Celia Witten CBER’s Perspective on Advanced Manufacturing

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CBER’s Perspective on Advanced Manufacturing Celia M. Witten, Ph.D., M.D. Deputy Director Center for Biologics Evaluation and Research, FDA ISCMP 2018 London October 4 2018


Outline • CBER Overview • CBER Products/Manufacturing Challenges – Vaccines – Cells/Tissues/Gene Therapy • CBER engagements • 21st Century Cures • Summary

www.fda.gov

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FDA Organization • Office of the Commissioner • Center for Biologics Evaluation and Research (CBER) – Office of Vaccines Research and Review (OVRR) – Office of Tissues and Advanced Therapies (OTAT) – Office of Blood Research and Review (OBRR) • Center for Drug Evaluation and Research (CDER) • Center for Devices and Radiological Health (CDRH) • National Center for Toxicological Research (NCTR) • Center for Food Safety and Applied Nutrition 9CFSAN) • Center for Veterinary Medicine (CVM) • Center for Tobacco Products (CTP) www.fda.gov

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What Products Does CBER Regulate? • • • • • • • • www.fda.gov

Allergenics Blood Products Devices (subset including some IVDs) Gene Therapy Products Human Tissues and Cellular Products Vaccines (preventative and therapeutic) Xenotransplantation products Certain combination products 4


Advanced Manufacturing? • Why advanced manufacturing? Products may require complex manufacturing processes, advanced manufacturing may bring new tools to address: – Flexibility – Availability – Scalability – Cost • What do we mean by advanced manufacturing? Innovative technologies that could include: – Cell culture systems supporting large scale or rapid production – Enabling tools such as measurement technology www.fda.gov

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OVRR

www.fda.gov

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Vaccines Types •

• •

Inactivated/Killed Vaccines • Influenza • Polio (IPV) • Rabies Live, attenuated Vaccines • Influenza (nasal spray) • Measles, mumps, rubella (MMR combined vaccine) • Yellow fever Toxoid (inactivated toxin) Vaccines • Diphtheria, tetanus (part of DTaP combined immunization) Subunit/conjugate Vaccines • Hepatitis B • Human papillomavirus (HPV) • Pneumococcal

www.fda.gov

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Seasonal Flu Vaccine Manufacturing Cycle Northern Hemisphere/USA

CBER

Produce Reassortants

Produce & Standardize Reagents

Annual License Approval Lot release

Select Vaccine Strain(s) WHO-FDA

Jan

Manufacturer

Dec

Feb

Mar

Apr

May

Produce Working Seeds (4 strains)

Jul

Aug

Sep

Oct

Nov

Dec

Formulation, Fill, Packaging of Vaccine

Manufacture Strain 1 Under risk Strain 2 Strain 3 Strain 4

www.fda.gov

Jun

Strain Balancing Strain Balancing Strain Balancing Strain Balancing

Distribution

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Applying Advanced Manufacturing Technology to Vaccines • Modernization of vaccine production process to incorporate advanced manufacturing technologies could improve agility to respond to existing and emerging pathogens • Plans for internal research program and collaborations with federal partners initially focused on influenza vaccine – Optimize cell lines for production – Improve yield of recombinant technology – Apply continuous manufacturing www.fda.gov

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OTAT

www.fda.gov

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OTAT-Regulated Products •

Blood- and Plasma-derived products – – – – – – – –

Functionally mature/differentiated cells (e.g., retinal pigment epithelial cells, Therapeutic vaccines and other antigen-specific active immunotherapies

www.fda.gov

Gene Therapy Products – –

Coagulation factors Fibrin sealants Fibrinogen Thrombin Plasminogen Immune globulins Anti-toxins Snake venom antisera

pancreatic islets, chondrocytes, keratinocytes)

– –

• • •

Stem cells/stem cell-derived Products for xenotransplantation Combination products –

• •

Plasmid DNA and RNA products Viral vectors • Adeno-associated virus; Adenovirus • Retrovirus, lentivirus • Herpesvirus, vaccinia virus, fowlpox, alphavirus Bacterial vectors • E.coli • Listeria Ex vivo genetically modified cells • Transfected, transduced, electroporation Engineered nucleases for gene editing • CRISPR, TALEN, Zinc finger nucleases

Engineered tissues/organs

Devices Tissues

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CMC expected to comply with applicable regulations

Product development should progress in parallel with clinical development Assure product quality and manufacturing consistency to support clinical studies for licensure Increasing expectation for product characterization & compliance with cGMPs Product safety, comparability to preclinical material, feasibility of process

Development

www.fda.gov

Full compliance required for licensure

Preclinical

Phase I

Phase II

Phase III

BLA

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GT Product Approvals by FDA • Kymriah (Tisagenlecleucel) • CD19-directed genetically modified autologous T cell immunotherapy • For treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse

• Yescarta (Axicabtagene Ciloleucel) • CD19-directed genetically modified autologous T cell immunotherapy • Indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

• Luxturna (Voretigene Neparvovec) • adeno-associated virus vector-based gene therapy • Indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. www.fda.gov

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Potential Challenges to Use of Cell and Gene Therapies • Process must be developed to consistently manufacture and characterize cells • Logistics of manufacturing for autologous cells can be challenging – Though an allogeneic cell line (one product) may be preferable, there are developmental challenges

www.fda.gov

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Challenges in Manufacture of Cell and Gene Therapies • Challenges of developing and validating manufacturing processes for autologous cell therapies • Need for standards for the reproducible production of regenerative medicine products such as cellular therapies

www.fda.gov

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Challenges in Manufacture of Cell and Gene Therapies • Lack of capacity for manufacture of lentiviral and adeno-associated virus (AAV) vectors is limiting clinical development • Process of production in current cell lines is still not able to meet demand despite some improvement over past few years

www.fda.gov

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Improving the Manufacture of Cell and Gene Therapies • Plans for CBER laboratory research programs and collaborations with academic and public private partners to advance field – Improved cell lines for vector production – Advanced manufacturing technologies

www.fda.gov

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Standards for Development for Human Tissues and Cellular Products • Working with National Institute of Standards and Technology (NIST) • Collaboration with the Standards Coordinating Body (outgrowth from Alliance for Regenerative Medicine) – Contract with Nexight group

• Publication of Report on the Regenerative Medicine Standards Landscape in February 2018 https://static1.squarespace.com/static/58a331b0db29d63c7fb64528/t/5ab 254f9352f5362833b9cff/1521636606100/Landscape+Report_3-2-2018.pdf

www.fda.gov

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CBER Engagement • • • • • •

Product specific meetings Liaison meetings Standards activities International activities Collaborations Research opportunities

www.fda.gov

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FOA: Enhancing Innovations in Emerging Technologies for Advanced Manufacturing of Complex Biologic Products (R01) • Section 3016 (Grants for Studying Continuous Manufacturing) of the 21st Century Cures Act • Support the application of novel technologies for advanced manufacturing of complex biologic products • Support innovative analytical approaches to improve product manufacturing and quality through active research • Advance innovative manufacturing by developing and making technologies accessible to industry in the near term www.fda.gov

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The Path Toward Progress • • • •

Keep pace with advancing technology Refine regulatory framework as necessary Overcome limitations in manufacturing Facilitate optimal product development

www.fda.gov

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Summary FDA is committed to bringing the promise of innovative, safe and effective new therapies to those in need of them, as quickly as possible.

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Contact Information Celia Witten, Ph.D., M.D. Deputy Director Center For Biologics Evaluation And Research, FDA 10903 New Hampshire Ave Silver Spring, MD 20993 240-402-8351 celia.witten@fda.hhs.gov

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Public Access to CBER Ø CBER website:

http://www.fda.gov/BiologicsBloodVaccines/default.htm

Ø Phone: 1-800-835-4709 Ø Consumer Affairs Branch (CAB)

Email: ocod@fda.hhs.gov Ø Manufacturers Assistance and Technical Training Branch (MATTB) Email: industry.biologics@fda.gov Ø Follow us on Twitter https://www.twitter.com/fdacber

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