challenges that need to be assessed in order to prevent compromising the quality of the final product. Two examples of real PAT applications are presented in this study. The first case tackles the challenges of process development in an international environment, with different locations for manufacture and traditional analytics. Showing how PAT enables a lean evaluation of the product quality, better understanding and supports process transfer. By means of in-line monitoring of the blending process, at-line content uniformity determination on high number of tablets and by helping the troubleshooting of segregation. The second case describes in-line monitoring by NIRS for assay determination in a wet met media milling process of a nano-suspension. NIRS proved to be a versatile and valuable tool for the pharmaceutical development and manufacturing of solid dosage forms.

Using PAT to accelerate and optimize the process development

Full Title: Applications of industry 4.0 concepts in continuous pharmaceutical tablet manufacturing process

Currently, Industry 4.0 concepts are being applied to pharma industry to achieve Pharma 4.0 paradigm. Pharma 4.0 reduces the time and resources needed for continuous pharmaceutical manufacturing and also improves the product quality and production consistency. It has many advantages but also have bigger challenges on the applications of artificial intelligence (AI)/machine learning (ML), and advanced control systems because of different level of complexities.

Four machine learning (ML) models have been trained to predict the response of continuous pharmaceutical manufacturing process and the performance of these ML models has been compared. The investigated ML methods are long short term memory (LSTM), 1D convolution neural network (CNN), random forest (RF), and artificial neural network (ANN). The best performing ML model is then implemented into the continuous pharmaceutical tablet manufacturing process. An advanced model predictive control (MPC) system coupled with an RTD based control system has been also implemented in the continuous pharmaceutical manufacturing (CPM) pilot-plant [1]. The CPP’s and CQA’s are controlled in real time using advanced model predictive control (MPC) system while the none-confirming products are diverted in real time in waste using RTD based control system to assure the final CQA’s of qualified tablet lots. All the relevant data generated during continuous manufacturing has been systematically collected, stored and organized in a data hub (OSI PI) and cloud system as per industry 4.0 standard.

The objective of this presentation is two-fold; first to highlight the pharma 4.0 technology and then demonstrate the development and implementation of machine learning (ML) and advanced control systems into continuous pharmaceutical tablet manufacturing process.

Applications of industry 4.0 concepts in continuous pharmaceutical tablet...

Full Title: Validation Of Endotoxin Testing For CAR T-cell Manufacturing Quality Control & Benefits of Cartridge Technology

During manufacture of CAR T-cells there is a risk of contamination of the final product and/or materials with endotoxins. Endotoxins are lipopolysaccharide molecules produced by gram-negative bacteria that can cause toxic reactions in patients and lead to serious complications. 

Endotoxins can be detected reliably by the limulus amoebocyte lysate (LAL) test. Endosafe nexgen-PTS, (Charles River) is a portable system designed to read cartridges loaded with LAL reagents and endotoxin control. Each cartridge is supplied with a predetermined spike recovery with two sample and two spiked channels enabling quick and easy endotoxin detection.

Materials used in cell manufacturing may interfere with the test and therefore validation of bacterial endotoxin testing (BET) is mandated for each cell product. We’ll present the validation approach for endotoxin testing using Endosafe nexgen-PTS designed to meet Australian regulatory requirements.

In this webinar, you will learn from our experts:

Introduction to cartridge technology and its benefits
How the Endosafe nexgen-PTS provides a rapid quantitative method for Endotoxin detection in CAR T-cell products.
Why Maximum Valid Dilution (MVD) needs to be calculated and validated for each CAR T-cell product formulation and volume of infusion.
Why it is important to perform interference testing using I/E cartridges and serial dilutions of the CAR T-cell product up to the MVD.

Validation Of Endotoxin Testing For CAR T-cell Manufacturing Quality Control...

Following on the commercial success of Spinraza® (the first successful treatment for patients with spinal muscular atrophy), antisense oligonucleotides (ASO) are now an important part of Biogen’s drug portfolio that enables us to better treat neuromuscular diseases. Development of the ASO process employs orthogonal chromatography to achieve industry high purities while maintaining good yield along with detritylation and UF/DF steps.  This purification platform process is all aqueous based on green chemistry principals that easily fits into our existing biologics manufacturing facilities. To date, we now leverage this ASO platform process to purify 13+ ASO molecules that contain different sequences, chemistries, and most recently incorporating conjugation reactions.

Having completed process characterization for our lead ASO candidate, we have achieved a greater understanding of the process, its capabilities to clear process and product related impurities and understand the mechanisms that control the chromatography. On the manufacturing side, Biogen recently completed at scale PPQ validation batches of an ASO clinical candidate.  Cases studies and learnings will be presented on results from characterization studies and PPQ batches.

Advances in the Purification of Antisense Oligonucleotides

Full Title: Application of Next Generation Sequencing (NGS) Based Methods for Detection of Viral Contaminants in Biomanufacturing

Contamination of a biological product with viruses, potentially harmful for humans, is of concern for therapeutics derived from human and animal sources, i.e. plasma, and for protein therapeutics and vaccines produced in mammalian cells.  More recent “Advanced Therapeutic Medicinal Products (ATMPs)”, such as gene and cell therapies, share the same concern.  Tests for viral contaminants are performed at several stages of manufacturing.  Current tests for detection of viruses are lengthy; cell culture based assays and animal experiments are required.  Alternative molecular tests, such as “next generation sequencing (NGS)”, provide faster results, and can eventually replace in vivo animal studies.  It is noteworthy that identification of a viral contaminant that evaded detection in classical tests, by NGS, has been demonstrated.  In addition, due to the fast turnaround time, application of targeted NGS for “in process” detection of viral contaminants can be envisioned.  Current efforts for development of unbiased and targeted NGS based viral safety assays will be discussed

Application of Next Generation Sequencing (NGS) Based Methods...

Single-use technologies are more and more used in critical sterile applications, e.g. close to final manufacturing steps handling Drug Product, leading to increasing concern related to integrity. In this presentation, we make a review of the regulatory environment and present key elements to consider to defined and apply a sound integrity control strategy.

The regulatory environment has significantly evolved in last years, with the publication of new guidance and standards and additional ones in preparation.  Current draft of EU GMP Annex 1 illustrates the increased scrutiny of regulatory authorities on this topic.  

We will position integrity tests in the more global picture around integrity strategy. Concepts such as QbD and QRM, as well as close collaboration between supplier and end-user are required to build a good strategy and enhance the integrity assurance for processes using single-use systems. A defined integrity control strategy is very important for critical applications where single use systems are used after last sterile filtration step or in a process where no sterile filtration is possible.

We will discuss the different technologies available on the market to control integrity of single-use systems and key parameters that are affecting integrity measurements, at supplier’s and at end-user’s side.

Several case studies will be shared, illustrating how integrity concerns can be practically addressed for cGMP manufacturing applications, and what are the results observed after a few years of use.

Integrity Assurance for Single-Use Systems: End-User Perspective

In the past decade, there has been a growing interest in the application of continuous processing in the pharmaceutical industry with 100s millions of investments and several products delivered to the market using this technology. 

Continuous processing demonstrates several value propositions for the Pharmaceutical industry. Amongst them we can name, access to better chemistry, product quality enhancement, reduction of CoGs but mostly speed to market where phase 3 to launch is drastically accelerated. 

Sanofi R&D is building capacities to perform future GMP clinical batches using this technology. The first investment was completed last year, and we are in the process of expansion. It is a really changing time for science at Sanofi.  

Sanofi is investing in modular concept with high capability of production of API and ability of infinite reconfiguration. We are not only thinking machine; to enhance our ability to always produce best quality drugs to our patient, we are also implementing digital twin system, tracking and controlling the quality of our product at any moment of time. 

We are ready to meet the challenges of tomorrow and produce the new APIs to help patients.

Sanofi’s Journey & Strategy for Continuous Processing for Small Molecules

Presented by Dr. Ruth Daniels, Senior Scientist - Microbiology Expert at Janssen

This webinar presentation will discuss:

• Endotoxin hold time studies to identify LER
• In silico assessment of interfering factors and associated LER mitigation strategies
• Case study: optimization of product-specific LAL assay to overcome LER

Followed By A Presentation From Kevin L. Williams, Microbiological Test Development at bioMérieux

Strategies to Overcome Low Endotoxin Recovery Using the Conventional LAL Assay

Biopharma

biologics

Low Endotoxin Recovery

Conventional LAL Assay

In silico assessment

LER Mitigation Strategies

Bacterial Endotoxin Testing

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Strategies to Overcome Low Endotoxin Recovery Using the Conventional LAL Assay

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