Bringing you the latest cutting-edge research and commentary in bioscience.

Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

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Journal

Welcome to the latest issue of Cell and Gene Therapy Insights – the open access, peer-reviewed publication that brings you the latest insight and commentary from leading experts from academia and industry.

Foreword

Raw and Starting Materials – Foreword

Spotlight Article

Foreword

Robert G Piperno

Raw and Starting Materials

Robert G Piperno is the Director of CGT Quality Assurance in the Global Pharma QA organization. In this role he is responsible for providing the global quality oversight and management of internal and external activities supporting clinical and commercial Cell and Gene Therapy Products, including the approval of STRIMVELIS™ by EMA. Rob joined GSK in 2009 as part of the Corporate Audit and Assurance function and transitioned to R&D QA in 2012, and to CGT QA in 2014. He has over 20 years of experience in the pharmaceutical industry and prior to GSK he was employed at Johnson & Johnson for 9 years holding positions including, site quality operations and leading a corporate team supporting the management of external partners and CMOs. Rob has a Bachelor’s and Master’s degree in Biology from Rutgers University and an MBA in Pharmaceutical Management from St. Joseph’s University.

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Expert Roundtable

Tackling the critical issues pertaining to raw & starting materials for cell & gene therapy manufacturing

Spotlight Article

Expert Roundtable

Raw and Starting Materials

Richard McFarland, ARMI (Advanced Regenerative Manufacturing Institute) Ivar Kljavin, Thermo Fisher Scientific & Timothy Moore,Kite, a Gilead Company

Richard McFarland, Chief Regulatory Officer, ARMI (Advanced Regenerative Manufacturing Institute)

Richard McFarland, PhD, MD, joined ARMI as its Chief Regulatory Officer in May 2018 having been at the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA/CBER) where his career of over 16 years involved review of an extensive range of products and policy development in numerous areas inside FDA, across the federal government, and internationally. He spent almost two decades at the FDA, including time as Associate Director of Policy for FDA/CBER’s Office of Tissues and Advanced Therapies (OTAT), and its predecessor office, the Office of Cellular, Tissue and Gene Therapies (OCTGT).

Ivar Kljavin , Head of Quality, Bioproduction Division at Thermo Fisher Scientific

Ivar joined Thermo Fisher in January 2018 having spent 24 years in the pharmaceutical industry with Roche – five years in research and the rest in Global Quality roles, QC/QA. What drew him to the Thermo Fisher role is the opportunity to influence the future state of supply of medicine to patients. Ivar is passionate about the transition of Thermo Fisher’s quality system – and the need to integrate Quality process and goals with customers so that we are aligned with the mission of insuring supply of medicine to patients. Thermo Fisher definitely has the capability to make this happen.

Timothy Moore, Executive Vice President, Technical Operations, Kite, a Gilead Company

Tim Moore has more than three decades of leadership experience in biopharmaceutical manufacturing and operations. Most recently, he served as Senior Vice President, Head of Global Technical Operations – Biologics of Genentech, Inc. and as a member of the Genentech Executive Committee since 2010. In this role, Mr. Moore oversaw global leadership for more than 7,500 professionals across 10 internal sites and over 37 contract manufacturing organizations, as well as global manufacturing and end-to-end quality supply performance of more than 20 biological product families. Prior to that, Mr. Moore was Genentech’s Senior Vice President, Global Supply Chain and Global Engineering from 2007 to 2010. Previously, Mr. Moore served as Vice President, Operations at ZLB Behring (formerly Aventis Behring). He is currently a member of the Executive Committee of BioPhorum Operations Group (BPOG) and the Manufacturing Leadership Council. Mr. Moore received a B.S. in Chemical Engineering from Tulsa University and a M.S. in Engineering Management from Northwestern University.

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Tackling the critical issues pertaining to raw & starting materials for cell & gene therapy manufacturing

Spotlight Article

Expert Roundtable

Richard McFarland, Ivar Kljavin, Timothy Moore

Raw and Starting Materials

Richard McFarland, Chief Regulatory Officer, ARMI (Advanced Regenerative Manufacturing Institute)

Richard McFarland, PhD, MD, joined ARMI as its Chief Regulatory Officer in May 2018 having been at the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA/CBER) where his career of over 16 years involved review of an extensive range of products and policy development in numerous areas inside FDA, across the federal government, and internationally. He spent almost two decades at the FDA, including time as Associate Director of Policy for FDA/CBER’s Office of Tissues and Advanced Therapies (OTAT), and its predecessor office, the Office of Cellular, Tissue and Gene Therapies (OCTGT).

Ivar Kljavin , Head of Quality, Bioproduction Division at Thermo Fisher Scientific

Ivar joined Thermo Fisher in January 2018 having spent 24 years in the pharmaceutical industry with Roche – five years in research and the rest in Global Quality roles, QC/QA. What drew him to the Thermo Fisher role is the opportunity to influence the future state of supply of medicine to patients. Ivar is passionate about the transition of Thermo Fisher’s quality system – and the need to integrate Quality process and goals with customers so that we are aligned with the mission of insuring supply of medicine to patients. Thermo Fisher definitely has the capability to make this happen.

Timothy Moore, Executive Vice President, Technical Operations, Kite, a Gilead Company

Tim Moore has more than three decades of leadership experience in biopharmaceutical manufacturing and operations. Most recently, he served as Senior Vice President, Head of Global Technical Operations – Biologics of Genentech, Inc. and as a member of the Genentech Executive Committee since 2010. In this role, Mr. Moore oversaw global leadership for more than 7,500 professionals across 10 internal sites and over 37 contract manufacturing organizations, as well as global manufacturing and end-to-end quality supply performance of more than 20 biological product families. Prior to that, Mr. Moore was Genentech’s Senior Vice President, Global Supply Chain and Global Engineering from 2007 to 2010. Previously, Mr. Moore served as Vice President, Operations at ZLB Behring (formerly Aventis Behring). He is currently a member of the Executive Committee of BioPhorum Operations Group (BPOG) and the Manufacturing Leadership Council. Mr. Moore received a B.S. in Chemical Engineering from Tulsa University and a M.S. in Engineering Management from Northwestern University.

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Commercial Insights

Cell & Gene Therapy Commercial Insight – February 2019

Commercial Insights

Mark Curtis & Richard Philipson

Raw and Starting Materials

CELL THERAPY:

We saw Gilead drop its anti-BCMA CAR-T therapy this past month amidst a crowded competitive landscape and clinical data that didn’t support further development work. The BCMA space has picked up rapidly the last few years and some companies that are further along in the clinic than Gilead, including bluebird, have generated impressive data. Certainly, with the plethora of CAR-T technologies that are in the clinic for hematological malignancy Gilead won’t be the only company pulling candidates as the pool of clinical data grows and the leading products are identified.

GENE THERAPY:

This month’s news sees good progress for several companies, with the announcement of positive data for AVROBIO’s treatment for Fabry disease and uniQure’s treatment for haemophilia B, and advances in clinical trials for Solid Biosciences in Duchenne muscular dystrophy and Lysogene’s treatment for Sanfilippo A. It’s not all good news though, with disappointment coming from Gensight Biologic’s treatment for Leber’s hereditary optic neuropathy (LHON); this was always going to be a tough nut to crack, and thus it proved. There’s only one treatment available for LHON – Santhera’s idebenone (Raxone), approved under exceptional circumstances in Europe – and the negative interim results from Gensight’s RESCUE study suggest there will be no new therapies for this devastating condition in the near future.

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Interview

Making an efficient & effective transition to GMP raw materials

Spotlight Article

Interview

DR UDO NIRENBERG

Raw and Starting Materials

Dr Udo Nirenberg is Vice President ofDr Udo Nirenberg is Vice President of Quality Management at CellGenix, where he is responsible for the quality system of CellGenix and the quality of the products. Udo has more than 25 years experience in the industry in leading positions in Quality Control, Quality Assurance as well as Regulatory Affairs. Udo holds a degree in chemistry and received his Ph.D. in analytical chemistry from the University of Frankfurt/Main, Germany. He started his carreear at Bachem, Switzerland, a leading GMP manufacturerer of peptides. In the following years he took over the responsibilities for quality control, quality assurance and regulatory affairs departments at Bachem affiliates in the United States. Prior to his position at CellGenix, Udo was responsible for quality control testing of biopharmaceuticals under GMP and quality management for more than 10 years at Solvias AG, a globally acting analytical contract laboratory in Switzerland. Quality Management at CellGenix, where he is responsible for the quality system of CellGenix and the quality of the products. Udo has more than 25 years experience in the industry in leading positions in Quality Control, Quality Assurance as well as Regulatory Affairs. Udo holds a degree in chemistry and received his Ph.D. in analytical chemistry from the University of Frankfurt/Main, Germany. He started his carreear at Bachem, Switzerland, a leading GMP manufacturerer of peptides. In the following years he took over the responsibilities for quality control, quality assurance and regulatory affairs departments at Bachem affiliates in the United States. Prior to his position at CellGenix, Udo was responsible for quality control testing of biopharmaceuticals under GMP and quality management for more than 10 years at Solvias AG, a globally acting analytical contract laboratory in Switzerland.

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Making an efficient & effective transition to GMP raw materials

Spotlight Article

Interview

Dr Udo Nirenberg

Raw and Starting Materials

Dr Udo Nirenberg is Vice President of Quality Management at CellGenix, where he is responsible for the quality system of CellGenix and the quality of the products. Udo has more than 25 years experience in the industry in leading positions in Quality Control, Quality Assurance as well as Regulatory Affairs. Udo holds a degree in chemistry and received his Ph.D. in analytical chemistry from the University of Frankfurt/Main, Germany. He started his carreear at Bachem, Switzerland, a leading GMP manufacturerer of peptides. In the following years he took over the responsibilities for quality control, quality assurance and regulatory affairs departments at Bachem affiliates in the United States. Prior to his position at CellGenix, Udo was responsible for quality control testing of biopharmaceuticals under GMP and quality management for more than 10 years at Solvias AG, a globally acting analytical contract laboratory in Switzerland.

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Identifying Critical Quality Attributes of cellular starting materials

Spotlight Article

Interview

Dr. Krishnendu Roy

Raw and Starting Materials

Dr. Krishnendu (Krish) Roy received his undergraduate degree from the Indian Institute of Technology (Kharagpur, India) followed by his MS from Boston University and his PhD in Biomedical Engineering from Johns Hopkins University. After working for 2 years at Zycos Inc., a start-up biotechnology company, Dr. Roy left his industrial position to join the Biomedical Engineering Faculty at The University of Texas at Austin in 2002, where he was most recently Professor and Fellow of the Cockrell Chair in Engineering Excellence. He left UT-Austin in July of 2013 to move to Georgia Tech. where he is now the Robert A. Milton Chaired Professor in Biomedical Engineering. At Georgia Tech, he also serves as the Director of the newly established NSF Engineering Research Center (ERC) for Cell Manufacturing Technologies (CMaT) and The Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M) – as well as the Director of the Center for ImmunoEngineering. He is also the Technical Lead of the NIST/AMTech National Cell Manufacturing Consortium (NCMC), a national public-private partnership, focused on addressing the challenges and solutions for large scale manufacturing of therapeutic cells. Dr. Roy’s research interests are in the areas of scalable cell manufacturing, Immuno-engineering, stem-cell engineering and controlled drug and vaccine delivery technologies, with particular focus in biomedical materials. In recognition of his seminal contributions to these fields, Dr. Roy has been elected Fellow of the American Institute for Medical and Biological Engineering (AIMBE) and Fellow of the Biomedical Engineering Society (BMES). In addition, Dr. Roy has received numerous awards and honors including Young Investigator Awards from both the Controlled Release Society (CRS) and The Society for Biomaterials (SFB), NSF CAREER award, Global Indus Technovator Award from MIT, the CRS Cygnus Award etc. He is also the recipient of Best Teacher Award given by the Biomedical Engineering Students at UT-Austin and the best advisor award given by bioengineering students at Georgia Tech. He serves as a member of the Editorial Boards of the Journal of Controlled Release, the European Journal of Pharmaceutics and Biopharmaceutics, and the Journal of Immunology and Regenerative Medicine. He is a member of the Forum on Regenerative Medicine of the National Academies of Science, Engineering and Medicine (NASEM) and a Board Member of the newly established Standards Coordinating Body (SCB) for Cell and Regenerative Therapies.

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Staying ahead of the game: understanding and managing patient-to-patient variability

Spotlight Article

Interview

Dr Jan Joseph (Jos) Melenhorst

Raw and Starting Materials

Dr Jan Joseph (Jos) Melenhorst graduated with a bachelor’s degree in continuing education from Tilburg Fontys Teacher’s College, a master’s degree in Medical Biology from the Nijmegen Catholic University, the Netherlands, and a doctorate of philosophy from the Leiden University, the Netherlands. After a post-doctoral fellowship followed by a staff scientist appointment at the National Institutes of Health he was recruited to the University of Pennsylvania in 2012 by Dr. Carl June, first as Deputy Director of the Clinical Cell and Vaccine Production Facility and later as the Director of Product Development & Correlative Sciences. In this role, he was at the cusp of the first ever CAR T cell therapy approved by FDA: Kymriah. Dr. Melenhorst contributed significantly to the evolution of the CAR manufacturing process and to in-depth mechanistic studies into the immunobiology of CAR T-cell therapies, work that was published in high impact journals such as Nature, Nature Medicine, Cancer Discovery, Science Translational Medicine, and the New England Journal of Medicine. Dr. Melenhorst’s research aims to understand and improve the efficacy, safety, and product consistency of adoptive cell immunotherapy through biomarker, mechanistic, and product development studies.

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Raw and starting material considerations for gamma delta T cell therapy

Spotlight Article

Interview

Stewart Abbot

Raw and Starting Materials

Stewart Abbot is the chief operating officer at Adicet Bio. He holds a BSc in Biological Sciences (Edinburgh), M.Sc. in Biomedical Engineering (Glasgow) and Ph.D. in Pathology (London). His academic career focused on basic and translational science initiatives in vascular biology, pharmacology and toxicology. He joined Amersham Biosciences in 2000 and developed Amersham’s and, following acquisition, General Electric’s stem cell-based drug screening capabilities. He was head of the Molecular and Cellular Biology research laboratory at GE’s Global Research Center from 2004-2007. In 2007 he joined Celgene to develop novel cell-based therapeutic candidates and subsequently development of external cellular therapy R&D collaborations and alliances. In 2015 he joined Fate Therapeutics and held roles of VP translational research and chief development officer. He joined Adicet Bio. in June 2018 and his current role oversees all research and development associated with genetically engineered gamma delta T cell-based therapy development.

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Perspective

How to effectively manage critical raw materials to support clinical development in CAR-T cell therapy

Spotlight Article

Perspective

Emilie Gauthy, Laure Lambricht & Sarah Snykers

Raw and Starting Materials

In CAR-T cell therapy, one of the main challenges to obtaining a consistent, reproducible manufacturing process and therapeutic product is the variation of the cellular starting material. However, one should not overlook the importance of raw materials. Proper selection and control of raw materials and their suppliers/manufacturers are critical moving forward during clinical development. It will impact process and product quality, safety, consistency, but also support continuous manufacturing and cost of goods control. In this opinion piece, we describe based on our experience a practical and effective risk-based tool to prioritize effort towards raw materials during clinical development. This approach should help identifying weaknesses and establish an action plan to prepare for commercial raw material readiness.

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Expert Insight

Raw materials in cell therapy: start right early in process development

Spotlight Article

Expert Insight

Anna Gilbert

Raw and Starting Materials

All drug products, whether they are small molecule, monoclonal antibodies or cell therapy share some of the same issues in drug development, including raw materials. Certainly, accelerated speed through clinical phases and into commercial manufacturing is something all sectors of drug manufacturing must balance with the ability to provide a robust production process. This article will discuss raw material issues specific to cellular therapy products but also common across all types of drug products. Raw and ancillary material regulations and guidelines can be further understood by reading regulatory publications such as USP <1043>, EP 5.2.L2 and new ISO Technical Standard 20399.

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Can iPSCs Address the Challenge of Maintaining Consistent Quality in Starting Materials Used in the Manufacture of Cell-Based Therapies?

Spotlight Article

Expert Insight

Kilian Kelly

Raw and Starting Materials

Despite the enormous progress being made in the clinical development of cell-based therapies, achieving consistency at scale remains a significant challenge. The fundamental problem is the inherent variability of human tissue donations: this donor to donor variability results in substantial inconsistency in therapeutic products each time a new donation is used as starting material. Further variability can arise during extensive culture expansion of therapeutic cells – a step which is often incorporated into manufacturing processes with the aim of minimising the number of new donations required.
Induced pluripotent stem cells (iPSCs) have the capacity to replicate indefinitely without loss of pluripotency, in addition to the ability to differentiate into any other type of cell in the body. Therefore, a single iPSC bank has the potential to give rise to an effectively limitless number of therapeutic cells. Great advances have been made in addressing challenges associated with the therapeutic use of iPSC-derived therapies, with the first clinical experience being gained in recent years, and numerous organisations are now actively engaged in the development of iPSC-derived therapies.

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Qualification of cellular starting materials for cell-based therapies

Spotlight Article

Expert Insight

Elizabeth Read

Raw and Starting Materials

Cellular starting material is unique because of the living, dynamic nature of cells that must be collected from a human donor. The process for donor screening and testing to reduce risk of infectious disease transmission is complex and not harmonized globally. Biologic, donor-to-donor variability is difficult to control and has major impacts on development of the manufacturing process and final product specifications. Maintaining stability of the material requires attention to the complex supply chain for a given manufacturing model. This article presents the key elements, regulatory expectations and special challenges for qualification of cellular starting material.

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Innovator Insight

Managing starting material stability to maximize manufacturing flexibility and downstream efficiency

Spotlight Article

Innovator Insight

Dominic Clarke & David Smith

Raw and Starting Materials

The cell and gene therapy industry is filled with excitement and promise as recent clinical and commercial successes make headlines worldwide. New therapies are entering clinical trials like never before [1]. With this growth comes underlying challenges, some of which are obvious and well documented, such as scale-up manufacturing and the need for cost of goods reduction [2] – but others are perhaps not currently given the amount of attention they deserve or require. Two such challenges are the increasing demand for quality starting materials and the logistical issues in getting those products, typically shipped fresh from the clinic or donor processing center to the manufacturing facility [1,3,4]. There are many time-sensitive elements within the cell and gene therapy supply chain and these present critical challenges. This article will explore some specific examples and look at how the industry can address them by improving quality and consistency of starting materials and reducing some of the existing bottlenecks which may impact downstream manufacturing and therapeutic success.

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Research Article

Genomic-QC: large-scale genomic data mining to assess the quality of HiPSC lines

Spotlight Article

Research Article

Ravi Prabhkar More, Mahendra Rao & Odity Mukherjee

Raw and Starting Materials

Human-induced pluripotent stem cells (HiPSC) are increasingly being used as input material to make differentiated cells for drug discovery, toxicity assays and for cell-based therapy. In the myriad uses of these pluripotent cells, quality and consistency of the cells and what they make is paramount. Currently, several concerns remain when considering the use of HiPSC-derived differentiated cells. These include the presence of integrated vectors used to generate HiPSC; the presence of mutations (germline or somatic) that may exist in the donor sample and/or be introduced in the derivation process; absence of detailed clinical information about donors; and the lack of tracking of the stability and integrity of HiPSC cells as they are propagated in culture. Although specific tests exist to address each of these concerns it can rapidly become time-consuming and prohibitively expensive. To address these issues, we propose a strategy based on mining the wealth of information present in whole genome sequencing (WGS) data and describe a comprehensive Genomic-QC report (dx.doi.org/10.17504/protocols.io.vuae6se) generated by mining mapped and unmapped reads to provide: (1) basic QC profile of a cell line; (2) an assessment of cell line integrity and purity; (3) analysis of foreign DNA for cell line sterility and genomic fidelity; (4) cell line mutation burden profile; and (5) inferred donor specific information. In this manuscript, we propose a set of sequencing data based tests that are relatively cheap but very informative and as such should be included as for information only (FIO) tests along with the regular battery of mandatory test for cell line QC analysis.

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