Welcome to the CMC Strategy Forum “Next Generation” Biotechnology Product Development, Manufacturing and Control Strategies

We are pleased to welcome you to the CMC Strategy Forum. The purpose of the CMC Strategy Forum is to provide a venue for biotechnology/biological product discussion. The meetings focus on relevant CMC issues throughout the lifecycle of a product and thereby foster collaborative technical and regulatory interactions. The Forum strives to share information with the regulatory agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum meetings are published in an appropriate peer-reviewed journal. Each meeting will focus on a CMC related issue such as product characterization, comparability, specifications, etc. The format of each meeting will consist of case studies and presentations by industry and/or regulatory experts to introduce the topic and the key issues of concern. Workshop sessions, which consist of panel discussions and Q&A, will then be conducted to allow for additional discussion on the technical and regulatory details of the topics. It is envisioned that the final outcome of the workshop discussions will be the development of a document to be submitted to the appropriate Regulatory Agency designees for their consideration in developing and/or clarifying good regulatory practice guidelines for biotechnology derived products. The success of the CMC Strategy Forum will depend on your active participation in discussing and raising issues pertaining to development of biologics. We encourage you to participate wholeheartedly in the workshops that have been designed to stimulate exchange of ideas and information. We would like to thank the speakers who are giving generously of their time and resources, and to you, for your attendance. We acknowledge the generosity of our program partners: Amgen Inc., Biogen, Bristol-Myers Squibb Company, Celgene Corporation, Eli Lilly and Company, Genentech, a Member of the Roche Group, MedImmune, A member of the AstraZeneca Group, Merck & Co., Inc., Novo Nordisk A/S, and Pfizer Inc. We are grateful for the expert management from CASSS and the audio-visual expertise of Michael Johnstone from MJ Audio-Visual Productions. Their experience and guidance in the preparation of this Forum has been invaluable.

ACKNOWLEDGEMENTS CMC STRATEGY FORUM NORTH AMERICA PROGRAM COMMITTEE Siddharth Advant, Celgene Corporation Kristopher Barnthouse, Janssen Pharmaceuticals R&D LLC Barry Cherney, Amgen Inc. Fiona Cornel, Health Canada JR Dobbins, Eli Lilly and Company Taro Fujimori, AbbVie Bioresearch Center, Inc. Carmilia Jiménez Ramirez, Gilead Scineces, Inc. Michael Kennedy, CBER, FDA Sarah Kennett, CDER, FDA Joseph Kutza, MedImmune, A member of the AstraZeneca Group Emanuela Lacana, CDER, FDA Kimberly May, Merck & Co., Inc. Anthony Mire-Sluis, AstraZeneca Stefanie Pluschkell, Pfizer, Inc. Nadine Ritter, Global Biotech Experts, LLC Timothy Schofield, GlaxoSmithKline Zahra Shahrokh, ZDev Consulting Jason Starkey, Pfizer, Inc. Andrew Weiskopf, Biogen Heidi Zhang, Juno Therapeutics, A Celgene Company Marcel Zocher, Bristol-Myers Squibb Company CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Celgene Corporation, USA Daniela Cerqueria, ANVISA-Brasilian National Health Surveillance Agency, Brasil Yasuhiro Kishioka, PMDA-Pharmaceutical and Medical Devices Agency, Japan Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, AstraZeneca., USA Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair) Ilona Reischl, BASG-Federal Office for Safety in Health Care, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, CMC Biotech-MAS Consulting, USA Karin Sewerin, BioTech Development AB, Sweden

Mobile App Information We are pleased to offer the CASSS mobile app for the CMC Strategy Forum July 2018! The mobile app allows you to access the schedule, learn about sessions, read speaker abstracts, download presentation slides, and network with your peers. It contains information that you won’t find here in the printed program. You won't want to miss this!

Seven Excellent Reasons to Download the App Today!

• Connect and network with fellow attendees • View the schedule and create a personalized agenda • Download speaker abstracts and learn about sessions

• Take notes during the presentations to export later • Receive all the latest information on schedule changes or updates

• Have all your questions answered through the meeting message board • Learn about and post job opportunities in the industry

HOW TO DOWNLOAD THE APP STEP ONE

• On your mobile phone or tablet, go to the app store (ex. Apple App Store, Google Play Store) and search for "CASSS 365” OR

• Use a QR code reader to scan the QR code on this page OR • To use the HTML version of the app, go to the internet browser on your mobile phone, tablet, or

computer and go to the link www.tripbuildermedia.com/apps/casss365 STEP TWO Follow store instructions to download the CASSS 365 mobile app. STEP THREE Open the app. It will ask for your username and password. THIS IS THE SAME INFORMATION YOU USE TO REGISTER FOR A CASSS MEETING. STEP FOUR Go to Events and select CMC Strategy Forum July 2018 from the list. Enter your username and password again. This is the same username and password used in step three.

You now have access to the entire schedule, session abstracts, speaker information, and as the ability to connect with your fellow attendees

Need Help?

Still not sure how to get the most out of the mobile app? Contact CASSS’ Program Planning Specialist, Julie Fowle at jfowle@casss.org stop by the registration desk in the Washingtonian Ballroom Foyer.

The Scientific Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support

of the CMC Strategy Forum North America series:

STRATEGIC DIAMOND PROGRAM PARTNERS

Genentech, a Member of the Roche Group STRATEGIC PLATINUM PROGRAM PARTNERS

Amgen Inc. Biogen

MedImmune, A member of the AstraZeneca Group

STRATEGIC GOLD PROGRAM PARTNERS

Eli Lilly and Company Novo Nordisk A/S

Pfizer, Inc. STRATEGIC SILVER PROGRAM PARTNER

Merck & Co., Inc. FORUM PROGRAM PARTNERS

Bristol-Myers Squibb Company Celgene Corporation

The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of the CMC

Strategy Forum North America July 2018:

LEADING MEDIA PARTNERS

BioProcess International International Pharmaceutical Quality

MEDIA PARTNERS

American Laboratory / LabCompare American Pharmaceutical Review

The Analytical Scientist BioProcessing Journal

Genetic Engineering & Biotechnology News The Pathologist

Pharmaceutical Outsourcing Technology Networks

Forum Abstract “Next Generation” Biotechnology Product Development, Manufacturing and Control Strategies FORUM CO-CHAIRS: Sarah Kennett, Genentech, a Member of the Roche Group Anthony Mire-Sluis, AstraZeneca SCIENTIFIC ORGANIZING COMMITTEE: Siddharth Advant, Celgene Corporation Cristina Ausin-Moreno, CDER, FDA Barry Cherney, Amgen Inc. Steven Falcone, Sanofi Jie He, CBER, FDA Alexey Khrenov, CBER, FDA Michael Tarlov, NIST-National Institute of Standards and Technology Kimberly Wolfram, Biogen The future of biotechnology manufacturing has to enable the drivers facing the biotechnology industry – the need to decrease cost of goods, market globalization, more rapid development of pipeline products, reduced risk to patient supply, increased product quality etc. The utilization of new technologies such as single use bioreactors, alternating tangential flow during fermentation, modular and closed process equipment, process analytical technology and Analytics of the Future will allow for a more robust process, reduced waste, increased titers, fewer non-conformances, less staffing required and dramatically less risk to technology transfer to new sites. The ability to utilize single use, pre-sterilized bioreactors and raw materials in a closed process eliminates the need for cleaning and steaming in place and reduces the risk of contaminations. The ability to create modular, essentially identical, manufacturing sites across the globe means that technology transfer will require much less effort and risk. PAT and analytics of the future should allow for much more real time control of the process and less reliance on lot release assays and for driving more testing onto the manufacturing floor and reducing the costly footprint of the Quality Control Laboratories. In addition, advances in molecular modeling and cell cloning, and the ability to model processes such as column chromatography should allow for improved titers, less molecular variability and more rapid process development. However, the use of these novel technologies and the design of future biotechnology manufacturing sites will challenge regulatory paradigms and hence the need to partner with regulatory authorities as the future becomes a reality.

CMC Strategy Forum Program Summary

“Next Generation” Biotechnology Product Development, Manufacturing and Control Strategies

Monday, July 16, 2018

07:30 – 17:00 Registration in the Washingtonian Ballroom Foyer 07:30 – 08:30 Breakfast in the Washingtonian Ballroom Foyer 08:30 – 08:45 CASSS Welcome and Introductory Comments in Salons D - G Nadine Ritter, Global Biotech Experts, LLC

CMC Strategy Forum Welcome and Introductory Comments in Salons D - G Sarah Kennett, Genentech, a Member of the Roche Group Anthony Mire-Sluis, AstraZeneca

Continuous and Advances in Manufacturing – Upstream Workshop Session One in Salons D - G

Session Chairs: Barry Cherney, Amgen Inc. and Siddharth Advant, Celgene Corporation 08:45 – 09:10 Second Generation Cell Culture Processes for Therapeutic Enzymes

Brian Turner, Sanofi, Framingham, MA USA 09:10 – 09:35 Next Generations Manufacturing with a Focus on Bioreactor Perfusion

Technology Frank Ritacco, Bristol-Myers Squibb Company, Hopewell, NJ USA 09:35 – 10:00 Evaluation of Raman Spectroscopy for Online Monitoring of Cell Culture

Product Quality Brian Horvath, Genentech, a Member of the Roche Group, South San Francisco,

CA USA 10:00 – 10:25 Upstream Manufacturing Platforms for Viral Vectors Christopher Murphy, Brammer Bio, Cambridge, MA USA 10:25 – 10:45 Networking Break in the Washingtonian Ballroom Foyer 10:45 – 12:00 PANEL DISCUSSION – Questions and Answers

Brian Horvath, Genentech, a Member of the Roche Group Nobuko Katagiri, CBER, FDA Christopher Murphy, Brammer Bio Frank Ritacco, Bristol-Myers Squibb Company Brian Turner, Sanofi Haoheng Yan, CDER, FDA

Monday, July 16 continued… 12:00 – 13:30 Networking Lunch in the Washingtonian Ballroom Foyer

Continuous and Advances in Manufacturing – Downstream Workshop Session Two in Salons D - G

Session Chairs: Cristina Ausin-Moreno, CDER, FDA and Sean Richardson, Sanofi 13:30 – 13:55 Regulatory Perspective on New Developments in Manufacture of Biological

Products Scott Nichols, CDER, FDA, Silver Spring, MD USA 13:55 – 14:20 Multi Column Chromatography: A Major Step Towards Continuous

Purification of Biopharmaceuticals Rickey Lu, AstraZeneca, Gaithersburg, MD USA

14:20 – 14:45 Recent Developments in Downstream Bioprocessing: Multimodal

Chromatography, Affinity Precipitation and Integrated Bioprocessing Steven Cramer, Rensselaer Polytechnic Institute, Troy, NY USA

14:45 – 15:10 Commercialization of an Integrated Continuous Biomanufacturing Process Franqui Jimenez, Sanofi Specialty Care Operation, Westborough, MA USA 15:15 – 15:45 Networking Break in the Washingtonian Ballroom Foyer 15:45 – 17:00 PANEL DISCUSSION – Questions and Answers

Sarah Nilou Arden, CDER, FDA Steven Cramer, Rensselaer Polytechnic Institute

Franqui Jimenez, Sanofi Specialty Care Operation Rickey Lu, MedImmune, A member of the AstraZeneca Group Scott Nichols, CDER, FDA

17:00 – 18:30 Networking Reception in the Washingtonian Ballroom Foyer 18:30 Adjourn Day One

Tuesday, July 17, 2018

08:00 – 17:00 Registration in the Washingtonian Ballroom Foyer 07:45 – 08:45 Breakfast in the Washingtonian Ballroom Foyer

Modelling and Control Strategies Workshop Session Three in Salons D - G

Session Chairs: Sarah Kennett, Genentech, a Member of the Roche Group and Kim Wolfram, Biogen 08:45 – 09:10 Leveraging an Integrated Data Platform to Advance Process Understanding

and Enhance Continued Process Verification (CPV) Patrick Gammell, Amgen Inc., Thousand Oaks, CA USA 09:10 – 09:35 Paving the Road towards Real-time Release Testing

Michalle Adkins, Emerson Automation Solutions, Royersford, PA USA 09:35 – 10:00 Advanced Process Controls and/or Process Modeling for Biopharmaceutical

Manufacturing in Practice in a New Manufacturing Plant Saly Romero-Torres, Biogen, Cambridge, MA USA 10:00 – 10:25 DSP Meets Data Science: Applying Modeling and Machine Learning for

Bioprocess Development Ferdinand Stueckler, Roche Diagnostics GmbH, Penzberg, Germany 10:25 – 10:45 Networking Break in the Washingtonian Ballroom Foyer 10:45 – 12:00 PANEL DISCUSSION – Questions and Answers

Michalle Adkins, Emerson Automation Solutions Aikaterini Alexaki, CBER, FDA Katia Ethier, Health Canada Patrick Gammell, Amgen Inc. Thomas O’Connor, CDER, FDA

Saly Romero-Torres, Biogen Ferdinand Stueckler, F. Hoffmann-La Roche Ltd.

12:00 – 13:30 Networking Lunch in the Washingtonian Ballroom Foyer

Emerging Analytical Technologies Workshop Session Four in Salons D - G

Session Chairs: Mike Tarlov, NIST-National Institute of Standards and Technology and Katia Ethier, Health Canada

13:30 – 13:55 Regulatory Perspective on Emerging Analytical Technologies

Yan Wang, CDER, FDA, Silver Spring, MD USA 13:55 – 14:20 Development and Characterization of mRNA Therapeutics

Charles Bowerman, Moderna Therapeutics, Cambridge, MA USA

Tuesday, July 17 continued… 14:20 – 14:45 Analytical Strategies to Measure Heterogeneous Protein-Protein Interactions

in Formulated Therapeutic Protein Solutions George Svitel, Merck Research Laboratories, Kenilworth, NJ USA

14:45 – 15:10 Next Generation Nanoscale Biosensors using Single Walled Carbon

Nanotubes Corona Phase Molecular Recognition Xun Gong, Massachusetts Institute of Technology (MIT), Cambridge, MA USA

15:10 – 15:30 Networking Break in the Washingtonian Ballroom Foyer 15:30 – 16:45 PANEL DISCUSSION – Questions and Answers

Charles Bowerman, Moderna Therapeutics Anil Choudhary, CBER, FDA Xun Gong, Massachusetts Institute of Technology (MIT) Manju Joshi, CBER, FDA, Silver Spring, MD USA George Svitel, Merck Research Laboratories Yan Wang, CDER, FDA, Silver Spring, MD USA

16:45 – 17:15 Recap of Program Summary Slide Presentation Anthony Mire-Sluis, AstraZeneca 17:15 – 17:30 Invitation to CMC Strategy Forum January 2019 17:30 Adjournment

Continuous and Advances in Manufacturing – Upstream Workshop Session One

Session Chairs: Barry Cherney, Amgen Inc. and Siddharth Advant, Celgene Corporation Recombinant protein products using continuous manufacturing such as perfusion cultures or other advances in manufacturing technologies for upstream processes are increasingly being adopted by manufacturers and are being introduced for other biological modalities beyond protein products. This session will explore the use of advances in technologies for upstream processes and associated changes to the process control strategies including PAT applications for biological products. Presentations will provide case studies and will be followed by discussions that will explore the opportunities, challenges and solutions associated with the use of advances in manufacturing and control strategies for cell cultivation and harvesting processes for various biological products. NOTES:

Presenter’s Abstracts Second Generation Cell Culture Processes for Therapeutic Enzymes Brian Turner Sanofi, Framingham, MA USA Sanofi Genyzme has a long history of manufacturing recombinant enzyme therapies to treat patients with rare lysosomal storage diseases. Cerezyme, Fabrazyme and Myozyme are currently manufactured in large stainless-steel bioreactors using a microcarrier-based perfusion technology platform developed more than 25 years ago. More recently, second generation process development programs have been launched to increase bioreactor productivity, reduce equipment footprint, simplify operations, decrease cost of goods and ensure reliable supply for our patients. The new manufacturing processes will be installed in a state of the art multiproduct facility that makes extensive use of single-use technologies to maximize operational flexibility. This presentation will compare the second generation and legacy cell culture platforms to highlight the improvements that will ensure these life-saving therapies can continue to be manufactured in a cost-effective manner. NOTES:

Next Generations Manufacturing with a Focus on Bioreactor Perfusion Technology Frank V. Ritacco; Yongqi Wu; Michael Borys; Joon Chong Yee; Anurag Khetan; Zhengjian Li Bristol-Myers Squibb Company, Hopewell, NJ USA The use of N-1 perfusion, coupled with high-inoculum fed batch in CHO cell culture manufacturing processes, has been shown to increase volumetric productivity and shorten the duration of the fed-batch production phase. Implementation of N-1 perfusion as part of a platform process requires the ability to screen multiple clones and to optimize media and process parameters in a high-throughput manner. We have developed an N-1 perfusion process, along with a series of scale-down models for N-1 perfusion using shake flasks, cell culture tubes, and deep-well plates. Optimized scale down models of N-1 perfusion, coupled with Ambr15 fed-batch production micro-bioreactors, have now been integrated into a high-throughput and robust workflow to enable DOE and screening experiments for clone selection, media development and parameter optimization in a platform N-1 perfusion process for monoclonal antibody manufacturing. NOTES:

Evaluation of Raman Spectroscopy for Online Monitoring of Cell Culture Product Quality Gordon Magill; Brian Horvath Genentech, a Member of the Roche Group, South San Francisco, CA USA Recent years have shown an increase in the development and application of Raman spectroscopy for process monitoring and control in the biopharmaceutical industry. While Raman has been successfully used to predict cell density and conventional metabolites, limited work has been presented on its capability to measure product titer and quality. Here, we present results using Raman spectroscopy to obtain online predictions of CHO antibody titer, charge variants, size variants, and glycan species across several products and cell lines. Products assessed include standard antibodies and complex molecular formats. We are interested in using Raman in the GMP setting to guide operational decisions. NOTES:

Upstream Manufacturing Platforms for Viral Vectors Christopher Murphy Brammer Bio, Cambridge, MA USA Gene therapy and gene modified cell therapies are rapidly advancing through clinical development with a number of new medicines approved in the last year. Viral vectors used in these medicines are complex to manufacture and upstream processes employ a wide variety of technologies and reagents. This talk will provide a review of these upstream platforms, scalability and discuss the management of critical raw materials required to make viral vectors. NOTES:

Continuous and Advances in Manufacturing – Upstream Workshop Session One

Panel Members: Brian Horvath, Genentech, a Member of the Roche Group Nobuko Katagiri, CBER, FDA Christopher Murphy, Brammer Bio Frank Ritacco, Bristol-Myers Squibb Company Brian Turner, Sanofi Haoheng Yan, CDER, FDA The following questions will guide the discussion:

• What are the advantages and disadvantages of utilizing Continuous Manufacturing or other newer technologies for upstream processes?

• What are the unique challenges, technical or regulatory, associated with advances in technologies for upstream processes?

• When is the best time during product development to introduce these approaches for upstream processes?

• Are the answers to these questions different for different modalities and the technology being introduced?

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Continuous and Advances in Manufacturing – Downstream Workshop Session Two

Session Chairs: Cristina Ausin-Moreno, CDER, FDA and Steven Falcone, Sanofi Continuous manufacturing techniques have been used for several years in the upstream part of biotech manufacturing and, for example, multiple biotech products with perfusion fermentation have been approved to date. The use of continuous manufacturing techniques in the downstream part of the manufacturing process has been more limited. However, the technology exists to implement continuous manufacturing for clarification, initial capture, purification, polishing, and formulation. The presentations will discuss various considerations for technology strategies, provide examples of migrating legacy products to next generation manufacturing platforms as well as provide points to consider for both inclusion and exclusion in process development. Multiple perspectives will be shared and explored as the downstream manufacturing discussion panel includes participation of key experts and opinion leaders from regulatory bodies, academia and industry. NOTES:

Presenter’s Abstracts Regulatory Perspective on New Developments in Manufacture of Biological Products Scott Nichols CDER, FDA, Silver Spring, MD USA The FDA has several initiatives to support new developments in the manufacture of biotechnology products: the 21st Century CGMP Initiative, the Process Analytical Technology, and the Emerging Technology Team. Traditional biotechnology processes and products are protein to microbial contamination. However, commercial biotechnology products are embracing new technologies that may more effectively control for contamination. Two new technologies (single use systems and multi-column chromatography) are discussed from a microbial control perspective. In addition, potential sources of contamination in recently submitted processes are discussed. NOTES:

Multi Column Chromatography: A Major Step Towards Continuous Purification of Biopharmaceuticals Rickey Lu AstraZeneca, Gaithersburg, MD USA Though continuous manufacturing of biologics represents a major step change in the industry, it need not be taken in one step. Many challenges and questions arise when moving away from one manufacturing platform to another including what to do with the burden of installed capital assets, the likelihood of technical success, regulatory acceptance hurdles and the pressures of launching new products on time. In this talk, AstraZeneca will provide their approach to initiating the transition to continuous manufacturing through a discussion of the technical and business benefits of multicolumn chromatography. Multicolumn chromatography presents an opportunity to develop and implement a technology that lends itself to connection into a fully continuous manufacturing process while providing near term benefits. These benefits create a standalone return on investment that does not require the promise of continuous manufacturing. This stepwise approach to the implementation of continuous-enabling unit operations provides companies the ability to develop expertise and comfort with new unit operations while buying down technical risk and capital expense as opposed to leaping into a fully continuous process.

• What are the downsides of multicolumn chromatography? • What challenges have you faced in putting forth the business case? • What technical or installation challenges have you run across with the implementation of the

system? • Does multicolumn chromatography affect process performance or product quality?

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Recent Developments in Downstream Bioprocessing: Multimodal Chromatography, Affinity Precipitation and Integrated Bioprocessing Steven Cramer Rensselaer Polytechnic Institute, Troy, NY USA This talk will present recent developments in our lab in three areas of downstream bioprocessing; multimodal chromatography, affinity precipitation and integrated bioprocessing. Targeted experiments with different domains of mAbs with varying properties, biophysics, thermodynamics and molecular simulations will be used to shed light on the importance of protein surface cluster properties and multimodal ligand hydration and flexibility on creating selective separations. Hierarchical clustering is employed to examine preferred ligand conformations and the impact of water and dewetting phenomena in multimodal systems. NMR and molecular simulations will be used to examine the molecular basis for multimodal ligand binding to the FC region of mAbs both in solution and immobilized on SAM surfaces. In addition, pH and ligand chemistry will be employed to shift domain dominance in mAb multimodal chromatography from (Fab)2 interactions to Fc binding. Affinity precipitation using smart biopolymers for the simultaneous recovery and purification of both mAb and non-mAb biologics will then be presented. The use of ELP-Z for mAb purification as well as the development of efficient processes based on this approach will be presented with industrial feed stocks. The extension of this approach using ELP-affinity peptides as well as the application to a new class of biologics will also be discussed. Finally, results will be given on a novel approach for the rapid development of integrated downstream biomanufacturing processes for biological products from Pichia Pastoris. This approach employs linear gradient screens in concert with high-throughput uplc analytics and custom software to identify sequences of orthogonal chromatography steps likely to recover and purify the product while also being amenable to integrated processing and a continuous flowpath. To illustrate the power of this novel approach, the rapid development of 3-step purification processes for three commercial biological products will be shown. NOTES:

Commercialization of an Integrated Continuous Biomanufacturing Process Franqui Jimenez Sanofi, Westborough, MA USA Abstract not available at time of printing. NOTES:

Continuous and Advances in Manufacturing – Downstream

Workshop Session Two Panel Members: Sarah Nilou Arden, CDER, FDA Steven Cramer, Rensselaer Polytechnic Institute Franqui Jimenez, Sanofi Specialty Care Operation Rickey Lu, MedImmune, A member of the AstraZeneca Group Scott Nichols, CDER, FDA The following topics will guide the discussion:

• Advantages of continuous manufacturing in downstream part; • Definition of batch; • Process controls/sampling; • Deviations/material rejection; • Process validation and qualification of small scale models; • Hybrid systems or continuous versus integrated platforms; • Existing gaps; • Lessons learned from interaction with regulators; • Consideration of disposable lifecycle management; • Resin re-use practices; • Consideration of continuous precipitation vs continuous chromatography.

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Modeling and Control Strategies Workshop Session Three

Session Chairs: Sarah Kennett, Genentech, a Member of the Roche Group and Kim Wolfram, Biogen Advances in analytics and modeling and applying these tools to biotechnology products is driving a resurgence in endeavors to transform process development and control strategies. The strategic use of analytical methods, data, and models to drive rapid advancement in process understanding, adjustments to manufacturing operations in real time, and different types of real-time release testing may allow for significant savings in resources, faster development cycles, and increased robustness & reliability; however, the appropriateness of these mechanisms with respect to the assurance of acceptable product quality and health authority requirements must be demonstrated. This session will provide a discussion of some of the new modeling applications and control strategies that are currently being developed and implemented for biotechnology products. NOTES:

Presenter’s Abstracts Leveraging an Integrated Data Platform to Advance Process Understanding and Enhance Continued Process Verification (CPV) Patrick Gammell Amgen Inc., Thousand Oaks, CA USA Biopharmaceutical manufacturing processes are highly monitored and hence data rich, however the ability to access the significant amounts of data generated and then maximize the value of that data to generate usable information requires an integrated data platform. This presentation will describe a systematic approach to leverage data from across the validation lifecycle as part of a systematic approach to determine sources of variation and hence maximize process capability. This presentation will also describe the impact that data infrastructure can have on continued process verification (CPV) through near real-time access to process and product data from across an entire portfolio. NOTES:

Paving the Road towards Real-time Release Testing Michalle Adkins Emerson Automation Solutions, Royersford, PA USA The BioPhorum Technology Roadmap team, consisting of multiple end-user and supplier companies published a Biomanufacturing Technology Roadmap in July 2017. As part of the Roadmap process, the team has defined several working groups, one of which is the In-Line Monitoring / Real Time Release team (ILM/RTR). This team was established with the ultimate goal of decreasing product release times while improving quality, efficiency and supply. The ILM/RTR team has been working to develop a prioritized list of tests that are required for a typical biotech process. During this session, the team goals, process, and status will be reviewed. Feedback on the results and direction are appreciated. NOTES:

Advanced Process Controls and/or Process Modeling for Biopharmaceutical Manufacturing in Practice in a New Manufacturing Plant Saly Romero-Torres Biogen, Cambridge, MA USA The primary goal of the PAT framework is to promote process understanding/predictability with the goal that it evolves into process intelligence and vertical/horizontal control. Process predictability relies on deep process knowledge. Knowledge can be derived from first principles or by experience. Modeling can enable different levels of process intelligence―prediction and prescription― depending on the model robustness and the available data package. With regards to data analytics, Biogen is adopting modeling maturity models similar to the ones used by high tech industries such as semiconductors, electronics and AI. The focus of this maturity model is ensuring that a plan for model evolution (and evolutionary intended use) is conceived, and socialized, among SMEs and regulatory agencies early on during process development. This plan is crucial particularly when implementing data driven models that rely on process experience― which is not available at early development or even at early commercial manufacturing stages. A well-planned modeling continuum should allow the pharmaceutical industry to realize the benefits from modeling activities early on, while evolving into more mature prescriptive controllers and release by exemption activities. These efforts are in support of supply chain predictability/reliability and advanced process control (from fault detection to model-based optimization). NOTES:

DSP Meets Data Science: Applying Modeling and Machine Learning for Bioprocess Development Ferdinand Stueckler Roche Diagnostics GmbH, Penzberg, Germany Modeling, simulation and machine learning techniques nowadays allow for a data-driven analysis of complex processes. These computational modeling techniques can be used to summarize process characteristics from experimental data and offer a framework to also include process knowledge from historical data. The development of biopharmaceutical purification processes can benefit from applying these methods to ensure an efficient and robust DSP design. The application of models for the description of chromatography processes has been shown in various examples and case studies. Model-based techniques allow for analyzing experimental results and help to improve process development by guiding experimental design. Based on model predictions optimal conditions for protein purification can be chosen. The success of model-based process development depends on the prediction accuracy of in silico simulations. Factors which influence this accuracy are for instance: general model assumptions, quality of the data used for calibrating the model, and model parameter estimation results. We will therefore discuss strategies which take into account these factors with respect to their influence on the required prediction accuracy for specific DSP process development stages. For instance, at early stage development limited data sets are available. While it remains challenging to establish high accuracy semi-quantitative model predictions have shown to be satisfying in order to guide process development and optimize protein purification processes. We will highlight applications of this approach for case studies with in-silico generated data and experimental data from multivariate studies. In particular we will discuss statistical and computational methods that were applied to evaluate the model prediction quality. Finally, we will also address challenges and gaps which need to be addressed for a successful implementation of data-based technologies as a tool in purification process development. NOTES:

Modeling and Control Strategies Workshop Session Three

Panel Members: Michalle Adkins, Emerson Automation Solutions Aikaterini Alexaki, CBER, FDA Katia Ethier, Health Canada Patrick Gammell, Amgen Inc. Thomas O’Connor, CDER, FDA Saly Romero-Torres, Biogen Ferdinand Stueckler, F. Hoffmann-La Roche Ltd. The following questions will guide the discussion:

• How can process modeling be used to support resource savings during manufacturing operations or as a replacement for in-process or release testing?

• What kind of engineering advanced process controls have been implemented to improve process capability and what were the hurdles that needed to be overcome?

• What types of real time release testing have been implemented in lieu of standard release testing for biological products, and what were the hurdles that needed to be overcome?

• What are the currently perceived risks, barriers, and accelerators to real-time-release? • What needs to be “proven” for real time release approval and acceptance? • What type of validation and lifecycle management is required for these types of new technologies

and to bring in new capabilities? • When starting to implement these technologies, how should one approach or plan for the

possibilities of seeing something that is unexpected and has not been seen before? • What ways can regulatory bodies and the industry work together to make this a reality in the

future? • Are there any plans for additional guidance documents?

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Emerging Analytical Technologies Workshop Session Four

Session Chairs: Mike Tarlov, NIST-National Institute of Standards and Technology and Katia Ethier, Health Canada Advances in analytical technologies help drive progress in biopharmaceutical development and manufacturing. Improved analytical technologies can also produce new general knowledge about biopharmaceuticals that can inform regulatory decisions and provide the basis for designing better products. This session will include the FDA’s perspective on the implementation of state-of-the-art analytical methods for the development of therapeutic proteins. Analytical technologies for characterizing a novel modality class, messenger RNA products will also be discussed. Biophysical methods to examine heterogeneous protein-protein interactions in formulated therapeutic protein solutions will also be presented. The last presentation in the session will describe a novel sensing technology based on carbon nanotubes for assessing glycosylation. NOTES:

Presenter’s Abstracts A Regulatory Perspective on Emerging Analytical Technologies Yan Wang CDER, FDA, Silver Spring, MD USA Analytical methods are key for product and process understanding and control. Emerging analytical technologies may greatly extend product and process knowledge and help to establish better control strategies for biotechnology products. However, it is critical to understand the limitations and potential uses of new analytical technologies during method development. This presentation will provide an overview of analytical method lifecycle management. In addition, the presentation will describe the regulatory expectations for different uses of emerging analytical technologies. Furthermore, the presentation will discuss the concerns of using emerging analytical technologies in quality control environment though a case study. NOTES:

Development and Characterization of mRNA Therapeutics Charles Bowerman Moderna Therapeutics, Cambridge, MA USA Using mRNA to create new therapeutics is complex and requires overcoming novel scientific and technical challenges. mRNA production process heavily relies on in vitro enzymatic synthesis instead of chemical synthesis due to its length. Recent advances towards mRNA production and delivery prompt a need for robust analytical methods capable of characterizing this new class of drugs. mRNA product-related impurities include short mRNAs resulting from either premature termination of transcription or in-process degradation, uncapped mRNAs, and point mutations, insertions/deletions. Multiple case studies utilizing a combination of biochemical and biophysical methods will be discussed on characterization of mRNA product- related impurities and variants for successful development of mRNA therapeutics. NOTES:

Analytical Strategies to Measure Heterogeneous Protein-Protein Interactions in Formulated Therapeutic Protein Solutions George Svitel Merck Research Laboratories, Kenilworth, NJ USA Co-formulating multiple monoclonal antibodies into a single drug product image is an emerging strategy for delivering biologics to patients. This approach brings multiple benefits including combined therapeutic effect, streamlined manufacturing and distribution and also elevated convenience to the patients. However, co-formulated products also bring additional challenges to product characterization. Analytical methods originally developed for individual products need to be further developed for co-formulated products. There are also additional questions regarding mechanisms of degradation, aggregation pathways and possibility of creation of mixed aggregated species in co-formulated products. NOTES:

Next Generation Nanoscale Biosensors using Single Walled Carbon Nanotubes Corona Phase Molecular Recognition Xun Gong Massachusetts Institute of Technology (MIT), Cambridge, MA USA Our lab at MIT has been interested in how the electronic structures of carbon can be utilized to advance new concepts in molecular detection. We have pioneered a novel technique called Corona Phase Molecular Recognition, or CoPhMoRe, for discovering synthetic, heteropolymer corona phases that form molecular recognition sites at the nanoparticle interface. By screening libraries of synthetic heteropolymers chemically adsorbed onto single-walled carbon nanotubes (SWCNTs), we have engineered new optical biosensors that exhibit high selective recognition for biomolecules, such as riboflavin, L-thyroxine, dopamine, nitric oxide, sugar alcohols, estradiol, insulin and fibrinogen. We have also extended these sensor capabilities to include small molecules and heavy metals in the case of food and water safety. These recognition sites can be designed with both high sensitivity in serum-like environments as well as specificity such as to differentiate D and L-Arabinose. In addition to CoPhMoRe based sensor design, existing recognition elements can also be tethered via Histidine tags to Ni2+ complexes that act as fluorescent quenchers for SWCNT. In this manner an array employing recombinant lectins can be utilized for glycan detection with micromolar KD. We also developed a mathematical model of glycan binding dynamics linking the matrix of observed dissociation constants, kinetics of binding, and occupancy to distinct glycoforms for identification. This formulation allows for straightforward calculation of the minimum array size necessary to distinguish a given set of glycans. NOTES:

Emerging Analytical Technologies Workshop Session Four

Panel Members: Charles Bowerman, Moderna Therapeutics Anil Choudhary, CBER, FDA Xun Gong, Massachusetts Institute of Technology (MIT) Manju Joshi, CBER, FDA, Silver Spring, MD USA George Svitel, Merck Research Laboratories Yan Wang, CDER, FDA, Silver Spring, MD USA The following questions will guide the discussion:

• How can regulators be confident with new analytical technologies implemented to replace methods with historical data? Are there any risks associated with new methods not measuring the same quality attributes? What are the data requirements expected from regulators in cases where new species are detected with these new technologies to demonstrate their safety profile in retrospect of their overall post-market data? Can Continuous Process Verification be implemented to ensure monitoring of quality attributes until sufficient data are gathered with a new analytical technology?

• How could the information sharing between industry and regulators be improved to accelerate innovation in new analytical technologies?

• What is the critical issue in terms of approval of new testing technologies? • Reference materials or standard test materials can be used to evaluate the performance of an

analytical technology or compare the results between different analytical technologies. Are there reference materials that currently do not exist that if available would be useful in benchmarking emerging analytical technologies that you are considering?

• Are biosimilars facilitating the adoption of higher resolution methods, especially for higher order structure? If so, will this facilitate adoption for new molecules? Likewise, is the development of new modalities (RNA therapeutics, cell and gene therapies) stimulating the use of new, emerging analytical technologies?

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