Cell & Gene Therapy Process Map: A beginning…

Authors
Manjula Aysola, EMD Millipore Jay Harp, Integra (division of VWR) Derek Pendelbury, Colder Products Company
Jerry Branscomb, Thermo Fisher Eva Heinz, Solvay Erika Trauzzi, Sartorius-Stedim Biotech
Dominic Clarke, Charter Medical Brian Horowski, Jacobs Engineering Samantha Sbardella, EMD Millipore
Clive Glover, Pall Corporation Todd Kapp, Entegris Jiwen Zhang, Tmunity Therapeutics, Inc
Jayanthi Grebin, Entegris Brendan Lucy, ILC Dover

Introduction C&G Therapy Methodology

Activity
Sterile Welding
Implication
Particulate
Bioprocess
Frequently used. Particulates
Cell and Gene Therapy
Particulate generation presents a
Generation can be removed through major safety issue to CGT as
The Bioprocess Systems Alliance Cell & Gene Therapy Sub-committee multiple downstream downstream steps exists and those
has set forth to provide an educational review paper to assist the C&G processing steps that do, do not remove particulates
therapy community to begin to more fully understand the role of Single Holdup Volume Product loss Commonplace in bioprocessing By utilized unfit SUS for CGT
Use Technology and the role it may play in the C&G therapy but loss has minimal impact manufacturing, holdup volume can
marketplace. . considering high concentration greatly impact product yield
and volume of product
Cell therapy is defined as the administration of cells to a patient to treat SUS Sterility Contamination Common in upstream Leveraging SUS from bioprocess is
disease. Cell therapies can use either a patient’s own cells as starting processing material and final high risk for CGT because there is
material (autologous cell therapy) or a donor cell that is expanded and formulation; minimal SUS no final filtration step for the
used to treat several patients (allogeneic cell therapy). In many cases, cell sterile products found for product
therapies can involve genetically modifying cells. An example of this downstream processing because
type of therapy is chimeric antigen receptor T cell (CAR-T) cell of aseptic final filtration
therapies. These therapies have been successfully applied to treat a Materials of Extractables, Many bioprocesses leverage CGT process employs complex
variety of cancers by modifying a patient’s T cells ex vivo so that they Construction Leachables chemically defined materials media that can cause many issues to
attack and eliminate cancer cells within the patient. (SUS)– Polymers Biocompatibility for expansion, wash and membranes like fouling which
and Membranes Particulates formulation. Testing for results in product loss and protein
The Successful commercialization of these types of cell therapies rely on (filters) compatibility is more well- binding which can result in stripping
the development of scalable manufacturing process that can produce established of critical raw materials to support
products of appropriate quality on a routine basis in a cost-effective cell growth. Extractables and
manner. Single-use or disposable technologies have gained wide-use and leachables as well as particulates are
acceptance in the manufacture of monoclonal antibodies and recombinant a main concern for polymers
proteins as they allow for greater flexibility, speed and safety in the
development of these therapeutics. Due to their importance in this area, a
significant amount of effort has gone into development of a variety of
standards around the implementation and use of these products in
manufacturing and is now being assessed in development of cell and
gene therapies. Conclusion
Objective
The objective of the review paper is to:

Lay a foundation of considerations, risks and guidance for customers using

Single Use Technologies in Cell and Gene Therapy

References
Discussion CFR 211.65 Equipment Construction
CFR 211.94 Drug Product Containers and Closures
ICH Q7A Guidance for Industry
The bioprocessing industry has laid much of the groundwork for addressing the challenges and necessary CFR 211.63
changes to SUS standards, it is vital that CGT not only build on them, but further develop them. Bioprocess and 21 CFR 610 15 General Biological Products Standards
CGT are distinct and thus end user requirements are different. FDA 1989 Drug Master Files: Guidelines
FDA Center for Biologics Evaluation and Research March 1998 Guidance for Industry Guidance for Human
The CGT industry, together, is responsible for understanding and implementing SUS standards and ensuring Somatic Cell Therapy and Gene Therapy
correct actions are taken to provide, in the end, the safest products to patients. Although vendors and developers FDA Guidance for Industry: Class II Special Controls Guidance Document: Cord Blood Processing System and
have distinct responsibilities, it’s quite important that we utilize the knowledge and experience of all operating Storage Container
in this field. Furthermore, it is even more pressing that as the field begins to develop SUS products specific for ICH Q8 (R2) Pharmaceutical Development
CGT applications, that we ensure the education of all operators working with these consumables. It is vital to ICH Q9 Quality Risk Management
understand how specific processing steps with SUS can impact the final product. ICH Q10 Pharmaceutical Quality System
Define & Map commonalities between bioprocessing and C&G therapy
ISO 13022:2012 Medical products containing viable human cells -- Application of risk management and
High level documentation to identify information gaps Most manufacturers are testing critical attributes of a SUT using a standard process, however for many critical requirements for processing practices
attributes being tested there are multiple valid test methods (ASTM, ISO etc) that can be used to provide data, ASME BPE-2016 Bioprocessing Equipment
Share best practices: Scale up and scale out and the SUT manufacturers can select the test method that they want, usually based on familiarity with a testing Guidance for Industry: BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood
Identify regulatory and technical requirements of each stage body, previous experience of that specific process, or even selecting the test method that shows their product in Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the
the best light. This makes it very difficult, if not impossible, for an end user to effectively compare Hematopoietic System (PDF - 390KB) 3/2014. (This guidance finalizes the draft guidance of the same title dated
Education around single use technologies and what is available performance data from two or more suppliers when the test data presented are performed using different test June 2013.)
Define the language methods and therefore have different levels of impact on the final product. IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for
Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System -
The review paper looks to address these issues and provide the educational benchmark to move C&G therapy Guidance for Industry and FDA Staff (PDF - 120KB)
and SUS involvement forward successfully. 3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control
(CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) (PDF -
184KB)
4/2008