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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Issue Vol 6 Issue 2

Foreword

Raw and Starting Materials – Foreword

Spotlight Article

Foreword

Steven Goodman

Raw and starting materials: troubleshooting supply, management and optimization issues

    Attention to raw and starting materials used in the production of Advanced Therapeutic Medicinal Products (ATMPs) grows substantially with each successive year. This makes intuitive sense as the field continues to mature and more products approach or enter the commercial market. Companies have focused their development activities on clinical proof of concept and […]

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Editorial

Expert Roundtable

Overcoming raw material challenges in cell & gene therapy manufacturing

Spotlight Article

Expert Roundtable

David Digiusto, Bernd Leistler & Tom Walls

Raw and starting materials: troubleshooting supply, management and optimization issues


DAVID DIGIUSTO
Chief Technical Officer, Semma Therapeutics David has over 28 years of experience in the scientific, clinical and regulatory aspects of cells as therapeutic agents including the isolation, characterization and genetic modification of hematopoietic stem cells and T-cells for clinical applications. He has been instrumental in the creation of six GMP compliant biologics manufacturing facilities and associated quality systems, production and QC testing programs. Under his direction, plasmid DNA, CAR-T-cells, regulatory T-cells, engineered stem cell grafts and gene modified hematopoietic stem cell products have been manufactured and released for use in Phase I/II clinical trials.


BERND LEISTLER
Vice President Production, CellGenix Bernd has a long track record as protein specialist. He joined CellGenix in 2003, and is currently responsible for all GMP and preclinical cytokine products for further manufacturing use, as well as process development for protein production which includes new packaging formats. Following his degree in chemistry he completed his dissertation on the structure, function, folding and assembly of oligomeric proteins. His professional career started at a leading manufacturer of diagnostic autoantibody immunoassays, where he managed the Biotechnology Department and developed it as a corporate service unit for recombinant and conventional human autoantigens and allergens.


TOM WALLS
Associate Director of Supply Chain, Bluebird Bio Tom Walls has over 15 years of supply chain experience in life sciences. He has led initiatives in business process management, production capacity management, global trade compliance and global planning. He has experience in cell & gene therapies, as well as small molecules, branded, generics, commercial and pre-clinical stage companies.

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Expert Roundtable: overcoming raw material challenges in cell & gene therapy manufacturing

Spotlight Article

Expert Roundtable

David Digiusto, Bernd Leistler & Tom Walls

Raw and starting materials: troubleshooting supply, management and optimization issues




DAVID DIGIUSTO
Chief Technical Officer, Semma Therapeutics David has over 28 years of experience in the scientific, clinical and regulatory aspects of cells as therapeutic agents including the isolation, characterization and genetic modification of hematopoietic stem cells and T-cells for clinical applications. He has been instrumental in the creation of six GMP compliant biologics manufacturing facilities and associated quality systems, production and QC testing programs. Under his direction, plasmid DNA, CAR-T-cells, regulatory T-cells, engineered stem cell grafts and gene modified hematopoietic stem cell products have been manufactured and released for use in Phase I/II clinical trials.


BERND LEISTLER
Vice President Production, CellGenix Bernd has a long track record as protein specialist. He joined CellGenix in 2003, and is currently responsible for all GMP and preclinical cytokine products for further manufacturing use, as well as process development for protein production which includes new packaging formats. Following his degree in chemistry he completed his dissertation on the structure, function, folding and assembly of oligomeric proteins. His professional career started at a leading manufacturer of diagnostic autoantibody immunoassays, where he managed the Biotechnology Department and developed it as a corporate service unit for recombinant and conventional human autoantigens and allergens.


TOM WALLS
Associate Director of Supply Chain, Bluebird Bio Tom Walls has over 15 years of supply chain experience in life sciences. He has led initiatives in business process management, production capacity management, global trade compliance and global planning. He has experience in cell & gene therapies, as well as small molecules, branded, generics, commercial and pre-clinical stage companies.

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Regulatory Insight

Regulatory FAQs & common concerns for cell & gene therapy raw & starting materials

Spotlight Article

Regulatory Insight

Kasey Kime, Jerrod Denham & Christopher Bravery

Raw and starting materials: troubleshooting supply, management and optimization issues

In cell and gene therapy, materials matter. However, misconceptions abound, exacerbating a lack of harmonization and standardization in key areas. For example, uncertainty around quality grades at the various stages of R&D is commonplace, and everyday terms are frequently misinterpreted or misunderstood, with potentially damaging ramifications for advanced therapy development, manufacturing and commercialization. Here, we aim to debunk some popular myths, provide practical guidance based upon long experience in the field, and clarify key regulatory considerations and requirements across the cell and gene therapy raw and starting materials area.

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Interview

Maximizing speed to market: flexibility benefits of single-use technology for gene therapy manufacture – Podcast

Spotlight Article

Interview

Hélène Pora

Raw and starting materials: troubleshooting supply, management and optimization issues

INTERVIEW with:

Hélène Pora, Vice President Technical Communication & Regulatory Strategy, Pall Biotech

“Gene therapy usually addresses small patient populations, so batch sizes tend to be small and relatively few in number. This is a ‘sweet spot’ for single-use technology.”

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Enabling clinical development of cell and gene therapies on a global basis

Interview

Brandon Fletcher, Tamie Joeckel, Martin Lachs, Olivier Saulin

Raw and starting materials: troubleshooting supply, management and optimization issues


Supply Chain Focus: Global Commercial Strategies


INTERVIEW with:

Brandon Fletcher, Cell and Gene Therapy Principal;

Tamie Joeckel, Cell & Gene Therapy Business Lead;

Martin Lachs,Vice President, Project Management, Oncology & Cell Therapeutics;

Olivier Saulin, Cell & Gene Therapy Principal at ICON, plc

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Enabling clinical development of cell and gene therapies on a global basis

Interview

Brandon Fletcher, Tamie Joeckel, Martin Lachs, Olivier Saulin

Raw and starting materials: troubleshooting supply, management and optimization issues


Supply Chain Focus: Global Commercial Strategies


PODCAST INTERVIEW with:

Brandon Fletcher, Cell and Gene Therapy Principal;

Tamie Joeckel, Cell & Gene Therapy Business Lead;

Martin Lachs,Vice President, Project Management, Oncology & Cell Therapeutics;

Olivier Saulin, Cell & Gene Therapy Principal at ICON, plc

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Maximizing speed to market: flexibility benefits of single-use technology for gene therapy manufacture

Spotlight Article

Interview

Hélène Pora

Raw and starting materials: troubleshooting supply, management and optimization issues

INTERVIEW with:

Hélène Pora, Vice President Technical Communication & Regulatory Strategy, Pall Biotech

“Gene therapy usually addresses small patient populations, so batch sizes tend to be small and relatively few in number. This is a ‘sweet spot’ for single-use technology.”

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Best practice for raw materials management on a global basis

Interview

Raw and starting materials: troubleshooting supply, management and optimization issues


Supply Chain Focus: Global Commercial Strategies


STEPHANE LAMEYNARDIE has a Pharm D from the University of Montpellier with specialization in Industrial and Biomedical Pharmaceutical Sciences. He has worked in the industry for the last 20 years in various domains ranging from QA and GMP manufacturing to Project Management and Development, and across both small and large organizations.

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Raw material qualification and optimization: the Janssen approach

Spotlight Article

Interview

Lili Belcastro

Raw and starting materials: troubleshooting supply, management and optimization issues

LILI BELCASTRO is a Scientist at Janssen and is responsible for the qualification of raw materials used in Janssen’s cell and gene therapy products. Dr. Belcastro has over 10 years of experience in preclinical and clinical cancer biology, cell and gene therapy product development, and analytical method development. Prior to joining Janssen in 2017, she was finishing her PhD in cancer biology in a joint program with the University of the Sciences and The Wistar Institute in Philadelphia. Prior to joining industry, Dr Belcastro led pediatric, preclinical, in vivo testing programs at the Children’s Hospital of Philadelphia for small molecule inhibitors, oncolytic viruses, antibody-drug conjugates, and radiopharmaceuticals. Dr Belcastro holds two bachelor’s degrees from Temple University and the University of the Sciences.

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ATMP innovation in liver disease

Interview

Anil Dhawan

Raw and starting materials: troubleshooting supply, management and optimization issues


INNOVATION INSIGHTS


ANIL DHAWAN graduated in medicine in 1986 and after completing his residency in Pediatrics in India, joined King’s College Hospital, London as a trainee in Paediatric Hepatology in 1992. In March 1995, he was appointed visiting professor and consultant in pediatric gastroenterology at the University of Nebraska Medical Center, Omaha, NE, and USA. He relocated to King’s College Hospital, London in August 1996 as a consultant Paediatric Hepatologist. He was appointed Professor of Paediatric Hepatology at Kings College London in 2005. He became the Director of the Paediatric Liver Center and the Head of the Paediatrics department of King’s College Hospital, London in 2009. Professor Dhawan’s basic science research interest is liver cell transplantation. His lab was the first to transplant human liver cells in the UK for liver based metabolic disorders and first in the world to transplant human hepatocytes in alginate beads to treat acute liver failure in children. His other research interests are the outcome of children after liver transplantation, immunosuppression, metabolic liver disease and acute liver failure. He has published over 300 research papers and edited four books in pediatric hepatology and human hepatocyte transplantation. He has been a board member of ESPGHAN, ILTS, BSPGHAN and CTRMS and is the chair of the membership committee of ILTS. He is on the editorial board of the Journal of Hepatology, Pediatric Research, Pediatric Transplantation and Experimental and Clinical Hepatology. Professor Dhawan is proud of developing basic science laboratories for research in liver disease (Mowat Labs) and the Slorech International learning hub. He has served as the President of the Cell Transplantation and Regenerative Medicine Society.

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Current and future directions for dendritic cell vaccines

Interview

Gerard Bos

Raw and starting materials: troubleshooting supply, management and optimization issues


INNOVATION INSIGHTS


GERARD BOS was born in Wageningen, The Netherlands. After Medical School and a PhD program on immunology (both at the medical school in Maastricht) Gerard Bos started training in internal medicine in Maastricht and The Hague. After training for internal medicine he was trained as a Hematologist followed with a fellowship at the Daniel den Hoed Cancer Centre, Rotterdam, for 3 years (head Professor Dr B Lowenberg). Thereafter he obtained a fellowship (Clinical Research Award by the Dutch Cancer Foundation) to perform a 2-year research program on tumor-immunology (Leiden, Brussels and Utrecht). He started in Maastricht 2000, as internist-hematologist. His extra focus is on M. myeloma and chronic myeloid leukemia. Preclinical research has a focus on cell therapy: development of cancer vaccines, the role of natural killer cells in the fight against cancer and immune reconstitution after bone marrow transplantation. Under this topic special attention is present for a possible role for vitamin C in immune reconstitution. In 2013, he was appointed a professor of medical education and tumor-immunology. In 2016, he was appointed a professor of immunology of cancer. Since 2015 he has been CEO of CiMaas, a biotech company with a focus on immunotherapy.

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Optimizing and standardizing apheresis: critical next steps for the cell therapy industry

Spotlight Article

Interview

Joseph M Roig

Raw and starting materials: troubleshooting supply, management and optimization issues

JOSEPH M ROIG got his BSc in Chemistry in 1980 (University of Barcelona) and started his professional career at Coulter (Beckman-Coulter nowadays), where he worked in cell counting and flow cytometry. He joined COBE BCT (currently Terumo BCT) in 1991 to help the company start operations in Spain, moving to the US to continue working for the same company in 2000. During the years that he worked for COBE/Terumo BCT he was involved with all existing apheresis variants (donor collections, leukapheresis, therapeutic apheresis) as well as cell processing. He became part of the Terumo BCT Scientific Support group in 2012 and the Medical Affairs group in 2016, the year he got a Masters in Transfusion Medicine and Advanced Cell Therapies (EMTACT) by the Autonomous University of Barcelona. He is currently working as an autonomous cell collections/cell therapy consultant for the industry.

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Perspective

The role of raw materials in the manufacturing of cell and gene therapy medicinal products: practices and challenges

Spotlight Article

Perspective

José Caraballo

Raw and starting materials: troubleshooting supply, management and optimization issues

The biopharmaceutical industry has increased the number of cell and gene therapy medicinal products under development. The complexity of the new technologies to enable these therapies and the regulatory expectations have also increased. Within this context, the role of raw materials in the manufacture of CGT medicinal products is examined. This commentary assesses the controls applied to raw materials and evaluates challenges and best practices ensuring product quality. The fundamentals of good manufacturing practices still apply. Well characterized materials from reliable suppliers are key elements to maintain a dependable supply of products for our patients.

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Expert Insight

Supply chain challenges and issues facing the autologous cell manufacturing industry

Expert Insight

Kan Wang, Ben Wang, Aaron D Levine & Chip White

Raw and starting materials: troubleshooting supply, management and optimization issues


Supply Chain Focus: Global Commercial Strategies


We discuss three supply chain challenges and issues facing the autologous cell manufacturing industry that may impact patient outcome and supply chain performance in a commercial setting. These are (i) the potential value of giving priority to the sickest patients with respect to the start of manufacturing their therapy, (ii) determining the optimal manufacturing capacity and reagent replenishment policy for a single cell manufacturing facility, given demand forecasts and patient service levels, and (iii) the resilience of reconfigurable supply chain networks for supply chains with geographically distributed manufacturing capacity.

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Considerations on impact of raw material variability in gene therapy manufacturing: applying lessons learned from biologics manufacturing

Spotlight Article

Expert Insight

Aaron Mack, Thomas Matthews, Bryan St. Germain, John Kerwin, David Kolwyck & Greg Stromberg

Raw and starting materials: troubleshooting supply, management and optimization issues

As the number of cell and gene therapy products grow it is important to consider aspects of gene therapy production process robustness, and one key characteristic is the variability of incoming raw materials. Understanding and controlling raw material variability is an important aspect of process development, characterization and commercialization. In the recent history of therapeutic protein production with cell cultures, many problems caused by raw material variability were only discovered post-commercialization, and failure to understand and address key raw material variability during process development led to costly underperformance and batch failure. In this article, we consider some known sources of raw material variability and specifically, those that have been known to impact cell culture production processes. Trace element impurity variation, particularly iron, copper, manganese and zinc, are candidates for high process impact risk. Compositional variation of undefined material (i.e., fetal bovine serum [FBS]) is another important potential failure mode. This includes known nutrient components, such as amino acids and cholesterol, as well as unidentified components, such as growth factors. Cell and gene therapy processes also include relatively new materials for cell culture, such as plasmid DNA and the transfection agent polyethyleneimine, the understanding of the variability of which must be considered.

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Developing and implementing a supply chain management system for cellular therapy programs

Spotlight Article

Expert Insight

David L DiGiusto, Rakib Ouro-Djobo & Uzair Rajput

Raw and starting materials: troubleshooting supply, management and optimization issues

The past few years have seen explosive growth in the development of cell and gene therapy drug candidates for oncology and genetic diseases. There are currently 17 approved Cell and Gene therapy products as listed by the US FDA (FDA Approved Cellular and Gene Therapy Products). Current and pending approvals of immune cell products in particular (CAR-T, Dendritic, hematopoietic stem cells) have driven substantial demand for increased cell manufacturing technologies and capacity. Additional advancements in iPSC-derived cell-based therapeutics (nerve, bone, skin, cartilage, bladder, cardiac, liver tissue repair and regeneration) are also driving the development of cell manufacturing technologies. The combined growth and demand for increased production capacity has led directly to an increased need for raw materials, facilities and services. The raw material and product supply chain is a critical element of a manufacturing program for cell therapies. The development and implementation of a robust supply chain management system (SCMS) is required for the successful development of any cell therapy platform. An SCMS is the collection of policies, procedures and tools used by manufacturers to define, control and document the flow of materials into and out of manufacturing campaigns. The main purpose of SCMS is to ensure the provision of an uninterrupted supply of clinical materials that meets all regulatory requirements as per the Code of Federal Regulations 21CFR§210,211 Good Manufacturing Practices (GMP). The SCMS must include identification and specifications for raw materials as well as sourcing and qualification of all providers of raw materials and services. It, also, must provide for documentation on procurement, shipping, holding, testing and product distribution with traceability throughout the process and tracking of process intermediates and final drug product. The system must reliably capture and report out supply chain data in a manner that supports continuous cell manufacturing and future process planning and optimization (e.g., materials mass balance). In this piece we highlight the major components of a successful SCMS and give examples of approaches for supply chain management that help to facilitate control and compliance, reduce risk and ensure the continuity of clinical materials production.

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Durable and curative responses in heart disease: promises and practicalities

Expert Insight

Gabor Foldes & Vasiliki E Kalodimou

Raw and starting materials: troubleshooting supply, management and optimization issues


INNOVATION INSIGHTS


Stem cell research led to many therapies becoming available to treat or repair injured or diseased tissues in a range of diseases, from cancers to spinal cord injuries. For cardiovascular therapy, the unique capacity of pluripotent stem cells to replicate and provide large numbers of replacement cells in culture for transplantation purposes may give an advantage over the use of adult stem cells. Mechanisms of their retention are in correlation with route and method of cell delivery, a build-up of cell constructs with materials as well as delivered doses and optimal timing. Yet, their cell potency in vivo is a critical element which warrants a better description. Reliable biomarker identification will advance our understanding of how long the replacement cells will continue to function and their mechanism of action; leading to accelerated novel therapies where cell therapy products show a better homing, integration, quantity, or overall quality upon transplantation.

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Innovator Insight

Improving the quality cell yield of T-cell immunotherapies through selective pressures imparted by culture media supplements

Spotlight Article

Innovator Insight

Steven Thompson, Alex Klarer, David Smith, Steve Charlebois, Hayley Steidinger & Amanda Taylor

Raw and starting materials: troubleshooting supply, management and optimization issues

New T-cell based therapies use the adaptive immune system as a modality in multiple blood cancer indications and are being investigated in some solid tumor indications. This study looks at both total yield and memory character as measures of cell quality and those traits were used to evaluate human AB serum (ABS) and human platelet lysate (nLiven) as culture media supplements. Two independent labs showed statistically significant increases in both total cell yield and final T-cell central memory phenotype after expanding isolated cells in medium supplemented with nLiven as opposed to ABS. There was an additional, unexpected observation of increased donor to donor consistency when cultured with nLiven which may be a result of a more homogenous source of proteins and chemicals typically required to expand T-cells. Developing commercially viable manufacturing processes for T-cell-based therapies requires the adoption of new technologies that will facilitate process robustness. This study investigates media supplements within this context.

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Ensuring source material consistency & continuity for commercialization of advanced therapies

Spotlight Article

Innovator Insight

Dominic Clarke, Christopher Good & Amy Shaw

Raw and starting materials: troubleshooting supply, management and optimization issues

A critical aspect to ensuring patient access to cell and gene therapies (CGT) and continued growth of the industry is having a proper awareness for managing the source material quality and supply chain continuity. The combination of rapid growth, individual product and process complexity, and limited industry-specific guidance or awareness presents ongoing challenges for transitioning from development to clinical and commercial manufacturing scale. For allogeneic therapies, having access to consistent and reliable donors and high quality, GMP-compliant starting material, coupled with the ability to consistently deliver this clinical source material to the required point of use, will be key to long-term success.

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Ensuring viral vector and gene therapy commercial readiness

Innovator Insight

Raw and starting materials: troubleshooting supply, management and optimization issues

The field of viral vector-driven gene therapy, incorporating both direct in vivo and ex vivo cell-based approaches, has enjoyed tremendous growth in recent years. However, the speed with which gene therapy is driving towards a commercially successful future does present challenges. This article will explore three vitally important areas in which strategic and technical manufacturing innovation is required to support commercialization. Success in these key areas will be critical if we are to get past the current imbalance between supply and demand and effectively deliver on the enormous potential of gene therapy.

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Research Article

A simple RP-HPLC method for the stability-indicating determination of N-acetyl-L-cysteine and N,N’-diacetyl-L-cystine in cell culture media

Spotlight Article

Research Article

AS Prakasha Gowda, Andrew D Schaefer & Terry K Schuck

Raw and starting materials: troubleshooting supply, management and optimization issues

N'-Acetyl-L-Cysteine (NAC) can exist in the reduced form, containing the sulfhydryl (-SH) group, and it can exist in its oxidized disulfide form N,N'-Diacetyl-L-Cystine (Di-NAC). However, an analytical method that can separate and quantify both compounds in cell treatment supplement media is not yet available, to the best of our knowledge. A stability-indicating RP-HPLC assay method for the determination of NAC and Di-NAC in the cell culture media has been developed. The proposed method showed good linearity for NAC (R = 1.00) and Di-NAC (R = 1.00), accuracy, precision, specificity and system suitability results within the acceptance criteria. The limit of detection and limit of quantitation were found to be 0.0001 mg/ml and 0.00018 mg/ml for NAC, and 0.00015 mg/ml and 0.00045 mg/ml for DI-NAC. However, our method can be used for the separation and quantification of NAC in cell treatment media, in vitro dissolution studies and pharmaceutical formulations.

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